Eur J Med Chem. 2023 Mar 15;250:115238. doi: 10.1016/j.ejmech.2023.115238. Epub 2023 Feb 27.

ABSTRACT

Conjunctival melanoma (CM), a rare and fatal malignant ocular tumor, lacks proper diagnostic biomarkers and therapy. Herein, we revealed the novel application of propafenone, an FDA-approved antiarrhythmic medication, which was identified effective in inhibiting CM cells viability and homologous recombination pathway. Detailed structure-activity relationships generated D34 as one of the most promising derivatives, which strongly suppressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase γ-H2AX nuclear foci and aggravated DNA damage by suppressing homologous recombination pathway and its factors, particularly the complex of MRE11-RAD50-NBS1. D34 bound to human recombinant MRE11 protein and inhibited its endonuclease activity. Moreover, D34 dihydrochloride significantly suppressed tumor growth in the CRMM1 NCG xenograft model without obvious toxicity. Our finding shows that propafenone derivatives modulating the MRE11-RAD50-NBS1 complex will most likely provide an approach for CM targeted therapy, especially for improving chemo- and radio-sensitivity for CM patients.

PMID:36868105 | DOI:10.1016/j.ejmech.2023.115238

Am J Hum Genet. 2023 Mar 2;110(3):419-426. doi: 10.1016/j.ajhg.2023.01.018.

ABSTRACT

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

PMID:36868206 | DOI:10.1016/j.ajhg.2023.01.018

Turk J Pediatr. 2023;65(1):124-128. doi: 10.24953/turkjped.2022.254.

ABSTRACT

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome associated with capillary/venous/ lymphatic malformations with limb hypertrophy and cancer risk. Various cancers, mostly Wilms tumor, have been reported in patients with KTS, but not leukemia. Chronic myeloid leukemia (CML) is also a rare disease in children, where there is no known disease or syndrome to predispose to CML.

CASE: We report a case of CML incidentally diagnosed in a child with KTS when he was bleeding from surgery of the left groin for vascular malformation.

CONCLUSIONS: This case reflects the variety of cancer types that may accompany KTS and provides information about CML prognosis in such patients.

PMID:36866992 | DOI:10.24953/turkjped.2022.254

Blood. 2023 Mar 2;141(9):963-964. doi: 10.1182/blood.2022019105.

NO ABSTRACT

PMID:36862438 | DOI:10.1182/blood.2022019105

Am J Med Genet C Semin Med Genet. 2023 Mar;193(1):64-76. doi: 10.1002/ajmg.c.32037. Epub 2023 Feb 28.

ABSTRACT

The National Center for Advancing Translational Sciences' virtual 2021 conference on gene-targeted therapies (GTTs) encouraged multidisciplinary dialogue on a wide range of GTT topic areas. Each of three parallel working groups included social scientists and clinical scientists, and the three major sessions included a presentation on economic issues related to their focus area. These experts also coordinated their efforts across the three groups. The economics-related presentations covered three areas with some overlap: (1) value assessment, uncertainty, and dynamic efficiency; (2) affordability, pricing, and financing; and (3) evidence generation, coverage, and access. This article provides a synopsis of three presentations, some of their key recommendations, and an update on related developments in the past year. The key high-level findings are that GTTs present unique data and policy challenges, and that existing regulatory, health technology assessment, as well as payment and financing systems will need to adapt. But these adjustments can build on our existing foundation of regulatory and incentive systems for innovation, and much can be done to accelerate progress in GTTs. Given the substantial unmet medical need that exists for these oft-neglected patients suffering from rare diseases, it would be a tragedy to not leverage these exciting scientific advances in GTTs.

PMID:36854952 | DOI:10.1002/ajmg.c.32037

Eur J Dermatol. 2022 Nov 1;32(6):812-814. doi: 10.1684/ejd.2022.4384.

NO ABSTRACT

PMID:36856400 | DOI:10.1684/ejd.2022.4384

Minerva Gastroenterol (Torino). 2023 Mar;69(1):50-60. doi: 10.23736/S2724-5895.20.02792-0.

ABSTRACT

Assessment of Health-Related Quality of Life (HRQoL) has emerged as an important tool in the evaluation of both the well-being of patients and the results of their clinical management. Over the years, a large number of questionnaires focusing on various aspects of quality of life have been developed. They are frequently divided into generic questionnaires, which can be used under various conditions, disease-specific and symptom-specific questionnaires. Autoimmune liver diseases, such as autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis, comprise a group of rare liver conditions (i.e. affecting fewer than 5 in 10,000 people in the general population). Unfortunately, HRQoL has not been well-studied in this group of patients. In this review, we comprehensively summarize the data available in the literature on HRQoL in these conditions, emphasizing the important role that quality of life plays in the successful management of such patients.

PMID:36856273 | DOI:10.23736/S2724-5895.20.02792-0

BMC Neurol. 2023 Feb 28;23(1):88. doi: 10.1186/s12883-023-03133-6.

ABSTRACT

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland.

METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed.

RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter.

CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

PMID:36855136 | DOI:10.1186/s12883-023-03133-6

J Transl Med. 2023 Feb 28;21(1):157. doi: 10.1186/s12967-023-04011-y.

ABSTRACT

BACKGROUND: The United Nations recently made a call to address the challenges of an estimated 300 million persons worldwide living with a rare disease through the collection, analysis, and dissemination of disaggregated data. Epidemiologic Information (EI) regarding prevalence and incidence data of rare diseases is sparse and current paradigms of identifying, extracting, and curating EI rely upon time-intensive, error-prone manual processes. With these limitations, a clear understanding of the variation in epidemiology and outcomes for rare disease patients is hampered. This challenges the public health of rare diseases patients through a lack of information necessary to prioritize research, policy decisions, therapeutic development, and health system allocations.

METHODS: In this study, we developed a newly curated epidemiology corpus for Named Entity Recognition (NER), a deep learning framework, and a novel rare disease epidemiologic information pipeline named EpiPipeline4RD consisting of a web interface and Restful API. For the corpus creation, we programmatically gathered a representative sample of rare disease epidemiologic abstracts, utilized weakly-supervised machine learning techniques to label the dataset, and manually validated the labeled dataset. For the deep learning framework development, we fine-tuned our dataset and adapted the BioBERT model for NER. We measured the performance of our BioBERT model for epidemiology entity recognition quantitatively with precision, recall, and F1 and qualitatively through a comparison with Orphanet. We demonstrated the ability for our pipeline to gather, identify, and extract epidemiology information from rare disease abstracts through three case studies.

RESULTS: We developed a deep learning model to extract EI with overall F1 scores of 0.817 and 0.878, evaluated at the entity-level and token-level respectively, and which achieved comparable qualitative results to Orphanet's collection paradigm. Additionally, case studies of the rare diseases Classic homocystinuria, GRACILE syndrome, Phenylketonuria demonstrated the adequate recall of abstracts with epidemiology information, high precision of epidemiology information extraction through our deep learning model, and the increased efficiency of EpiPipeline4RD compared to a manual curation paradigm.

CONCLUSIONS: EpiPipeline4RD demonstrated high performance of EI extraction from rare disease literature to augment manual curation processes. This automated information curation paradigm will not only effectively empower development of the NIH Genetic and Rare Diseases Information Center (GARD), but also support the public health of the rare disease community.

PMID:36855134 | DOI:10.1186/s12967-023-04011-y

Hum Genomics. 2023 Mar 2;17(1):16. doi: 10.1186/s40246-023-00464-w.

ABSTRACT

BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.

MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.

RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.

CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

PMID:36859317 | DOI:10.1186/s40246-023-00464-w

BMJ. 2023 Feb 28;380:p483. doi: 10.1136/bmj.p483.

NO ABSTRACT

PMID:36854467 | DOI:10.1136/bmj.p483

MMW Fortschr Med. 2023 Feb;165(Suppl 1):6-10. doi: 10.1007/s15006-023-2322-4.

NO ABSTRACT

PMID:36849763 | DOI:10.1007/s15006-023-2322-4

MMW Fortschr Med. 2023 Feb;165(Suppl 1):3. doi: 10.1007/s15006-023-2338-9.

NO ABSTRACT

PMID:36849762 | DOI:10.1007/s15006-023-2338-9

PLoS Genet. 2023 Feb 27;19(2):e1010587. doi: 10.1371/journal.pgen.1010587. eCollection 2023 Feb.

ABSTRACT

Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease.

PMID:36848389 | PMC:PMC9997913 | DOI:10.1371/journal.pgen.1010587

J Ayub Med Coll Abbottabad. 2023 Feb-Mar;35(1):177-179. doi: 10.55519/JAMC-01-11210.

ABSTRACT

Proteus syndrome is a rare disease manifested by progressive segmental overgrowth involving the skeletal, Cutaneous, subcutaneous, and nervous systems. We report the case of a 24-year-old female who was born with no obvious abnormality at birth. From the age of 1 year, she developed asymmetric enlargement of her left upper limb and bilateral lower limbs leading to enlargement of the right-hand phalanges with radial deviation, enlargement of the right big toe, lateral deviation of left foot, and discrepancy in the length of lower extremities and kyphoscoliosis. She had become bed-bound for the last few years due to increasing disability. She was diagnosed with Proteus syndrome based on clinical features of progressive course, mosaic distribution, and sporadic occurrence of the lesions.

PMID:36849404 | DOI:10.55519/JAMC-01-11210

Dtsch Med Wochenschr. 2023 Mar;148(5):242-245. doi: 10.1055/a-1976-4185. Epub 2023 Feb 27.

ABSTRACT

INTRODUCTION: Cystic adventitial degeneration (CAD) is a rare vascular disease, affects mostly middle-aged men, and as a nonatherosclerotic disease, is an uncommon differential diagnosis of intermittent claudication.

CASE HISTORY: A 56-year-old female patient presented to our medical office because of unexplained right-sided calf pain that was not constantly load-dependent. The complaints fluctuated considerably with longer symptom-free intervals.

EXAMINATION AND FINDINGS: Clinically, the patient presented regular pulses, which were maintained even with provocative maneuvers such as plantar flexion and knee flexion. Duplex sonography showed cystic masses around the popliteal artery. On MRI examination, a tubular tortuous connection to the knee joint capsule also appeared to be visualizable. A diagnosis of cystic adventitial degeneration was made.

THERAPY AND COURSE: In the absence of constant impairment of walking performance with symptom-free intervals as well as morphological and functional signs of stenosis, interventional or surgical therapy was not desired by the patient. Short-term follow-up revealed stable clinical and sonomorphologic findings over an observation period of 6 months so far.

DISCUSSION: CAD should also be considered in female patients with atypical leg symptoms. There are no uniform treatment recommendations for CAD, which is why it is a challenge to select the optimal, usually interventional procedure. In patients with few symptoms and no critical ischemia, a conservative approach with close follow-up may be justified, as in our case report.

PMID:36848887 | DOI:10.1055/a-1976-4185

Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2300988120. doi: 10.1073/pnas.2300988120. Epub 2023 Feb 27.

NO ABSTRACT

PMID:36848568 | DOI:10.1073/pnas.2300988120

Turk J Ophthalmol. 2023 Feb 24;53(1):70-73. doi: 10.4274/tjo.galenos.2022.37605.

ABSTRACT

Fibrous dysplasia is a benign, rare bone disease in which bone is replaced by fibro-osseous tissue to varying degrees. It can present differently depending on the amount of compression caused by the fibro-osseous tissue. Patients are usually asymptomatic, but symptoms related to cranial nerve compression may occur. In this case report, we describe a 45-year-old woman with sphenoid bone dysplasia which compressed the optic nerve and caused unilateral optic disc cupping that mimicked glaucoma. Our case highlights the importance of including compressive etiologies associated with optic disc cupping in the differential diagnosis of glaucoma.

PMID:36847644 | PMC:PMC9973207 | DOI:10.4274/tjo.galenos.2022.37605

Turk J Ophthalmol. 2023 Feb 24;53(1):44-57. doi: 10.4274/tjo.galenos.2022.76436.

ABSTRACT

Avascular peripheral retina in an infant is a common characteristic of numerous pediatric retinal vascular disorders and often presents a diagnostic challenge to the clinician. In this review, key features of each disease in the differential diagnosis, from retinopathy of prematurity, familial exudative vitreoretinopathy, Coats disease, incontinentia pigmenti, Norrie disease, and persistent fetal vasculature, to other rare hematologic conditions and telomere disorders, will be discussed by expert ophthalmologists in the field.

PMID:36847634 | PMC:PMC9973209 | DOI:10.4274/tjo.galenos.2022.76436

J Oncol. 2023 Feb 17;2023:3144086. doi: 10.1155/2023/3144086. eCollection 2023.

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) is still a slightly less orphan disease after immunotherapy, and routine treatment has low efficiency and adverse events. Ginseng is commonly used in the treatment of NSCLC. The purpose of this study is to assess the efficacy and hemorheological indexes of ginseng and its active components in patients with non-small cell lung cancer.

METHODS: A comprehensive literature search was performed in PubMed, the Cochrane Library, Medline (Ovid), the Web of Science, Embase, CKNI, Wan Fang, VIP, and SinoMed up to July 2021. Only randomized controlled trials evaluating ginseng in combination with chemotherapy versus chemotherapy alone in NSCLC patients were included. Primary outcomes included patients' condition after using ginseng or its active components. Secondary outcomes included changes in immune cells, cytokines, and secretions in serum. Data were extracted by two independent individuals, and the Cochrane Risk of Bias tool version 2.0 was applied for the included studies. Systematic review and meta-analysis were performed by RevMan 5.3 software.

RESULTS: The results included 1480 cases in 17 studies. The results of the integration of clinical outcomes showed that the treatment of ginseng (or combination of ginseng with chemotherapy) can improve the quality of life for patients with NSCLC. Analysis of immune cell subtypes revealed that ginseng and its active ingredients can upregulate the percentages of antitumor immunocyte subtypes and downregulate the accounts of immunosuppressive cells. In addition, a reduction of the inflammatory level and an increase of antitumor indicators in serum were reported. Meta-analysis showed that Karnofsky score: WMD = 16, 95% CI (9.52, 22.47); quality-of-life score: WMD = 8.55, 95%CI (6.08, 11.03); lesion diameter: WMD = -0.45, 95% CI (-0.75, -0.15); weight: WMD = 4.49, 95% CI (1.18, 7.80); CD3+: WMD = 8.46, 95% CI (5.71, 11.20); CD4+: WMD = 8.45, 95% CI (6.32, 10.57)+; CD8+: WMD = -3.76, 95% CI (-6.34, -1.18); CD4+/CD8+: WMD = 0.32, 95% CI (0.10, 0.53); MDSC: WMD = -2.88, 95% CI (-4.59, -1.17); NK: WMD = 3.67, 95% CI (2.63, 4.71); Treg: WMD = -1.42, 95% CI (-2.33, -0.51); CEA: WMD = -4.01, 95% CI (-4.12, -3.90); NSE: WMD = -4.00, 95% CI (-4.14, -3.86); IL-2: WMD = 9.45, 95% CI (8.08, 10.82); IL-4: WMD = -9.61, 95% CI (-11.16, -8.06); IL-5: WMD = -11.95, 95% CI (-13.51, -10.39); IL-6: WMD = -7.65, 95% CI (-8.70, -6.60); IL-2/IL-5: WMD = 0.51, 95% CI (0.47, 0.55); IFN-γ: WMD = 15.19, 95% CI (3.16, 27.23); IFN-γ/IL-4: WMD = 0.91, 95% CI (0.85, 0.97); VEGF: WMD = -59.29, 95% CI (-72.99, -45.58); TGF-α: WMD = -10.09, 95% CI (-12.24, -7.94); TGF-β: WMD = -135.62, 95% CI (-147.00, -124.24); TGF-β1: WMD = -4.22, 95% CI (-5.04, -3.41); arginase: WMD = -1.81, 95% CI (-3.57, -0.05); IgG: WMD = 1.62, 95% CI (0.18, 3.06); IgM: WMD = -0.45, 95% CI (-0.59, -0.31). All results are statistically significant. No adverse events were reported in the included articles.

CONCLUSION: It is a reasonable choice to use ginseng and its active components as adjuvant therapy for NSCLC. Ginseng is helpful for NSCLC patients' conditions, immune cells, cytokines, and secretions in the serum.

PMID:36844875 | PMC:PMC9957625 | DOI:10.1155/2023/3144086