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BACKGROUND: Dysfunctional uterine peristalsis seems to play a pivotal role in hindering embryo implantation among women diagnosed with adenomyosis. This research aims to investigate whether administering an oxytocin receptor antagonist during a frozen embryo transfer (FET) cycle using a hormone replacement therapy (HRT) protocol can enhance in vitro fertilization (IVF) outcomes for infertile women affected by adenomyosis. METHODS: Between January 2018 and June 2022, our reproductive center conducted IVF-FET HRT cycles for infertile women diagnosed with adenomyosis. Propensity score matching was employed to select matched subjects between the two groups in a 1:1 ratio. Following this, 168 women received an oxytocin receptor antagonist during FET, constituting the study group, while the matched 168 women underwent FET without this antagonist, forming the control group. We conducted comparative analyses of baseline and cycle characteristics between the two groups, along with additional subgroup analyses. RESULTS: The study group exhibited notably lower rates of early miscarriage compared to the control group, although there were no significant differences in clinical pregnancy rates, ongoing pregnancy rates, and live birth rates between the two groups. Multivariate analysis revealed a negative correlation between the use of oxytocin receptor antagonists and early miscarriage rates in women with adenomyosis. Subgroup analyses, categorized by age, infertility types, and embryo transfer day, showed a substantial decrease in early miscarriage rates within specific subgroups: women aged ≥ 37 years, those with secondary infertility, and individuals undergoing day 3 embryo transfers in the study group compared to the control group. Furthermore, subgroup analysis based on adenomyosis types indicated significantly higher clinical pregnancy rates, ongoing pregnancy rates and live birth rates in the study group compared to the control group among women with diffuse adenomyosis. CONCLUSIONS: Administering an oxytocin receptor antagonist during FET may reduce the early miscarriage rates in women with adenomyosis.
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Aborto Espontâneo , Adenomiose , Transferência Embrionária , Fertilização in vitro , Infertilidade Feminina , Taxa de Gravidez , Pontuação de Propensão , Receptores de Ocitocina , Humanos , Feminino , Transferência Embrionária/métodos , Adulto , Gravidez , Adenomiose/complicações , Adenomiose/tratamento farmacológico , Fertilização in vitro/métodos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/prevenção & controle , Receptores de Ocitocina/antagonistas & inibidores , Infertilidade Feminina/terapia , Infertilidade Feminina/etiologia , Infertilidade Feminina/epidemiologia , Estudos Retrospectivos , Criopreservação , Terapia de Reposição Hormonal/métodos , Antagonistas de Hormônios/uso terapêutico , Antagonistas de Hormônios/administração & dosagemRESUMO
OBJECTIVES: Cochlear implants are an option for children with sensorineural hearing loss who do not benefit from hearing aids. Although bilateral cochlear implantation (CI) has been shown to enhance hearing performance and quality of life, its cost-effectiveness remains unclear. This study aimed to evaluate the cost-effectiveness of bilateral CI compared with bimodal hearing for children with sensorineural hearing loss in Taiwan from both the perspectives of patients and Taiwan's National Health Insurance Administration (TNHIA). DESIGN: A four-state Markov model was utilized in the study, including "use the first internal device," "use the second internal device," "use the third internal device," and "death." Health utility values were obtained from a local survey of health professionals and then adjusted by a scale to reflect both the negative impact of aging on hearing and the time needed to develop the full benefit of treatment in the earliest years of life. The cost data were derived from a caregiver survey, hospital databases, clinical experts, and the TNHIA. The incremental cost-effectiveness ratio (ICER) was calculated over the lifetime horizon and presented as cost per quality-adjusted life year (QALY) to evaluate the cost-effectiveness of simultaneous bilateral CI, sequential bilateral CI, and bimodal hearing. In addition, one-way sensitivity analyses and probabilistic sensitivity analyses were conducted to investigate the impact of uncertainty and the robustness of the model. RESULTS: The base-case analysis showed that children with bilateral CI gained more QALYs while incurring more costs when compared with those with bimodal hearing. From the TNHIA perspective, compared with bimodal hearing, the ICER of simultaneous bilateral CI was New Taiwan Dollars 232,662 per QALY whereas from the patient perspective, the ICER was New Taiwan Dollars 1,006,965 per QALY. Moreover, simultaneous bilateral CI dominated sequential bilateral CI from both perspectives. Compared with bimodal hearing, the ICER of sequential bilateral CI did not exceed twice the gross domestic product per capita in Taiwan from either perspective. One-way sensitivity analysis demonstrated that the utility gain of bilateral CI compared with bimodal hearing was the most impactful parameter from both perspectives. Probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results. CONCLUSIONS: Our findings reveal that bilateral CI was cost-effective when using the threshold of one to three times the 2022 gross domestic product per capita in Taiwan from both the TNHIA and patient perspectives. Future research incorporating cost and effectiveness data from other dimensions is needed to help decision-makers assess the cost-effectiveness of bilateral CI more comprehensively.
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OBJECTIVES: To translate and validate the Chinese version of the Speech, Spatial, and Qualities of Hearing Scale (SSQ) for children with hearing impairment (C-SSQ-C) and for their parents (C-SSQ-P). DESIGN: We translated the SSQ for children into Chinese and verified its readability and comprehensibility. A total of 105 participants with moderate-to-profound hearing loss (HL) and 54 with normal hearing were enrolled in the validation process. The participants with HL were fitted with bilateral hearing aids, bimodal hearing, or bilateral cochlear implants. The C-SSQ-P was administered to the parents of participants aged 3 to 6.9 years, and the C-SSQ-C was administered to participants aged 7 to 18 years. The internal consistency, test-retest reliability, and validity were evaluated for both questionnaires. RESULTS: Both C-SSQ-P and C-SSQ-C demonstrated high internal consistency (Cronbach's α >0.8) and good validity (generalized linear model revealed significant negative relationships between the C-SSQ-P subscales with aided better-hearing threshold [ß = -0.08 to -0.12, p ≤ 0.001] and between the C-SSQ-C subscales with worse-hearing threshold [ß = -0.13 to -0.14, p < 0.001]). Among the children with HL, the participants with bilateral cochlear implants had demonstrated better performance than those with bimodal hearing and bilateral hearing aids, as evidenced by the highest mean scores in three subscales. CONCLUSIONS: Both C-SSQ-P and C-SSQ-C are reliable and valid for assessing HL in children and adolescents. The C-SSQ-P is applicable in evaluating young children aged 3 to 6.9 years after a 7-day observation period, while the C-SSQ-C is appropriate for children and adolescents aged 7 to 18 years.
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BACKGROUND: GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression. METHODS: The retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups. RESULTS: Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20-3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20-3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69-12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59-11.65, P = 0.004). CONCLUSIONS: Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.
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Coeficiente de Natalidade , Fase Luteal , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Hormônio Liberador de Gonadotropina , Transferência Embrionária/métodos , Taxa de Gravidez , Fertilização in vitro , Nascido VivoRESUMO
BACKGROUND: Alcohol is known to modulate the immune system. Neuroinflammatory cytokine dysregulation plays an essential role in the pathophysiology of alcohol dependence (AD). Preclinical studies have indicated that alcohol consumption upregulates the pro-inflammatory cytokine CC motif ligand 11 (CCL11, also known as eotaxin-1). We examined CCL11 levels in patients with AD and in mice administered alcohol. METHODS: The plasma CCL11 levels of 151 patients with AD and 116 healthy controls were measured. In addition, we followed the CCL11 levels, alcohol cravings and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. Furthermore, we examined CCL11 changes in mice administered alcohol for 5 days. RESULTS: CCL11 levels were higher in patients with AD than in controls and declined during detoxification. CCL11 levels were positively correlated with AD severity (p < 0.001). Furthermore, mice exposed to alcohol exhibited a higher CCL11 level. The receiver operating characteristic curve revealed that a CCL11 level of 72.5 pg/mL could significantly differentiate patients with AD from controls (area under the curve: 0.77; p < 0.001). Reductions in CCL11 levels during detoxification were correlated with reductions in alcohol craving, depression, and anxiety. CONCLUSIONS: Our data from humans and mice suggest that chronic alcohol consumption is associated with an increase in CCL11 levels. CCL11 levels are correlated with AD severity and may be a potential indicator of AD. The CCL11 reduction after alcohol discontinuation is associated with alleviation of clinical symptoms. Collectively, our findings suggest that CCL11 is involved in the neurobiological mechanisms underlying AD.
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Alcoolismo , Animais , Ansiedade , Quimiocina CCL11 , Citocinas , Humanos , CamundongosRESUMO
Interactions between charged amino acids significantly influence the structure and function of proteins. The encoded charged amino acids Asp, Glu, Arg, and Lys have different number of hydrophobic methylenes linking the backbone to the charged functionality. It remains to be fully understood how does this difference in the number of methylenes affect protein structure stability. Protein secondary structures are the fundamental three-dimensional building blocks of protein structures. ß-Sheet structures are particularly interesting, because these structures have been associated with a number of protein misfolding diseases. Herein, we report the effect of charged amino acid side chain length at two ß-strand positions individually on the stability of a ß-hairpin. The charged amino acids include side chains with a carboxylate, an ammonium, or a guanidinium group. The experimental peptides, fully folded reference peptides, and fully unfolded reference peptides were synthesized by solid phase peptide synthesis and analyzed by 2D NMR methods including TOCSY, DQF-COSY, and ROESY. Sequence specific assignments were performed for all peptides. The chemical shift data were used to derive the fraction folded population and the folding free energy for the experimental peptides. Results showed that the fraction folded population increased with increasing charged amino acid side chain length. These results should be useful for developing functional peptides that adopt the ß-conformation.
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Aminoácidos , Peptídeos , Conformação Proteica em Folha beta , Dobramento de Proteína , Estrutura Secundária de Proteína , TermodinâmicaRESUMO
The phytohormone ethylene is widely involved in many developmental processes and is a crucial regulator of defense responses against biotic and abiotic stresses in plants. Ethylene-responsive element binding protein, a member of the APETALA2/ethylene response factor (AP2/ERF) superfamily, is a transcription factor that regulates stress-responsive genes by recognizing a specific cis-acting element of target DNA. A previous study showed only the NMR structure of the AP2/ERF domain of AtERF100 in complex with a GCC box DNA motif. In this report, we determined the crystal structure of AtERF96 in complex with a GCC box at atomic resolution. We analyzed the binding residues of the conserved AP2/ERF domain in the DNA recognition sequence. In addition to the AP2/ERF domain, an N-terminal α-helix of AtERF96 participates in DNA interaction in the flanking region. We also demonstrated the structure of AtERF96 EDLL motif, a unique conserved motif in the group IX of AP2/ERF family, might involve in the transactivation of defense-related genes. Our study establishes the structural basis of the AtERF96 transcription factor in complex with the GCC box, as well as the DNA binding mechanisms of the N-terminal α-helix and AP2/ERF domain.
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Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Arabidopsis/química , Arabidopsis/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Sítios de Ligação , Cristalografia por Raios X , DNA de Plantas/metabolismo , Modelos Moleculares , Mutação , Conformação Proteica , Protoplastos , Fatores de Transcrição/genéticaAssuntos
Oftalmopatias , Doença Relacionada a Imunoglobulina G4 , Olho , Oftalmopatias/diagnóstico , Oftalmopatias/etiologia , Humanos , Imunoglobulina G , Doença Relacionada a Imunoglobulina G4/complicações , Doença Relacionada a Imunoglobulina G4/diagnóstico , Pseudotumor Orbitário , Estudos RetrospectivosAssuntos
Implante Coclear/métodos , Síndrome LEOPARD/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Candida albicans is an important human fungal pathogen but its study has been hampered for being a natural diploid that lacks a complete sexual cycle. Gene knock-out and essential gene repression are used to study gene function in C. albicans. To effectively study essential genes in wild-type C. albicans, we took advantage of the compatible effects of the antibiotics hygromycin B and nourseothricin, the recyclable CaSAT1-flipper and the tetracycline-repressible (Tet-off) system. To allow deleting two alleles simultaneously, we created a cassette with a C. albicans HygB resistance gene (CaHygB) flanked with the FLP recombinase target sites that can be operated alongside the CaSAT1-flipper. Additionally, to enable conditionally switching off essential genes, we created a CaHygB-based Tet-off cassette that consisted of the CaTDH3 promoter, which is used for the constitutive expression of the tetracycline-regulated transactivator and a tetracycline response operator. To validate the new systems, all strains were constructed based on the wild-type strain and selected by the two dominant selectable markers, CaHygB and CaSAT1. The C. albicans general transcriptional activator CaGCN4 and its negative regulator CaPCL5 genes were targeted for gene deletion, and the essential cyclin-dependent kinase CaPHO85 gene was placed under the Tet-off system. Cagcn4, Capcl5, the conditional Tet-off CaPHO85 mutants, and mutants bearing two out of the three mutations were generated. By subjecting the mutants to various stress conditions, the functional relationship of the genes was revealed. This new system can efficiently delete genes and conditionally switch off essential genes in wild-type C. albicans to assess functional interaction between genes.
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Candida albicans/genética , Regulação Fúngica da Expressão Gênica , Inativação Gênica , Seleção Genética , Ativação Transcricional , Deleção de Genes , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Ordem dos Genes , Genes Fúngicos , Vetores Genéticos , Mutação , Fenótipo , Regiões Promotoras Genéticas , Tetraciclina/farmacologiaRESUMO
BACKGROUND: The epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3's action remain unanswered. RESULTS: We demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants. CONCLUSIONS: Our results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on mitochondria.
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Homeostase , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Proteínas/genética , Animais , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Potencial da Membrana Mitocondrial/genética , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Estrutura Terciária de Proteína/genética , Proteínas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
RATIONALE: Among the six positional isomers of dihydroxybenzoic acid (DHB), 2,5-DHB is a more favorable matrix for use in matrix-assisted laser desorption/ionization (MALDI) than the other isomers because of its high ion-generation efficiency at 337 and 355 nm. The generation of hydroquinone or p-benzoquinone through the decarboxylation of 2,5-DHB has been suggested to play a crucial role in the ion-generation efficiency of 2,5-DHB. METHODS: The mass spectra of desorbed neutrals generated from MALDI were measured using electron impact ionization (70 eV) and a quadrupole mass spectrometer and vacuum ultraviolet (118 nm) photoionization and a time-of-flight mass spectrometer. The mass spectra of desorbed ions generated from MALDI were investigated using a time-of-flight mass spectrometer. The dissociation barrier height and dissociation rate of decarboxylation were calculated by an ab initio method and RRKM theory. RESULTS: Decarboxylation of neutral 2,5-DHB and 2,5-DHB cations was not observed. Theoretical calculations indicated that decarboxylation of neutral 2,5-DHB and 2,5-DHB cations is too slow to occur. CONCLUSIONS: The high ion-generation efficiency of the 2,5-DHB matrix at 337 and 355 nm is not related to decarboxylation.
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Gentisatos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Cátions/química , Descarboxilação , Hidroquinonas/químicaRESUMO
Purpose: Cone-rod dystrophies (CORD) are inherited retinal dystrophies characterized by primary cone degeneration with secondary rod involvement. We report two patients from the same family with a dominant variant in the guanylate cyclase 2D (GUCY2D) gene with different phenotypes in the electroretinogram (ERG). Observations: A 21-year-old lady (Patient 1) was referred due to experiencing blurry vision and color vision impairment. Visual field testing revealed a central scotoma. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) documented macula dysfunction. Reduced amplitude was observed in the photopic responses of ERG. Her 54-year-old father (Patient 2) had similar issues with blurry vision. A dilated fundus examination displayed bilateral macular atrophy. Loss of the ellipsoid zone line and collapse of the outer nuclear segment were noted on the SD-OCT. Photopic ERG responses were extinguished, and an electronegative ERG was observed in the dark-adapted 3.0 ERG. The gene report revealed a c.2512C > T (p.Arg838Cys) variant in GUCY2D for both patients. They were respectively diagnosed as cone dystrophy (COD) and cone-rod dystrophy (CORD). Conclusions: We report two different clinical phenotypes in GUCY2D-associated COD despite sharing the same variant. A dysfunction in the synaptic junction between the photoreceptor and the secondary neuron was proposed to explain the electronegative ERG. This explanation might extend to other gene-related cases of CORD with electronegative ERG.
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Cuproptosis is a recently discovered mode of cell death that has garnered attention due to its association with various diseases. However, the intricate genetic relationship between cuproptosis and ovarian aging has remained largely unexplored. This study aimed to bridge this knowledge gap by leveraging data sets related to ovarian aging and cuproptosis. Through comprehensive bioinformatics analyses, facilitated by R software, we uncovered FDX1 as a potential cuproptosis-related gene with relevance to ovarian aging. To gain insights into FDX1's role, we conducted spatial transcriptome analyses in the ovaries of both young and aged female mice. These experiments revealed a significant reduction in FDX1 expression in the aging group compared to the young group. To substantiate these findings at the genetic level, we turned to clinical infertility biopsies. Impressively, we observed consistent results in biopsies from elderly infertile patients, reinforcing the link between FDX1 and ovarian aging. Moreover, we delved into the pharmacogenomics of ovarian cell lines and discovered that FDX1 expression levels were intricately associated with heightened sensitivity to specific small molecule drugs. This observation suggests that modulating FDX1 could potentially be a strategy to influence drug responses in ovarian-related therapies. In sum, this study marks a pioneering effort in identifying FDX1 as a cuproptosis-related gene implicated in ovarian aging. These findings hold substantial promise, not only in shedding light on the underlying mechanisms of ovarian aging but also in positioning FDX1 as a potential diagnostic biomarker and therapeutic target. With further research, FDX1 could play a pivotal role in advancing precision medicine and therapies for ovarian-related conditions.
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BACKGROUND: Ovarian aging is characterized by the accumulation of free radicals, leading to tissue damage and affecting reproductive health. Intravascular laser irradiation of blood (ILIB, using a low-energy He-Ne laser) is known for its efficacy in treating vascular-related diseases by reducing free radicals and inflammation. However, its impact on ovarian aging remains unexplored. This study aimed to investigate the effects of ILIB on oxidative stress and energy metabolism in aging ovaries. METHODS: Genetic analysis was conducted on 75 infertile patients with aging ovaries, divided into ILIB-treated and control (CTRL) groups. Patients underwent two courses of laser treatment, and clinical parameters were evaluated. Cumulus cells were collected for the genetic analysis of oxeiptosis, glycolysis, and the tricarboxylic acid (TCA) cycle. RESULTS: The analysis of gene expression patterns revealed intriguing findings in ILIB-treated patients compared to the untreated group. Notably, ILIB treatment resulted in significant upregulation of oxeiptosis-related genes AIFM1 and NRF2, suggesting a potential protective effect against oxidative stress-induced cell death. Furthermore, ILIB treatment led to a downregulation of glycolysis-associated gene hexokinase 2 (HK2), indicating a shift away from anaerobic metabolism, along with an increase in PDHA levels, indicative of enhanced mitochondrial function. Consistent with these changes, ILIB-treated patients exhibited elevated expression of the key TCA cycle genes citrate synthase (CS), succinate dehydrogenase complex subunit A (SDHA), and fumarate hydratase (FH), signifying improved energy metabolism. CONCLUSION: The findings from this study underscore the potential of ILIB as a therapeutic strategy for mitigating ovarian aging. By targeting oxidative stress and enhancing energy metabolism, ILIB holds promise for preserving ovarian function and reproductive health in aging individuals. Further research is warranted to elucidate the underlying mechanisms and optimize the application of ILIB in clinical settings, with the ultimate goal of improving fertility outcomes in women experiencing age-related ovarian decline.
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BACKGROUND: Copy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified. CASE PRESENTATION: A 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV. CONCLUSION: In conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately enhancing diagnostic precision in the field of genetic disorders.
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Aneurisma Intracraniano , Atrofia Óptica , Feminino , Humanos , Adulto , Mutação , Variações do Número de Cópias de DNA , Aneurisma Intracraniano/genética , Atrofia Óptica/genética , Fenótipo , Cromossomos , Linhagem , GTP Fosfo-Hidrolases/genéticaRESUMO
First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.
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Anticorpos Monoclonais , Imunoconjugados , Lenalidomida , Mieloma Múltiplo , Mieloma Múltiplo/tratamento farmacológico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/química , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos , Animais , Modelos Animais de DoençasRESUMO
BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention. METHOD: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds. RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years. CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.
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Conexina 26 , Perda Auditiva Neurossensorial , Aprendizado de Máquina , Humanos , Conexina 26/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Feminino , Masculino , Adulto , Criança , Adolescente , Pessoa de Meia-Idade , Pré-EscolarRESUMO
PURPOSE: This study aims to explore genetic variants that potentially lead to outer retinal tubulation (ORT), estimate the prevalence of ORT in these candidate genes, and investigate the clinical etiology of ORT in patients with inherited retinal diseases (IRDs), with respect to each gene. DESIGN: Retrospective cohort study. METHODS: A retrospective cross-sectional review was conducted on 565 patients with molecular diagnoses of IRD, confirming the presence of ORT as noted in each patient's respective spectral-domain optical coherence tomography (SD-OCT) imaging. Using SD-OCT imaging, the presence of ORT was analyzed in relation to specific genetic variants and phenotypic characteristics. Outcomes included the observed ORT frequencies across two gene-specific cohorts: non- retinal pigment epithelium (RPE)-specific genes, and RPE-specific genes; and to investigate the analogous characteristics caused by variants in these genes. RESULTS: Among the 565 patients included in this study, 104 exhibited ORT on SD-OCT. We observed ORT frequencies among the following genes from our patient cohort: 100% (23/23) forCHM, 100%(2/2) forPNPLA6, 100% (4/4) forRCBTB1, 100% formtDNA[100% (4/4) forMT-TL1and 100% (1/1) formtDNAdeletion], 100% (1/1) forOAT, 95.2% (20/21) forCYP4V2, 72.7% (8/11) forCHMfemale carriers, 66.7% (2/3) forC1QTNF5, 57.1% (8/14) forPROM1, 53.8% (7/13) forPRPH2, 42.9% (3/7) forCERKL, 28.6% (2/7) forCDHR1, 20% (1/5) forRPE65, 4% (18/445) forABCA4.In contrast, ORT was not observed in any patients with photoreceptor-specific gene variants, such asRHO(n=13),USH2A(n=118),EYS(n=70),PDE6B(n=10),PDE6A(n=4),and others. CONCLUSION: These results illustrate a compelling association between the presence of ORT and IRDs caused by variants in RPE-specific genes, as well as non-RPE-specific genes. In contrast, IRDs caused by photoreceptor-specific genes are typically not associated with ORT occurrence. Further analysis revealed that ORT tends to manifest in IRDs with milder intraretinal pigment migration (IPM), a finding that is typically associated with RPE-specific genes. These findings regarding ORT, genetic factors, atrophic patterns in the fundus, and IPM provide valuable insight into the complex etiology of IRDs. Future prospective studies are needed to further explore the association and underlying mechanisms of ORT in these contexts.