Target-Enhanced Whole-Genome Sequencing (TE-WGS) Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS. Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches. Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making. Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Strategy for developing a speech recognition model specialized for patients with depression or Parkinson's disease with small size speech database.

Most of speech recognition models currently in use have been dealt with speech of normal people. The speech recognition rate for patients with depression or Parkinson's disease (PD) who show differences in speech characteristics compared to normal subjects is lower than that of normal subjects. This study explores the model to enhance accuracy of speech recognition for individuals who have depression or PD, aiming to provide them more accurate service. In this study, considering the speech features of patients with depression or PD, we designed a model with the assumption that understanding the overall meaning and context of speech through the utilization of global information, rather than local information, is more effective in enhancing recognition accuracy. We propose the m-Globalformer, a model based on the Globalformer architecture that combines the squeeze-and-excitation (SE) module with the Transformer. The m-Globalformer enhances the utilization of global information by modifying the base SE module. The model employs pre-training and fine-tuning strategies, considering the limited speech data of the patients. In the initial training phase, a large-scale normal speech dataset was used, followed by fine-tuning the model with a small-scale dataset of depression or PD patients. The m-Globalformer demonstrated superior performance in our experiments, achieved character error rates (CER) of 11.28% for depression and 19.67% for PD.

Clinical application of whole-genome sequencing of solid tumors for precision oncology.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Mitochondrial DNA mosaicism in normal human somatic cells.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.

Clinical usefulness of the SARC-F questionnaire to assess sarcopenia in patients with Parkinson's disease.

OBJECTIVE: To investigate the accuracy of the SARC-F questionnaire to identify sarcopenia in patients with Parkinson's disease (PD). METHODS: We prospectively recruited patients with PD who had a score of 3 or lower on the Hoehn and Yahr (H&Y) scale. Appendicular skeletal muscle mass (ASM), hand grip strength, and the SARC-F were used to assess sarcopenia. The cutoffs for the ASM index and hand grip strength to diagnose sarcopenia were based on the Asian Working Group for Sarcopenia 2019 consensus. A score ≥4 on the SARC-F was considered at risk for sarcopenia. RESULTS: A total of 365 patients with PD were included (mean age, 71.1 years; men, 53.2 %), and 73 (20.0 %) were diagnosed with sarcopenia. The area under the receiver operating characteristic curve of the SARC-F was 0.702 (95 % confidence interval, 0.634-0.770). Using the recommended cutoff score of ≥4, the SARC-F showed a sensitivity of 38.4 %, specificity of 85.6 %, positive predictive value (PPV) of 40.0 %, and negative predictive value (NPV) of 84.7 %. The Youden's index was the highest at a cutoff score of ≥2, in which the SARC-F showed a sensitivity of 67.1 %, specificity of 65.4 %, PPV of 32.7 %, and NPV of 88.8 %. These predictive values were similar to those obtained using a cutoff score of ≥2.5 or 3 on the H&Y scale. CONCLUSION: The application of the SARC-F to the mild-to moderate PD population is not appropriate as a first-step screening tool to diagnose sarcopenia. Given the comparable predictive values of the SARC-F and H&Y scale, this questionnaire may be considered only for ruling out sarcopenia in patients with similar disease severity.

Whole-genome sequences reveal zygotic composition in chimeric twins.

While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin family to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine.

Role of exercise in modulating prefrontal cortical activation for improved gait and cognition in Parkinson's disease patients.

PURPOSE: This narrative review evaluated the impact of exercise on gait and cognitive functions in patients with Parkinson's disease (PD), focusing on prefrontal cortical (PFC) activation assessed using near-infrared spectroscopy (NIRS). METHODS: A literature search was conducted in the PubMed and Web of Science databases using keywords such as "Parkinson's disease," "gait," "cognitive functions," "exercise," and "NIRS," focusing on publications from the last decade. Studies measuring PFC activity using NIRS during gait tasks in patients with PD were selected. RESULTS: The review indicated that patients with PD demonstrate increased PFC activity during gait tasks compared to healthy controls, suggesting a greater cognitive demand for movement control. Exercise has been shown to enhance neural efficiency, thus improving gait and cognitive functions. CONCLUSION: Exercise is crucial for improving gait and cognitive functions in patients with PD through increased PFC activation. This emphasizes the importance of incorporating exercise into PD management plans and highlights the need for further studies on its long-term effects and the neurobiological mechanisms underlying its benefits, with the aim of optimizing therapeutic strategies and improving patients' quality of life.

Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia.

AIMS: In hypoxia, endothelial cells (ECs) proliferate, migrate, and form new vasculature in a process called angiogenesis. Recent studies have suggested that ECs rely on glycolysis to meet metabolic needs for angiogenesis in ischaemic tissues, and several studies have investigated the molecular mechanisms integrating angiogenesis and endothelial metabolism. Here, we investigated the role of stem cell factor (SCF) and its receptor, cKIT, in regulating endothelial glycolysis during hypoxia-driven angiogenesis. METHODS AND RESULTS: SCF and cKIT signalling increased the glucose uptake, lactate production, and glycolysis in human ECs under hypoxia. Mechanistically, SCF and cKIT signalling enhanced the expression of genes encoding glucose transporter 1 (GLUT1) and glycolytic enzymes via Akt- and ERK1/2-dependent increased translation of hypoxia inducible factor 1A (HIF1A). In hypoxic conditions, reduction of glycolysis and HIF-1α expression using chemical inhibitors significantly reduced the SCF-induced in vitro angiogenesis in human ECs. Compared with normal mice, mice with oxygen-induced retinopathy (OIR), characterized by ischaemia-driven pathological retinal neovascularization, displayed increased levels of SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina. Moreover, cKIT-positive neovessels in the retina of mice with OIR showed elevated expression of GLUT1 and glycolytic enzymes. Further, blocking SCF and cKIT signalling using anti-SCF neutralizing IgG and cKIT mutant mice significantly reduced the expression of HIF-1α, GLUT1, and glycolytic enzymes and decreased the pathological neovascularization in the retina of mice with OIR. CONCLUSION: We demonstrated that SCF and cKIT signalling regulate angiogenesis by controlling endothelial glycolysis in hypoxia and elucidated the SCF/cKIT/HIF-1α axis as a novel metabolic regulation pathway during hypoxia-driven pathological angiogenesis.

Clinical Utility of Whole-Genome Analysis as One-for-All Test for Breast Cancer: A Case Series.

Introduction: Breast cancer exhibits vast genomic diversity, leading to varied clinical manifestations. Integrating molecular subtyping with in-depth genomic profiling is pivotal for informed treatment choices and prognostic insights. Whole-genome clinical analysis provides a holistic view of genome-wide variations, capturing structural changes and affirming tumor suppressor gene loss of heterozygosity. Case Presentation: Here we detail four unique breast cancer cases from Seoul St. Mary's Hospital, highlighting the actionable benefits and clinical value of whole-genome sequencing (WGS). As an all-in-one test, WGS demonstrates significant clinical utility in these cases, including: (1) detecting homologous recombination deficiency with underlying somatic causal variants (case 1), (2) distinguishing double primary cancer from metastasis (case 2), (3) uncovering microsatellite instability (case 3), and (4) identifying rare germline pathogenic variants in TP53 gene (case 4). Our observations underscore the enhanced clinical relevance of WGS-based testing beyond pinpointing a few driver mutations in conventional targeted panel sequencing platforms. Conclusion: With genomic advancements and decreasing sequencing costs, WGS stands out as a transformative tool in oncology, paving the way for personalized treatment plans rooted in individual genetic blueprints.

Quantitative and qualitative mutational impact of ionizing radiation on normal cells.

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.

A Survey of Perspectives on Telemedicine for Patients With Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) patients often find it difficult to visit hospitals because of motor symptoms, distance to the hospital, or the absence of caregivers. Telemedicine is one way to solve this problem. METHODS: We surveyed 554 PD patients from eight university hospitals in Korea. The questionnaire consisted of the clinical characteristics of the participants, possible teleconferencing. METHODS: , and preferences for telemedicine. RESULTS: A total of 385 patients (70%) expressed interest in receiving telemedicine. Among them, 174 preferred telemedicine whereas 211 preferred in-person visits. The longer the duration of disease, and the longer the time required to visit the hospital, the more patients were interested in receiving telemedicine. CONCLUSION: This is the first study on PD patients' preferences regarding telemedicine in Korea. Although the majority of patients with PD have a positive view of telemedicine, their interest in receiving telemedicine depends on their different circumstances.

Analysis of HTT CAG repeat expansion among healthy individuals and patients with chorea in Korea.

BACKGROUND: Although the epidemiology of Huntington's disease (HD) in Korea differs notably from that in Western countries, the genetic disparities between these regions remain unclear. OBJECTIVE: To investigate the characteristics and clinical significance of cytosine-adenine-guanine (CAG) repeat size associated with HD in the Korean population. METHODS: We analyzed the CAG repeat lengths of the HTT gene in 941 healthy individuals (1,882 alleles) and 954 patients with chorea (1,908 alleles) from two referral hospitals in Korea. We presented normative CAG repeat length data for the Korean population and computed the reduced penetrance (36-39 CAG) and intermediate allele (27-35 CAG) frequencies in the two groups. Furthermore, we investigated the relationship between intermediate alleles and chorea development using logistic regression models in individuals aged ≥55 years. RESULTS: The mean (±standard deviation) CAG repeat length in healthy individuals was 17.5 ± 2.0, with a reduced penetrance allele frequency of 0.05 % (1/1882) and intermediate allele frequency of 0.69 % (13/1882). We identified 213 patients with genetically confirmed HD whose CAG repeat length ranged from 39 to 140, with a mean of 45.2 ± 7.9 in the longer allele. Compared with normal CAG repeat alleles, intermediate CAG repeat alleles were significantly related to a higher risk of developing chorea (age of onset range, 63-84 years) in individuals aged ≥55 years. CONCLUSIONS: This study provides insights into the specific characteristics of CAG repeat lengths in the HTT gene in the Korean population. The reduced penetrance and intermediate allele frequencies in the Korean general population seem to be lower than those reported in Western populations. The presence of intermediate alleles may increase the risk of chorea in the Korean elderly population, which requires further large-scale investigations.

Associations of Orthostatic Hypotension and Orthostatic Intolerance with Domain-Specific Cognitive Decline in Patients with Early Parkinson Disease: An 8-Year Follow-up.

OBJECTIVE: Although orthostatic hypotension (OH) and orthostatic intolerance (OI) are prevalent in patients with Parkinson disease (PD), it remains unclear how these conditions primarily affect the trajectory of decline in specific cognitive domains. This study aimed to explore the effects of OH and OI on longitudinal domain-specific cognitive changes in patients with PD. DESIGN: An 8-year follow-up of the Parkinson Progression Markers Initiative cohort study. SETTING AND PARTICIPANTS: A total of 403 patients with early, untreated PD and 195 matched healthy controls were included. They were classified into OH, OI, and normal groups. OH was defined according to the international consensus, and OI was defined as the presence of orthostatic symptoms without meeting the criteria for OH. METHODS: The patients underwent detailed neuropsychological testing annually for up to 8 years of follow-up. Linear mixed effects models were used to investigate the associations between OH, OI, and longitudinal cognitive changes. RESULTS: The prevalence of both OH and OI in patients with PD was significantly higher than that in controls (13.4% vs 7.2%, P = .002, for OH, and 29.3% vs 14.4%, P < .001, for OI). The OH group in patients with PD showed a faster decline in Letter-Number Sequencing (LNS) (ß = -0.11, 95% CI -0.20 to -0.02, t = -2.44, P = .015) and Semantic Fluency Test (SFT) (ß = -0.44, 95% CI -0.81 to -0.08, t = -2.42, P = .016) scores than the normal group. Similarly, the OI group showed a steeper decline in LNS (ß = -0.08, 95% CI -0.14 to -0.01, t = -2.20, P = .028) and SFT (ß = -0.36, 95% CI -0.63 to -0.08, t = -2.55, P = .011) scores compared to the normal group. There were no significant longitudinal changes in the other neuropsychological test scores between the groups. CONCLUSIONS AND IMPLICATIONS: Both OH and OI may be associated with a faster decline in executive function among cognitive domains of patients with PD. These findings may highlight the potential importance of orthostatic blood pressure control in PD patients with OH and even those with orthostatic symptoms without OH.

Effects of physical exercise interventions on cognitive function in Parkinson's disease: An updated systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine whether physical exercise interventions can improve cognitive function, including overall performance and specific domains, in patients with Parkinson's disease (PD) and to provide potential evidence on how cognitive benefits can be optimized by exercise prescriptions. METHODS: Using PubMed, Web of Science, and Cochrane Library (from inception to August 2022), four independent reviewers screened the search results and extracted data from randomized controlled trials of physical exercise interventions in patients with PD with an outcome measure of cognitive function. Random-effects meta-analysis models were used to report standardized mean differences (SMDs) with 95 % confidence intervals (CIs). RESULTS: Twenty-one randomized controlled trials including 761 patients with PD were eligible for inclusion. Physical exercise interventions led to significant improvements in global cognitive function (SMD = 0.69; 95 % CI = 0.31 to 1.06; P < 0.001). With respect to cognitive domains, the significant effect of exercise was found on executive function (SMD = 0.94; 95 % CI = 0.05 to 1.83; P = 0.039), but not on attention/working memory, language, memory, and visuospatial function. In moderator variable analyses, the effect on global cognition was observed in combined exercise programs (SMD = 0.79; 95 % CI = 0.46 to 1.12; P < 0.001), whereas there were no significant positive effects in aerobic exercise programs, strength exercise programs, and flexibility exercise programs. In addition, exercise interventions of light-to-moderate intensity with at least 60 min in duration, and of any frequency or period, were beneficial to the global cognitive function. CONCLUSION: This updated systematic review and meta-analysis suggests that physical exercise interventions are effective in improving global cognitive function and, to a lesser extent, executive function in patients with PD. At least 60 min a day of combined exercise programs on as many days of the week as feasible may be recommended as the non-pharmacological therapeutic option to improve cognitive function.

Effects of high-intensity interval training and moderate-intensity continuous training on sarcopenia-related parameters in participants with Parkinson's disease: A 24-week randomized pilot trial substudy.

OBJECTIVE: To evaluate the potential efficacy of two different supervised exercise regimens, namely high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), on sarcopenia-related parameters in participants with Parkinson's disease (PD). METHODS: We analyzed data from a randomized controlled pilot trial (CRIS identifier: KCT0007130). An aerobic exercise intervention using a cycle ergometer (40-60 min) in combination with calisthenics (5 min) was performed in three sessions/week for 24 weeks for HIIT (60% maximum aerobic power for 30-50 s with 1-min rest intervals) and MICT (50% peak oxygen consumption) groups. Changes in sarcopenia-related parameters, including appendicular skeletal muscle mass (ASM), ASM index (ASM/height2), handgrip strength, 6-min walking distance, and 30-s chair-stand test (30CST) score, were compared among the HIIT (n = 9), MICT (n = 10), and usual care (n = 11) groups. RESULTS: The HIIT group showed greater increases in leg lean mass (p = 0.011), ASM (p = 0.035), and ASM index (p = 0.025), and greater improvements in 6-min walking distance (p = 0.024) and 30CST scores (p = 0.026) compared with the usual care group. However, among these parameters, only the 30CST score significantly improved in the MICT group compared to the usual care group (p = 0.002). Three of the four (75%) sarcopenic patients who underwent HIIT showed improved sarcopenia after the 24-week exercise intervention, whereas it did not improve in the sarcopenic patients included in the MICT (n = 2) and usual care (n = 2) groups. CONCLUSION: This study suggests that HIIT may be superior to MICT in improving sarcopenia in patients with PD. Further large-scale investigations are required to confirm our findings.

Hybrid Machine Learning Framework for Multistage Parkinson's Disease Classification Using Acoustic Features of Sustained Korean Vowels.

Recent research has achieved a great classification rate for separating healthy people from those with Parkinson's disease (PD) using speech and the voice. However, these studies have primarily treated early and advanced stages of PD as equal entities, neglecting the distinctive speech impairments and other symptoms that vary across the different stages of the disease. To address this limitation, and improve diagnostic precision, this study assesses the selected acoustic features of dysphonia, as they relate to PD and the Hoehn and Yahr stages, by combining various preprocessing techniques and multiple classification algorithms, to create a comprehensive and robust solution for classification tasks. The dysphonia features extracted from the three sustained Korean vowels /아/(a), /이/(i), and /우/(u) exhibit diversity and strong correlations. To address this issue, the analysis of variance F-Value feature selection classifier from scikit-learn was employed, to identify the topmost relevant features. Additionally, to overcome the class imbalance problem, the synthetic minority over-sampling technique was utilized. To ensure fair comparisons, and mitigate the influence of individual classifiers, four commonly used machine learning classifiers, namely random forest (RF), support vector machine (SVM), k-nearest neighbor (kNN), and multi-layer perceptron (MLP), were employed. This approach enables a comprehensive evaluation of the feature extraction methods, and minimizes the variance in the final classification models. The proposed hybrid machine learning pipeline using the acoustic features of sustained vowels efficiently detects the early and mid-advanced stages of PD with a detection accuracy of 95.48%, and with a detection accuracy of 86.62% for the 4-stage, and a detection accuracy of 89.48% for the 3-stage classification of PD. This study successfully demonstrates the significance of utilizing the diverse acoustic features of dysphonia in the classification of PD and its stages.

Peripheral blood inflammatory cytokines in prodromal and overt α-synucleinopathies: a review of current evidence.

While the pathomechanisms of α-synucleinopathies are not completely understood, accumulating evidence suggests a role of neuroinflammation in the development and progression of the diseases. In addition, emerging data provide insights into the potential role of central neuroinflammation in prodromal α-synucleinopathies. Given the considerable bidirectional crosstalk between peripheral and central inflammation, peripheral blood inflammatory cytokines may be a useful tool to understand immune responses in association with α-synucleinopathies. Indeed, the accessibility and practicality of using blood samples have facilitated multiple investigations evaluating peripheral blood inflammatory cytokines in overt α-synucleinopathies, whereas the associations between these biomarkers and prodromal α-synucleinopathies remain unclear. In this review, we provide an overview of the current evidence available for the role of peripheral blood inflammatory cytokines in prodromal and overt α-synucleinopathies.