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BACKGROUND: The essential tremor (ET) course to 54 months post-unilateral VIM/PSA magnetic resonance-guided focused ultrasound (MRgFUS) in the treated arm (TA) and non-treated arm (NTA) of 12 patients is reported. METHODS: Tremor severity was rated using Bain Findley spirography (BFS) scores in the TA and NTA. We divided follow-up into 'Early' (0-6 months) and 'Late' (6-54 months) phases, to minimise the effect of peri-lesion oedema resolution on the latter. RESULTS: The mean baseline BFS score was 6.2 in TA and 5.7 in the NTA. After unilateral VIM/PSA MRgFUS, mean BFS improved in TA at all subsequent time points (p < 0.001), with no significant differences between BFS scores at consecutive assessments or between 1 and 54 months, while the NTA BFS scores worsened between 12 and 24 months (p < 0.003). Three patients showed worsening of their TA BFS scores and an increasing NTA-TA BFS difference, indicating slower tremor worsening in TA compared to NTA, whilst one patient showed a greater rate of worsening in the TA compared to NTA BFS. CONCLUSION: After 54 months, the beneficial effect of MRgFUS is usually maintained with any worsening of BFS scores in TA slower than in NTA. Loss of treatment benefit is rare.
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Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.
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Amino Álcoois , Rutênio , Hidrogenação , Catálise , Amino Álcoois/química , Amino Álcoois/síntese química , Rutênio/química , Estereoisomerismo , Estrutura Molecular , Aminas/químicaRESUMO
OBJECTIVE: Small-for-gestational-age (SGA) neonates are at increased risk of perinatal mortality and morbidity. We aimed to investigate the performance of uterine artery pulsatility index (UtA-PI) at 19-24 weeks' gestation to predict the delivery of a SGA neonate in a Chinese population. METHODS: This was a retrospective cohort study using data obtained between January 2010 and June 2018. Doppler ultrasonography was performed at 19-24 weeks' gestation. SGA was defined as birth weight below the 10th centile according to the INTERGROWTH-21st fetal growth standards. The performance of UtA-PI to predict the delivery of a SGA neonate was assessed using receiver-operating-characteristics (ROC)-curve analysis. RESULTS: We included 6964 singleton pregnancies, of which 748 (11%) delivered a SGA neonate, including 115 (15%) women with preterm delivery. Increased UtA-PI was associated with an elevated risk of SGA, both in neonates delivered at or after 37 weeks' gestation (term SGA) and those delivered before 37 weeks (preterm SGA). The areas under the ROC curve (AUCs) for UtA-PI were 64.4% (95% CI, 61.5-67.3%) and 75.8% (95% CI, 69.3-82.3%) for term and preterm SGA, respectively. The performance of combined screening by maternal demographic/clinical characteristics and estimated fetal weight in the detection of term and preterm SGA was improved significantly by the addition of UtA-PI, although the increase in AUC was modest (2.4% for term SGA and 4.9% for preterm SGA). CONCLUSIONS: This is the first Chinese study to evaluate the role of UtA-PI at 19-24 weeks' gestation in the prediction of the delivery of a neonate with SGA. The addition of UtA-PI to traditional risk factors improved the screening performance for SGA, and this improvement was greater in predicting preterm SGA compared with term SGA. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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Ultrassonografia Pré-Natal , Artéria Uterina , Gravidez , Recém-Nascido , Feminino , Humanos , Lactente , Masculino , Terceiro Trimestre da Gravidez , Artéria Uterina/diagnóstico por imagem , Estudos Retrospectivos , Estudos Prospectivos , Recém-Nascido Pequeno para a Idade Gestacional , Retardo do Crescimento Fetal/diagnóstico por imagem , Idade Gestacional , Ultrassonografia Doppler , Fluxo PulsátilRESUMO
The effects of cigarette smoking on the risk of herpes zoster (HZ) infection remain unclear. This study aimed to examine the association between cigarette smoking and HZ. Participants were collected from four rounds (2001, 2005, 2009 and 2013) of the Taiwan National Health Interview Survey. Incident cases of HZ were identified from the Taiwanese National Health Insurance database. Of the 57 641 participants, 3346 developed HZ during the observation period. After controlling for confounders, current smokers had a lower risk of incident HZ than never-smokers (adjusted hazard ratio 0.69; 95% CI 0.62-0.77). There was a trend toward a decreased risk of HZ with increasing numbers of cigarettes per day, years of smoking and cumulative pack-years of smoking among current smokers (Ptrend < 0.001). Former smoking was not associated with risk of HZ. In conclusion, current smoking was significantly associated with a decreased risk of developing HZ.
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Fumar Cigarros , Herpes Zoster/epidemiologia , Adulto , Estudos de Coortes , Feminino , Inquéritos Epidemiológicos , Herpes Zoster/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Conventional root canal treatment replaces the infected pulp with defined materials. Alternative cell-based tissue engineering strategies aim to regenerate a fully functional pulp within the root canal. Despite recent advances in this area, however, the regeneration of an innervated pulp remains a major challenge in the field. Both graphene (2DG) and pulsed electromagnetic fields (PEMFs) independently have been shown to promote diverse cellular developmental programs. The present study showed that 2DG promoted the neurogenic induction of human dental pulp stem cells (hDPSCs) by upregulating and accelerating the expression of mature neuronal markers. Notably, 2DG induced the highest expression of transient receptor potential canonical cation channel type 1 (TRPC1) during early neurogenesis. As brief PEMF exposure promotes in vitro differentiation by activating a TRPC1-mitochondrial axis, an opportunity to combine 2DG with developmentally targeted PEMF exposure for synergistic effects was realizable. Neurogenic gene expression, neurotransmitter release, and reactive oxygen species (ROS) production were greatly enhanced by a brief (10 min) and low amplitude (2 mT) PEMF exposure timed to coincide with the highest TRPC1 expression from hDPSCs on 2DG. In contrast, hDPSCs on glass were less responsive to PEMF exposure. The capacity of PEMFs to promote neurogenesis was precluded by the administration of penicillin/streptomycin, mirroring previous studies demonstrating that aminoglycoside antibiotics block TRPC1-mediated calcium entry and verifying the contribution of TRPC1 in this form of magnetoreception. Hence, graphene created a more conducive environment for subsequent PEMF-stimulated neurogenic induction of hDPSCs through their mutual capacity to activate TRPC1with subsequent ROS production.
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Polpa Dentária/citologia , Grafite/química , Neurogênese/fisiologia , Células-Tronco/citologia , Canais de Cátion TRPC/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Polpa Dentária/metabolismo , Campos Eletromagnéticos , Humanos , Regeneração/fisiologia , Células-Tronco/metabolismo , Engenharia Tecidual/métodosRESUMO
This study was designed to identify the relationship of four genes (GDF9, BMPR-IB, FecB and ESR) polymorphisms in the 3'UTR region with litter size and cashmere performance of Liaoning cashmere goats (LCG, n = 1140). The ESR C463T and T575G loci of LCG were genotyped. The results of correlation analysis showed that five effective single nucleotide polymorphisms (SNPs) loci (C47T, C94T, C299T, C463T and T575G) were found in the four genes. The lambing number of CC and CT genotypic individuals at FecB C94T locus was significantly higher than that of TT genotypic individuals (45.7 and 46.8%, respectively); the lambing number of CC genotypic individuals at ESR C463T locus was significantly higher than that of CT, TT genotypic individuals (9 and 15%, respectively); There was a positive correlation between CC genotype at C463T locus and cashmere fineness. In this study, the relationship between FecB C94T and ESR C463T loci C alleles and lambing number in LCG was preliminarily revealed. These results further confirmed that FecB and ESR genes may be significantly correlated with high fecundity of LCG.
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Cabras/genética , Cabelo/fisiologia , Tamanho da Ninhada de Vivíparos/genética , Polimorfismo de Nucleotídeo Único/genética , Animais , DNA/genética , Feminino , Reação em Cadeia da PolimeraseAssuntos
COVID-19 , Dermatoses da Mão/etiologia , Desinfecção das Mãos , Ceratodermia Palmar e Plantar/etiologia , Adulto , COVID-19/prevenção & controle , Feminino , Dermatoses da Mão/patologia , Dermatoses da Mão/terapia , Humanos , Ceratodermia Palmar e Plantar/patologia , Ceratodermia Palmar e Plantar/terapia , SARS-CoV-2 , Água/efeitos adversosRESUMO
BACKGROUND: Previous studies have shown that patients with psoriasis have a higher risk of depression. However, the risk of major depressive disorder (MDD) among unaffected siblings of psoriasis probands remains unknown. This study aimed to investigate the risk of MDD among probands with psoriasis and unaffected siblings. METHODS: We selected subjects from the National Health Insurance Research Database (NHIRD) in Taiwan. Subjects were followed up from 01 January 1996 until a diagnosis of MDD, death or 31 December 2011. The Breslow-Cox model was used to calculate the adjusted relative risk (aRR). RESULTS: This study included 1094 probands with psoriasis, 1202 unaffected siblings and 4808 matched controls. Overall, 11.9% of the psoriasis probands (n = 130) and 2.5% of the unaffected siblings (n = 30) developed MDD, as compared with 1.1% of the controls (n = 52). Compared with controls, probands with psoriasis and unaffected siblings had aRRs of 10.60 [95% confidence interval (CI): 7.73-14.52] and 2.17 (95% CI: 1.44-3.28), respectively, for MDD. CONCLUSIONS: Probands with psoriasis and unaffected siblings have an increased risk of subsequently developing MDD. Further studies are needed to investigate the shared familial mechanisms underlying psoriasis and MDD.
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Transtorno Depressivo Maior , Psoríase , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Humanos , Psoríase/epidemiologia , Psoríase/genética , Fatores de Risco , Irmãos , Taiwan/epidemiologiaRESUMO
There is conflicting evidence whether allogeneic blood transfusion influences survival or cancer recurrence after resection of hepatocellular cancer. We followed up 1469 patients who had undergone hepatocellular resection for a median (IQR [range]) of 45 (21-78 [0-162]) months, of whom 626 (43%) had had blood transfusion within 7 days of surgery. Both disease-free survival and patient survival were measured using a proportional hazards regression model and inverse probability of treatment weighting. We used restricted cubic splines for the association of the number of packed red blood cell units transfused with cancer recurrence and survival. We found that peri-operative blood transfusion was independently associated with survival and cancer recurrence after resection of hepatocellular carcinoma. Adjusted hazard ratios (95%CI) for the association of blood transfusion with cancer recurrence and all-cause mortality were 1.3 (1.1-1.4) and 1.9 (1.6-2.3), p < 0.001 for both. With more units transfused cancer recurrence was more likely and survival was shorter. The association of the number of transfused units was non-linear for cancer recurrence and linear response for all-cause mortality.
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Transfusão de Sangue/métodos , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Animal growth and development are regulated by long non-coding RNAs (lncRNAs). However, the functions of lncRNAs in regulating cashmere fineness are poorly understood. To identify the key lncRNAs that are related to cashmere fineness in skin, we have collected skin samples of Liaoning cashmere goats (LCG) and Inner Mongolia cashmere goats (MCG) in the anagen phase, and have performed RNA sequencing (RNA-seq) approach on these samples. The high-throughput sequencing and bioinformatics analyses identified 437 novel lncRNAs, including 93 differentially expressed lncRNAs. We also identified 3,084 differentially expressed messenger RNAs (mRNAs) out of 27,947 mRNAs. Gene ontology (GO) analyses of lncRNAs and target genes in cis show a predominant enrichment of targets that are related to intermediate filament and intermediate filament cytoskeleton. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, sphingolipid metabolism is a significant pathway for lncRNA targets. In addition, this is the first report to reveal the possible lncRNA-mRNA regulatory network for cashmere fineness in cashmere goats. We also found that lncRNA XLOC_008679 and its target gene, KRT35, may be related to cashmere fineness in the anagen phase. The characterization and expression analyses of lncRNAs will facilitate future studies on the potential value of fiber development in LCG.
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Cabras/genética , Folículo Piloso/química , RNA Longo não Codificante/genética , Pele/metabolismo , Animais , Biologia Computacional , Redes Reguladoras de Genes/genética , Cabras/crescimento & desenvolvimento , Folículo Piloso/crescimento & desenvolvimento , Sequenciamento de Nucleotídeos em Larga Escala , Metabolismo dos Lipídeos/genética , MicroRNAs/genética , RNA Mensageiro/genética , Pele/crescimento & desenvolvimentoRESUMO
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-κB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-κB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome.
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Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Humanos , Isoquinolinas/farmacologia , NF-kappa B/metabolismo , Prognóstico , Pirimidinas/farmacologia , Ribonucleoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Resultado do TratamentoRESUMO
Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM.
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Reparo do DNA/genética , Mieloma Múltiplo/genética , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Humanos , Transcrição Gênica/genética , Xeroderma Pigmentoso/genéticaRESUMO
This corrects the article DOI: 10.1038/leu.2016.388.
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Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells. Importantly, Rpn11 expression directly correlates with poor patient survival. Loss-of-function studies show that Rpn11-siRNA knockdown decreases MM cell viability. Pharmacological inhibition of Rpn11 with O-phenanthroline (OPA) blocks cellular proteasome function, induces apoptosis in MM cells and overcomes resistance to proteasome inhibitor bortezomib. Mechanistically, Rpn11 inhibition in MM cells activates caspase cascade and endoplasmic stress response signaling. Human MM xenograft model studies demonstrate that OPA treatment reduces progression of tumor growth and prolongs survival in mice. Finally, blockade of Rpn11 increases the cytotoxic activity of anti-MM agents lenalidomide, pomalidomide or dexamethasone. Overall, our preclinical data provide the rationale for targeting DUB enzyme Rpn11 upstream of 20S proteasome to enhance cytotoxicity and overcome proteasome inhibitor resistance in MM.