Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.

BACKGROUND: The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure. METHODS AND RESULTS: Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

Mapping of repeat-associated non-AUG (RAN) translation knowledge: A bibliometric analysis.

Over 50 genetic human disorders are attributed to the irregular expansion of microsatellites. These expanded microsatellite sequences can experience bidirectional transcription, leading to new reading frames. Beyond the standard AUG initiation or adjacent start codons, they are translated into proteins characterized by disease-causing amino acid repeats through repeat-associated non-AUG translation. Despite its significance, there's a discernible gap in comprehensive and objective articles on RAN translation. This study endeavors to evaluate and delineate the contemporary landscape and progress of RAN translation research via a bibliometric analysis. We sourced literature on RAN translation from the Web of Science Core Collection. Utilizing two bibliometric analysis tools, CiteSpace and VOSviewer, we gauged individual impacts and interactions by examining annual publications, journals, co-cited journals, countries/regions, institutions, authors, and co-cited authors. Following this, we assessed the co-occurrence and bursts of keywords and co-cited references to pinpoint research hotspots and trending in RAN translation. Between 2011 and 2022, 1317 authors across 359 institutions from 34 countries/regions contributed to 250 publications on RAN translation, spread across 118 academic journals. This article presents a systematic, objective, and comprehensive analysis of the current literature on RAN translation. Our findings emphasize that mechanisms related to C9orf72 ALS/FTD are pivotal topics in the realm of RAN translation, with cellular stress and the utilization of small molecule marking the trending research areas.

Detection of skin α-synuclein using RT-QuIC as a diagnostic biomarker for Parkinson's disease in the Chinese population.

BACKGROUND: Several studies have indicated that skin holds promise as a potential sample for detecting pathological α-Syn and serving as a diagnostic biomarker for α-synucleinopathies. Despite reports in Chinese PD patients, comprehensive research on skin α-Syn detection using RT-QuIC is lacking. OBJECTIVE: This study aimed to evaluate the diagnostic performance of skin samples using RT-QuIC from PD patients in the Chinese population. METHODS: Patients with sporadic PD and controls were included according to the British PD Association Brain Bank diagnostic criteria. The seeding activity of misfolded α-Syn in these skin samples was detected using the RT-QuIC assay after protein extraction. Biochemical and morphological analyses of RT-QuIC products were conducted by atomic force microscopy, transmission electron microscopy, Congo red staining, and dot blot analysis. RESULT: 30 patients clinically diagnosed with PD and 28 controls with non-α-synucleinopathies were included in this study. 28 of 30 PD patients demonstrated positive α-Syn seeding activity by RT-QuIC assay. In contrast, no α-Syn seeding activity was detected in the 28 control samples, with an overall sensitivity and specificity of 93.3% and 100%, respectively (P < 0.001). Biochemical characterization of the RT-QuIC product indicated fibrillary α-Syn species in PD-seeded reactions, while control samples failed in the conversion of recombinant α-Syn substrate. CONCLUSION: This study applied RT-QuIC technology to identify misfolded α-Syn seeding activity in skin samples from Chinese PD patients, demonstrating high specificity and sensitivity. Skin α-Syn RT-QuIC is expected to be a reliable approach for the diagnosis of PD.

Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis.

BACKGROUND: Commonly clinically diagnosed with relapsing polychondritis (RP), vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) is a recently identified autoinflammatory disease caused by UBA1 somatic mutations. The low frequency and dynamic changes challenge the accurate detection of somatic mutations. The present study monitored these mutations in Chinese patients with RP. We included 44 patients with RP. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood. Droplet digital polymerase chain reaction (ddPCR) was performed to screen low-prevalence somatic variants. RESULTS: Multiple ddPCR detections were performed using available blood samples collected at different follow-up time points. Three male patients were UBA1 somatic mutation carriers. Sanger sequencing detected the somatic UBA1 variant c.122T > C (p.Met41Thr) in two male patients. Initial ddPCR confirmed the variant in the two patients, with allele fractions of 73.75% and 88.46%, respectively, while yielding negative results in other patients. Subsequent ddPCR detected the somatic variant (c.122T > C) with low prevalence (1.02%) in another male patient from blood samples collected at a different time point, and confirmed dynamically fractional abundance in one patient with VEXAS, with allele fractions of 73.75%, 61.28%, 65.01%, and 73.75%. Nine patients assessed by ddPCR at different time points remained negative. CONCLUSION: We report UBA1 variants in patients with RP in the Chinese population for the first time. Multiple ddPCR detections from samples collected at different time points can enhance sensitivity and should be considered for patients with initial negative ddPCR results.

Seed amplification assay of nasal swab extracts for accurate and non-invasive molecular diagnosis of neurodegenerative diseases.

Nasal swabs are non-invasive testing methods for detecting diseases by collecting samples from the nasal cavity or nasopharynx. Dysosmia is regarded as an early sign of coronavirus disease 2019 (COVID-19), and nasal swabs are the gold standard for the detection. By nasal swabs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids can be cyclically amplified and detected using real-time reverse transcriptase-polymerase chain reaction after sampling. Similarly, olfactory dysfunction precedes the onset of typical clinical manifestations by several years in prion diseases and other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In neurodegenerative diseases, nasal swab tests are currently being explored using seed amplification assay (SAA) of pathogenic misfolded proteins, such as prion, α-synuclein, and tau. These misfolded proteins can serve as templates for the conformational change of other copies from the native form into the same misfolded form in a prion-like manner. SAA for misfolded prion-like proteins from nasal swab extracts has been developed, conceptually analogous to PCR, showing high sensitivity and specificity for molecular diagnosis of degenerative diseases even in the prodromal stage. Cyclic amplification assay of nasal swab extracts is an attractive and feasible method for accurate and non-invasive detection of trace amount of pathogenic substances for screening and diagnosis of neurodegenerative disease.

Clinical application of prion-like seeding in α-synucleinopathies: Early and non-invasive diagnosis and therapeutic development.

The accumulation and deposition of misfolded α-synuclein (α-Syn) aggregates in the brain is the central event in the pathogenesis of α-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various α-synucleinopathies subtypes remains challenging. Misfolded α-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of α-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of α-Syn and critically assessed the detection techniques of α-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of α-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting α-Syn-seeding mechanisms are presented.

Analysis of Cuttings' Minerals for Multistage Hydraulic Fracturing Optimization in Volcanic Rocks.

The fracturing of naturally fractured volcanic rocks has a significant impact on the logging due to the high degree of volcanic fracture development and the complex distribution of fractures. Such impact ultimately leads to the difficulty in determining the location of fracturing perforations and the increase in engineering costs. This article proposed a method of analyzing cuttings for geologging that return to the ground when drilling. After cleaning and further processing of the cuttings, samples at every depth are formed. Then, an electron microscope and supporting processing software are used to calculate the parameters of the sample at each depth and the rock mechanical parameters in the target well section based on the mineral content. Compared with mud logging data, the mineral analysis method of rock cuttings costs less time, and the materials are easier to obtain, thereby providing richer data. This method has an important guiding role for the selection of perforation positions in large-scale hydraulic fracturing.

Fatal multi-organ Clonorchis sinensis infection in dog: a case report.

We describe here a fatal case of a dog with extensive Clonorchis sinensis (C. sinensis) infection. C. sinensis were detected in organs including the abdomen, bladder and heart. The infection was very heavy with a total number of 155,183 worms. These worms were in different developmental stages, but the majority of them were adult.