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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 285: 121933, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36208578

RESUMO

Gliomas are the most common type of primary tumor originating in the central nervous system of adults. Tumor histological type, pathological grade, and molecular pathology are significant prognosis and predictive factors. In this study, we were aiming to predict histological type and molecular pathological features based on terahertz time-domain spectroscopy technology. Nine gliomas with different grades, one meningioma, and one lymphoma were enrolled. There were significant differences in terahertz absorption coefficient between normal brain tissue, tumoral-periphery, and tumoral-center tissue in specific frequency bands (0.2-1.4 THz). Histological type, pathological grade, and glioma-specific biomarkers were closely related to the terahertz absorption coefficient in both tumoral-periphery and tumoral-center tissues. Interestingly, tumoral-periphery showed more obvious differences than tumoral-center tissues in almost all aspects. All the results show that the terahertz technology has potential application value in the intraoperative real-time glioma recognition and diagnosis of glioma histological and molecular pathological features.


Assuntos
Neoplasias Encefálicas , Glioma , Espectroscopia Terahertz , Adulto , Humanos , Patologia Molecular , Glioma/diagnóstico , Espectroscopia Terahertz/métodos , Neoplasias Encefálicas/diagnóstico , Encéfalo
3.
Sci Signal ; 15(760): eabm3720, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36378750

RESUMO

Many dementias are propagated through the spread of "prion-like" misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer's disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M1 receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M1 receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doenças Priônicas , Príons , Humanos , Animais , Camundongos , Príons/genética , Doenças Neurodegenerativas/genética , Patologia Molecular , Proteômica , Doenças Priônicas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo
6.
Cells ; 11(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231030

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis due to the lack of methods or biomarkers for early diagnosis and its resistance to conventional treatment modalities, targeted therapies, and immunotherapies. PDACs are a heterogenous group of malignant epithelial neoplasms with various histomorphological patterns and complex, heterogenous genetic/molecular landscapes. The newly proposed molecular classifications of PDAC based on extensive genomic, transcriptomic, proteomic and epigenetic data have provided significant insights into the molecular heterogeneity and aggressive biology of this deadly disease. Recent studies characterizing the tumor microenvironment (TME) have shed light on the dynamic interplays between the tumor cells and the immunosuppressive TME of PDAC, which is essential to disease progression, as well as its resistance to chemotherapy, newly developed targeted therapy and immunotherapy. There is a critical need for the development of predictive markers that can be clinically utilized to select effective personalized therapies for PDAC patients. In this review, we provide an overview of the histological and molecular heterogeneity and subtypes of PDAC, as well as its precursor lesions, immunosuppressive TME, and currently available predictive molecular markers for patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/patologia , Patologia Molecular , Proteômica , Microambiente Tumoral/genética
8.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293374

RESUMO

For cancer treatment, diagnostics concerning tumor type and determination of molecular markers in short TAT is critical. The fully automated, real-time PCR-based molecular diagnostic Idylla assays are well established in many laboratories for qualitative detection, short TAT and routine screening of clinically relevant oncogenic mutations. According to the manufacturer, all IVD assays are recommended for use only with FFPE tissue samples of 5-10 µM dissections with at least 10% tumor content. In this study, we tested the performance and accuracy of the IVD assays along with the gene fusion assay (RUO) with different tissue/source materials like isolated DNA/RNA, cryomaterial, etc. The study also included testing archival FFPE tissue sections dating back from 20 years and a performance check for different pan-cancer samples individually. All the assays tested with FFPE sections and gDNA/RNA input showed above 96% accuracy and sensitivity, individually with 100% specificity. The Idylla assays also performed exceptionally well on the archival FFPE tissues, and the use of assays for other solid tumors was also remarkable. The performance test and accuracy of Idylla assays showed high efficiency with certain limitations. For the use of Idylla assays, both qualitative and quantitative applicability of different tumor source materials could produce efficient results in different diagnostic settings within a short TAT.


Assuntos
Neoplasias , Humanos , Análise Mutacional de DNA/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Patologia Molecular , RNA , Mutação
9.
Genes (Basel) ; 13(10)2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36292771

RESUMO

Retinal detachment (RD) is one of the most common, sight-threatening ocular conditions requiring emergency intervention. Posterior vitreous detachment (PVD) occurs in the majority of an aging population whereby the vitreous body separates from the retina. It is well established that PVD is the common precursor to the most common forms of RD; however, it remains unknown why in most individuals PVD will cause no/few complications (physiological PVD) but in a small percentage will cause retinal tears and detachment (pathological PVD). Despite over 100 years of scientific research, the anatomical definitions of PVD and its pathogenesis remain controversial. Recent research has identified a novel cell population (laminocyte), present at significantly higher numbers in pathological PVD when compared to physiological PVD. We review and summarise the seven distinct clinical sub-groups of retinal breaks and focus on the role of the laminocyte in those secondary to PVD and the transcriptomic profile of this unique cell. Provisional whole transcriptome analysis using bulk RNA-Seq shows marked differentially expressed genes when comparing physiological PVD with PVD associated with RD. The limitations of bulk RNA-Seq are considered and the potential to address these using spatial transcriptomics are discussed. Understanding the pathogenesis of PVD-related retinal tears will provide a baseline for the development of novel therapeutic targets and prophylactic treatments.


Assuntos
Descolamento Retiniano , Perfurações Retinianas , Descolamento do Vítreo , Humanos , Idoso , Descolamento Retiniano/genética , Perfurações Retinianas/complicações , Transcriptoma/genética , Patologia Molecular
10.
Stem Cell Reports ; 17(11): 2421-2437, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36240775

RESUMO

Usher syndrome-associated retinitis pigmentosa (RP) causes progressive retinal degeneration, which has no cure. The pathomechanism of Usher type 1B (USH1B)-RP caused by MYO7A mutation remains elusive because of the lack of faithful animal models and limited knowledge of MYO7A function. Here, we analyzed 3D retinal organoids generated from USH1B patient-derived induced pluripotent stem cells. Increased differential gene expression occurred over time without excessive photoreceptor cell death in USH1B organoids compared with controls. Dysregulated genes were enriched first for mitochondrial functions and then proteasomal ubiquitin-dependent protein catabolic processes and RNA splicing. Single-cell RNA sequencing revealed MYO7A expression in rod photoreceptor and Müller glial cells corresponding to upregulation of stress responses in NRL+ rods and apoptotic signaling pathways in VIM+ Müller cells, pointing to the defensive mechanisms that mitigate photoreceptor cell death. This first human model for USH1B-RP provides a representation of patient retina in vivo relevant for development of therapeutic strategies.


Assuntos
Organoides , Retinite Pigmentosa , Animais , Humanos , Miosina VIIa , Organoides/patologia , Patologia Molecular , Miosinas/genética , Miosinas/metabolismo , Retina/metabolismo , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Células Fotorreceptoras Retinianas Bastonetes/patologia
11.
J Trop Pediatr ; 68(6)2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36228307

RESUMO

BACKGROUND: The etiological diagnosis of community-acquired pneumonia (CAP) is still a challenge. We compared the conventional culture method and real-time polymerase chain reaction (RT-PCR) for the identification of Streptococcus pneumoniae in severe pediatric CAP. METHODS: A retrospective hospital-based study was conducted. From 2012 to 2018, we have selected patients who had peripheral blood and/or pleural fluid collected for etiological investigation by RT-PCR. RESULTS: We included 113 children (median age: 3 years; interquartile range 1-6 years). RT-PCR increased the detection rate of S. pneumoniae by 6.5 times using blood samples and eight times using pleural fluid samples. Patients subjected to RT-PCR showed more prolonged hospitalization (p = 0.006), fewer comorbidities (p = 0.03), presence of pleural effusion (p = 0.001), presence of young forms of leukocytes (p = 0.001) and radiograph with characteristics of pneumonia (p = 0.002). The presence of pleural effusion [odds ratio (OR) = 14.7, 95% confidence interval (CI) 1.6-133.9; p = 0.01] and young forms of leukocytes (OR = 8.9, 95% CI 0.9-84.4; p = 0.05) were risk factors for positive RT-PCR pneumococcal when multivariate analysis was performed. CONCLUSIONS: RT-PCR is a reliable method for diagnosing severe CAP using sterile materials and a potentially applicable method in patients with clinical, radiological and non-specific laboratory characteristics of lower respiratory tract infection, especially in complicated cases with pleural effusion.


Assuntos
Infecções Comunitárias Adquiridas , Derrame Pleural , Pneumonia , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/epidemiologia , Humanos , Patologia Molecular , Derrame Pleural/complicações , Derrame Pleural/diagnóstico , Vacinas Pneumocócicas , Pneumonia/complicações , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Estudos Retrospectivos , Streptococcus pneumoniae/genética
12.
Hum Mutat ; 43(11): 1531-1544, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36086952

RESUMO

Long-read sequencing (LRS) has been around for more than a decade, but widespread adoption of the technology has been slow due to the perceived high error rates and high sequencing cost. This is changing due to the recent advancements to produce highly accurate sequences and the reducing costs. LRS promises significant improvement over short read sequencing in four major areas: (1) better detection of structural variation (2) better resolution of highly repetitive or nonunique regions (3) accurate long-range haplotype phasing and (4) the detection of base modifications natively from the sequencing data. Several successful applications of LRS have demonstrated its ability to resolve molecular diagnoses where short-read sequencing fails to identify a cause. However, the argument for increased diagnostic yield from LRS remains to be validated. Larger cohort studies may be required to establish the realistic boundaries of LRS's clinical utility and analytical validity, as well as the development of standards for clinical applications. We discuss the limitations of the current standard of care, and contrast with the applications and advantages of two major LRS platforms, PacBio and Oxford Nanopore, for molecular diagnostics of constitutional disorders, and present a critical argument about the potential of LRS in diagnostic settings.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Patologia Molecular , Humanos , Análise de Sequência de DNA
14.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077104

RESUMO

Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet-Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus-Merzbacher disease), transcriptional deregulation diseases (Mowat-Wilson disease, Pitt-Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction.


Assuntos
Síndrome de Bardet-Biedl , Neuromielite Óptica , Animais , Cerebelo , Comorbidade , Patologia Molecular
15.
J Biotechnol ; 358: 64-66, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36100138

RESUMO

The growth of resistance to multiple herbicides in grass weeds is a major threat to global cereal production and in the UK, is epitomized by the loss of control of blackgrass (Alopecurus myosuroides), causing losses in winter wheat production equating to 5% of national consumption. With an urgent need to develop new black-grass management tools, we have developed a lateral flow assay (LFA) that can predict resistance to multiple herbicides within 10 min.


Assuntos
Resistência a Herbicidas , Herbicidas , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Patologia Molecular , Poaceae/genética , Triticum
16.
Surg Oncol ; 44: 101851, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36126350

RESUMO

Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares , Produtos Biológicos , Colangiocarcinoma , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Antígeno Carcinoembrionário , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Hepatectomia , Humanos , Patologia Molecular
18.
J Nanobiotechnology ; 20(1): 400, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064405

RESUMO

BACKGROUND: Sepsis is caused mainly by infection in the blood with a broad range of bacterial species. It can be diagnosed by molecular diagnostics once compounds in the blood that interfere with molecular diagnostics are removed. However, this removal relies on ultracentrifugation. Immunomagnetic separation (IMS), which typically uses antibody-conjugated silica-coated magnetic nanoparticles (Ab-SiO2-MNPs), has been widely applied to isolate specific pathogens in various types of samples, such as food and environmental samples. However, its direct use in blood samples containing bacteria is limited due to the aggregation of SiO2-MNPs in the blood and inability to isolate multiple species of bacteria causing sepsis. RESULTS: In this study, we report the synthesis of vancomycin-conjugated polydopamine-coated (van-PDA-MNPs) enabling preconcentration of multiple bacterial species from blood without aggregation. The presence of PDA and van on MNPs was verified using transmission electron microscopy, X-ray photoelectron spectroscopy, and energy disruptive spectroscopy. Unlike van-SiO2-MNPs, van-PDA-MNPs did not aggregate in the blood. Van-PDA-MNPs were able to preconcentrate several species of Gram-positive bacteria in the blood, lowering the limit of detection (LOD) to 10 colony forming units/mL by polymerase chain reaction (PCR) and quantitative PCR (qPCR). This is 10 times more sensitive than the LOD obtained by PCR and qPCR using van-SiO2-MNPs. CONCLUSION: These results suggest that PDA-MNPs can avoid aggregation in blood and be conjugated with receptors, thereby improving the sensitivity of molecular diagnostics of bacteria in blood samples.


Assuntos
Nanopartículas de Magnetita , Sepse , Bactérias , Bactérias Gram-Positivas , Humanos , Indóis , Nanopartículas de Magnetita/química , Patologia Molecular , Polímeros , Dióxido de Silício , Vancomicina/química
19.
Pest Manag Sci ; 78(11): 4994-5001, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36054028

RESUMO

BACKGROUND: Insecticide resistance has developed in several populations of the whitefly Bemisia tabaci worldwide and threatens to compromise the efficacy of chemical control. The molecular mechanisms underpinning resistance have been characterized and markers associated with the trait have been identified, allowing the development of diagnostics for individual insects. RESULTS: TaqMan and Droplet Digital PCR (ddPCR) assays were developed and validated, in individual and pooled whitefly samples, respectively, for the following target-site mutations: the acetylcholinesterase (ace1) F331W mutation conferring organophosphate-resistance; the voltage-gated sodium channel (vgsc) mutations L925I and T929V conferring pyrethroid-resistance; and the acetyl-CoA carboxylase (acc) A2083V mutation conferring ketoenol-resistance. The ddPCR's limit of detection (LoD) was <0.2% (i.e. detection of one heterozygote whitefly in a pool of 249 wild-type individuals). The assays were applied in 11 B. tabaci field populations from four locations in Crete, Greece. The F331W mutation was detected to be fixed or close to fixation in eight of 11 B. tabaci populations, and at lower frequency in the remaining ones. The pyrethroid-resistance mutations were detected at very high frequencies. The A2083V spiromesifen resistance mutation was detected in eight of 11 populations (frequencies = 6.16-89.56%). Spiromesifen phenotypic resistance monitoring showed that the populations tested had variable levels of resistance, ranging from full susceptibility to high resistance. A strong spiromesifen-resistance phenotype-genotype (A2083V) correlation (rs  = -0.839, P = 0.002) was observed confirming the ddPCR diagnostic value. CONCLUSION: The ddPCR diagnostics developed in this study are a valuable tool to support evidence-based rational use of insecticides and resistance management strategies. © 2022 Society of Chemical Industry.


Assuntos
Hemípteros , Inseticidas , Piretrinas , Canais de Sódio Disparados por Voltagem , Acetil-CoA Carboxilase , Acetilcolinesterase/genética , Animais , Hemípteros/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Organofosfatos , Patologia Molecular , Reação em Cadeia da Polimerase , Piretrinas/farmacologia , Compostos de Espiro , Canais de Sódio Disparados por Voltagem/genética
20.
Clin Lab Med ; 42(3): 349-365, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36150816

RESUMO

Pediatric neoplasms have unique demands, including triaging of small biopsies for multiple testing modalities, and a pediatric cancer genome that is notably different from the adult cancer genome. Pediatric cancers are more likely to be driven by gene fusions and typically have a lower tumor mutational burden. Clinically relevant unique molecular targets exist within pediatric cancers, with important implications for diagnosis, prognosis, and treatment selection. Hence, assays and interpretation workflows must be designed thoughtfully to support molecular tumor profiling for children with cancer, including accommodation of small samples, detection of gene fusions, and consideration of potential germline associations.


Assuntos
Neoplasias , Patologia Molecular , Adulto , Biomarcadores Tumorais/genética , Criança , Fusão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Neoplasias/genética
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