RESUMO
The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment.SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease.
Assuntos
Doença de Alzheimer , Memória Episódica , Adulto , Humanos , Feminino , Adulto Jovem , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/fisiologia , Lobo Temporal/fisiologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Transtornos da MemóriaRESUMO
PURPOSE: The inflow-based vascular-space-occupancy (iVASO) MRI was originally developed in a single-slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. METHODS: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single-slice iVASO, and the reproducibility of whole-brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall-superparamagnetic-iron-oxides-enhanced MRI to validate its arterial origin. RESULTS: 3D iVASO scans showed signal-to-noise ratio (SNR) and CBVa measures consistent with single-slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole-brain 3D iVASO scan with a motion-sensitized-driven-equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well-suppressed signals in venous vessels. CONCLUSION: A whole-brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion-sensitized-driven-equilibrium-based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO.
Assuntos
Volume Sanguíneo Cerebral , Imageamento por Ressonância Magnética , Humanos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , ArtériasRESUMO
AIMS: The role of maternal genetic factors in the association between high glycated haemoglobin (HbA1c) levels and adverse birth outcomes remains unclear. MATERIALS AND METHODS: In this study, the maternal HbA1c levels of 5108 normoglycemic pregnant women in China were measured, and A1298C and C677T polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene were genotyped. RESULTS: Elevated HbA1c levels during the second trimester were associated with increased risks of macrosomia, large-for-gestational age (LGA), preterm birth (PTB), and reduced gestational age (p < 0.05). Pregnant women with MTHFR A1298C AA or C677T CT + TT genotypes were susceptible to adverse pregnancy outcomes related to HbA1c levels. Among pregnant women with the A1298C AA genotype, each standard deviation (SD) increase in HbA1c levels increased the risk of PTB by 1.32-times and reduced the gestational age by 0.11 weeks (p < 0.05). For MTHFR C677T CC + TT genotype carriers, higher HbA1c levels were associated with 1.49-, 1.24-, and 1.23-times increased risks of macrosomia, LGA, and PTB, respectively (p < 0.05). A U-shaped curve for PTB risk in relation to HbA1c levels was observed among the C677T CC + TT participants, with a cut-off value of 4.58%. Among subjects with the A1298C AA genotype combined with the C677T CT + TT genotype, each SD increase in HbA1c levels was associated with 1.40 and 1.37-times increased risks of LGA and PTB, respectively. CONCLUSIONS: Our findings highlight the importance of glycaemic control during pregnancy and the potential impact of genetic factors on birth outcomes. However, further large-scale studies are required to confirm these findings.
Assuntos
Polimorfismo de Nucleotídeo Único , Nascimento Prematuro , Recém-Nascido , Humanos , Feminino , Gravidez , Hemoglobinas Glicadas , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Macrossomia Fetal/genética , Nascimento Prematuro/genética , Genótipo , Predisposição Genética para DoençaRESUMO
BACKGROUND: Increasing evidence suggests an association between maternal pre-pregnancy body mass index (pre-BMI) and adverse pregnancy outcomes. However, the effects of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on these relationships require further investigation. This study aimed to investigate whether the relationship between pre-BMI and the risk of adverse pregnancy outcomes was influenced by MTHFR gene polymorphisms. METHODS: A total of 5614 mother-fetus pairs were included in the study. The odds ratios (OR) of adverse pregnancy complications, including gestational diabetes mellitus (GDM), gestational hypertension (GHT), cesarean delivery (CS), and premature rupture of membranes (PROM), were estimated using adjusted logistic regression models and subgroup analysis. RESULTS: Pregnant women with higher pre-BMI values were positively related to the risk of GDM, GHT, and CS. In the subgroup analysis, underweight BMI was associated with a decreased risk of CS and GDM in pregnant women with the MTHFR A1298C AA or C677T CC genotype, while overweight/obese BMI was associated with an increased risk of GDM and CS in different MTHFR variants. Moreover, pregnant women with MTHFR A1298C AC + CC or C667T CC were found to have an increased risk of GHT in the MTHFR A1298C AA or C667T CT + TT genotype. A remarkable association was observed between the obesity group with MTHFR A1298C AC + CC (OR = 6.49, CI: 2.67-15.79) and the overweight group with the C667T CC genotype (OR = 4.72, CI: 2.13-10.45). CONCLUSIONS: MTHFR gene polymorphisms exert a modifying effect on the association between maternal pre-BMI and the risk of GHT, CS, and GDM. Pregnant women with a high pre-BMI with specific MTHFR genotypes should be considered for GHT development.
Assuntos
Diabetes Gestacional , Gestantes , Humanos , Feminino , Gravidez , Índice de Massa Corporal , Resultado da Gravidez , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sobrepeso/complicações , Sobrepeso/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Estudos Retrospectivos , Genótipo , China/epidemiologia , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Obesidade/complicações , Obesidade/genéticaRESUMO
Concerns regarding adverse effects of metal/metalloids exposure on brain development and neurological disorders among children are increasing. However, the transport patterns of metals/metalloids across the blood-cerebrospinal fluid barrier (BCSFB) need to be clarified in children. A total of 99 Chinese pediatric patients were enrolled from February 2020 to August 2021, with a median age of 6.76 months. We detected 16 metal/metalloid levels in matched serum and cerebrospinal fluid (CSF) samples using inductively coupled plasma mass spectrometry. The BCSFB permeability of metals/metalloids were estimated and the potential effects of biomedical parameters were explored. Most metals/metalloids were detectable among > 80.0% of CSF samples. Significant correlations were observed between strontium (Sr, r = 0.46), molybdenum (Mo, r = 0.50), and cadmium (Cd, r = 0.24) concentrations in serum and CSF (P < 0.05). Ratios of metal/metalloid levels in CSF to serum (Rmetal) ranged from 0.02 to 0.74, and hazardous metals/metalloids including arsenic (As), Cd, lead (Pb), thallium (Tl), and manganese (Mn) showed high transfer efficiencies across the BCSFB (Rmetals > 0.5). With the adjustment of age and sex, albumin, ß2-microglobulin, and total protein levels in CSF were positively associated with copper (Cu) permeability (FDR-adjusted P < 0.05), while glucose in CSF was negatively correlated with calcium (Ca), Cu, Sr, and Mo BCSFB permeability (FDR-adjusted P < 0.05). Q-Alb promoted Cu permeability across the BCSFB (FDR-adjusted P < 0.001), while C-reactive protein levels in serum were positively associated with selenium (Se) permeability (FDR-adjusted P = 0.046). For the first time, our findings provided data for the BCSFB permeability of 16 metals/metalloids in children, and indicated that some biomedical parameters could influence the transformation of metals/metalloids from serum to CSF. Metals/metalloids with strong BCSFB permeability warrant attention for their potential neurotoxicity.
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Metaloides , Humanos , Criança , Lactente , Metaloides/análise , Cádmio , Cobre , Cálcio , PermeabilidadeRESUMO
The data explosion driven by advancements in genomic research, such as high-throughput sequencing techniques, is constantly challenging conventional methods used in genomics. In parallel with the urgent demand for robust algorithms, deep learning has succeeded in various fields such as vision, speech, and text processing. Yet genomics entails unique challenges to deep learning, since we expect a superhuman intelligence that explores beyond our knowledge to interpret the genome from deep learning. A powerful deep learning model should rely on the insightful utilization of task-specific knowledge. In this paper, we briefly discuss the strengths of different deep learning models from a genomic perspective so as to fit each particular task with proper deep learning-based architecture, and we remark on practical considerations of developing deep learning architectures for genomics. We also provide a concise review of deep learning applications in various aspects of genomic research and point out current challenges and potential research directions for future genomics applications. We believe the collaborative use of ever-growing diverse data and the fast iteration of deep learning models will continue to contribute to the future of genomics.
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Aprendizado Profundo , Genômica/métodos , Algoritmos , Idioma , InteligênciaRESUMO
Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin-proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.
Assuntos
Berberina , Mieloma Múltiplo , Animais , Apoptose , Berberina/farmacologia , Berberina/uso terapêutico , Bortezomib/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Humanos , Camundongos , Simulação de Acoplamento Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/genética , UbiquitinaRESUMO
PURPOSE: A new regularizer is proposed for the magnitude least-squares optimization algorithm, to ensure robust parallel transmit RF shimming and small-tip-angle multispoke pulse designs for ultrahigh-field MRI. METHODS: A finite-difference regularization term is activated as an additional regularizer in the iterative magnitude-least-squares based pulse design algorithm when an unwanted flip angle null distribution is detected. Both simulated and experimental B1+ maps from different transmit arrays and different human subjects at 7 T were used to evaluate the proposed algorithm. The algorithm was further demonstrated in experiment with dynamic multislice RF shimming for a single-shot gradient-echo EPI for human functional MRI at 7 T. RESULTS: The proposed finite-difference regularizer effectively prevented excitation null to be formed for RF shimming and small-tip-angle multispoke pulses, and improved the latter with a monotonic trade-off relationship between flip angle error and RF power. The proposed algorithm was demonstrated to be effective with several head-array geometries by simulation and with a commercial head array with 12 healthy human subjects by experiment. During a functional MRI scan at 7 T with dynamic RF shimming, the proposed algorithm ensured high image SNR throughout the human brain, compared with near-complete local signal loss by the conventional magnitude-least-squares algorithm. CONCLUSION: Using finite-difference regularization to avoid unwanted solutions, the robustness of RF shimming and small-tip-angle multispoke pulse design algorithms are improved, with better flip angle homogeneity and a monotonic trade-off relationship between flip angle error and RF power.
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Algoritmos , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Simulação por Computador , Humanos , Análise dos Mínimos Quadrados , Imagens de Fantasmas , Ondas de RádioRESUMO
BACKGROUND: Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. RESULTS: Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. CONCLUSIONS: In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.
Assuntos
Anticarcinógenos/farmacologia , Berberina/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. OBJECTIVES: To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. METHODS: Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. RESULTS: Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. CONCLUSIONS: Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.
Assuntos
Arteríolas/diagnóstico por imagem , Volume Sanguíneo Cerebral , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Imageamento por Ressonância Magnética , Animais , Arteríolas/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Doença de Parkinson/patologiaRESUMO
Intracellular Ca2+ signals play many important cellular functions such as migration, proliferation and differentiation. Store-operated Ca2+ entry (SOCE) is a major route of Ca2+ entry in nonexcitable cells. The activation of SOCE requires engagement between stromal interaction molecule 1 (STIM1) molecules on the endoplasmic reticulum and Ca2+ release-activated Ca2+ (CRAC) channel Orais (Orai1-3) on the plasma membrane. Accumulating evidence indicates that SOCE plays critical roles in cancer cell proliferation, invasion and metastasis. Here, we used the synthetic intracellular peptides derived from the C-termini of Orai channels to treat the breast cancer cells. We have found that Orai3-CT peptide exhibits stronger binding to STIM1 than Orai1-CT, and Orai3-CT peptide acts in a dominant negative fashion, blocking the STIM1-Orai1 interaction and reducing the Ca2+ entry and proliferation of breast cancer cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Canais de Cálcio Ativados pela Liberação de Cálcio/farmacologia , Proliferação de Células/efeitos dos fármacos , Peptídeos/farmacologia , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Cálcio/metabolismo , Canais de Cálcio/química , Canais de Cálcio/farmacologia , Canais de Cálcio Ativados pela Liberação de Cálcio/química , Sinalização do Cálcio/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/química , Proteína ORAI1/farmacologia , Peptídeos/química , Mapas de Interação de Proteínas/efeitos dos fármacos , Molécula 1 de Interação Estromal/metabolismoRESUMO
In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Δα0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Δα0 is estimated by subtracting an initial value of Δα0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Δα0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Δα0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Δα0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Δα0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA.
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Técnicas de Ablação , Rim/diagnóstico por imagem , Rim/cirurgia , Fígado/diagnóstico por imagem , Fígado/cirurgia , Micro-Ondas/uso terapêutico , Animais , Suínos , UltrassonografiaRESUMO
Berberine (BBR), a traditional Chinese herbal medicine compound, has emerged as a novel class of anti-tumor agent. Our previous microRNA (miRNA) microarray demonstrated that miR-106b/25 was significantly down-regulated in BBR-treated multiple myeloma (MM) cells. Here, systematic integration showed that miR-106b/25 cluster is involved in multiple cancer-related signaling pathways and tumorigenesis. MiREnvironment database revealed that multiple environmental factors (drug, ionizing radiation, hypoxia) affected the miR-106b/25 cluster expression. By targeting the seed region in the miRNA, tiny anti-mir106b/25 cluster (t-anti-mir106b/25 cluster) significantly induced suppression in cell viability and colony formation. Western blot validated that t-anti-miR-106b/25 cluster effectively inhibited the expression of P38 MAPK and phospho-P38 MAPK in MM cells. These findings indicated the miR-106b/25 cluster functioned as oncogene and might provide a novel molecular insight into MM.
Assuntos
Berberina/farmacologia , MicroRNAs/genética , Mieloma Múltiplo/patologia , Transdução de Sinais , Linhagem Celular Tumoral , HumanosRESUMO
BACKGROUND: Berberine (BBR) is a natural alkaloid derived from a traditional Chinese herbal medicine. However, the exact mechanisms underlying the different effects of berberine on MM cells have not been fully elucidated. METHODS: A systematic analysis assay integrated common signaling pathways modulated by the 3 miRNA clusters and mRNAs in MM cells after BBR treatment. The role of the mir-99a â¼ 125b cluster, an important oncomir in MM, was identified by comparing the effects of t-anti-mirs with complete complementary antisense locked nucleic acids (LNAs) against mature mir-125b (anti-mir-125b). RESULTS: Three miRNAs clusters (miR-99a â¼ 125b, miR-17 â¼ 92 and miR-106 â¼ 25) were significantly down-regulated in BBR-treated MM cells and are involved in multiple cancer-related signaling pathways. Furthermore, the top 5 differentially regulated genes, RAC1, NFκB1, MYC, JUN and CCND1 might play key roles in the progression of MM. Systematic integration revealed that 3 common signaling pathways (TP53, Erb and MAPK) link the 3 miRNA clusters and the 5 key mRNAs. Meanwhile, both BBR and seed-targeting t-anti-mir-99a â¼ 125b cluster LNAs significantly induced apoptosis, G2-phase cell cycle arrest and colony inhibition. CONCLUSIONS: our results suggest that BBR suppresses multiple myeloma cells, partly by down-regulating the 3 miRNA clusters and many mRNAs, possibly through TP53, Erb and MAPK signaling pathways. The mir-99a â¼ 125b cluster might be a novel target for MM treatment. These findings provide new mechanistic insight into the anticancer effects of certain traditional Chinese herbal medicine compounds.
Assuntos
Alcaloides/farmacologia , Berberina/farmacologia , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Mieloma Múltiplo/patologia , Oligorribonucleotídeos Antissenso/metabolismoRESUMO
Background: Accumulating evidence has linked dyslipidemia during pregnancy to the risk of delivering infants born either large for gestational age (LGA) or small for gestational age (SGA). However, the effects of the vitamin D status on these relationships require further investigation. This study investigated whether the relationship between lipid profiles and the risk of LGA or SGA was influenced by vitamin D levels during the second trimester. Methods: Maternal lipid profile levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and vitamin D levels, were measured in a cohort of 6,499 pregnant women during the second trimester. Multivariate regression models and subgroup analyses were employed to evaluate the potential associations between maternal lipid profiles, vitamin D levels, and the risk of LGA or SGA. Results: The prevalence of SGA infants was 9.8% (n=635), whereas that of LGA infants was 6.9% (n=447). Maternal TG levels were found to be positively associated with the risk of LGA (odds ratio [OR] = 1.41, 95% confidence interval [CI]:1.17-1.70), whereas a negative association was observed between maternal TG, TC, LDL-C levels, and risk of SGA. Additionally, mothers with higher HDL-C levels were less likely to give birth to an LGA infant (OR=0.58, 95% CI:0.39-0.85). Importantly, associations between TG, TC, LDL-c, and SGA as well as between TG and LGA were primarily observed among pregnant women with insufficient vitamin D levels. As for HDL-C, the risk of LGA was lower in mothers with sufficient vitamin D (OR = 0.42, 95% CI:0.18-0.98) compared to those with insufficient vitamin D (OR = 0.65, 95% CI:0.42-0.99). Conclusion: Vitamin D status during the second trimester exerts a modifying effect on the association between lipid profiles and the risk of LGA and SGA infants.
Assuntos
Recém-Nascido Pequeno para a Idade Gestacional , Lipídeos , Segundo Trimestre da Gravidez , Vitamina D , Humanos , Feminino , Gravidez , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Adulto , Vitamina D/sangue , Segundo Trimestre da Gravidez/sangue , Estudos Retrospectivos , Recém-Nascido , Lipídeos/sangue , Peso ao Nascer , Macrossomia Fetal/sangue , Macrossomia Fetal/epidemiologia , Macrossomia Fetal/etiologia , Fatores de Risco , Complicações na Gravidez/sangue , Complicações na Gravidez/epidemiologiaRESUMO
Objective: Although the incidence of bloodstream infection (BSI) during pregnancy is relatively low, it can lead to unfavorable outcomes. The aim of our study was to analyze the clinical and microbiological characteristics of maternal bacteremia and to assess maternal and fetal outcomes. Methods: Our study was a retrospective study conducted in a tertiary women and children's hospital in Guangzhou, China, from 2013 to 2022. Data were extracted from medical records and the laboratory information system. The participants were divided into groups, and the difference between the groups was analyzed. Results: The incidence of maternal BSI during the 10 years study period was 10.2 cases/10,000 maternities, with a peak found from 2014 to 2016. Escherichia coli (48%) was the predominant causative pathogen, followed by Streptococcus agalactiae (13%). Gestational diabetes mellitus (GDM) (15%) was the most common underlying condition among maternal BSI episodes. Urinary tract (13%) and genital tract (28%) were the predominant source of BSI. About 14% of neonates were infected, and BSI was the most common type of infection. E. coli was the predominant pathogen in mother-neonate pairs with concurrent BSI. Premature rupture of membranes (PROM, OR:4.68) and preterm birth (OR:3.98) were the risk factors predicting neonatal infection. More than 85% of the E. coli were resistant to ampicillin (AMP) and 50% of the E. coli were extended-spectrum ß-lactamase (ESBL)-producing bacteria. Conclusion: Maternal BSI is a rare event, but continuous monitoring on the aspects of pathogen composition, antimicrobial resistance characteristics, and risk factors for adverse outcomes remains necessary to further reduce poor outcomes and mitigate bacterial resistance.
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Evidence suggests a potential relationship between gestational weight gain (GWG) and adverse birth outcomes. However, the role of maternal genetic polymorphisms remains unclear. This study was conducted to investigate whether the relationship of GWG with risk of adverse birth outcomes was modified by methylenetetrahydrofolate reductase (MTHFR) polymorphisms. A total of 2,967 Chinese pregnant women were included and divided into insufficient, sufficient, and excessive groups based on the Institute of Medicine (IOM) criteria. Polymorphisms of C677T and A1298C in gene MTHFR were genotyped. Multivariable logistic regression models were introduced after controlling major confounders. Excessive GWG was found to increase the odds ratio (OR) for macrosomia [OR = 3.47, 95% confidence interval (CI): 1.86-6.48] and large-for-gestational age (LGA, OR = 3.25, 95% CI: 2.23-4.74), and decreased the OR for small-for-gestational age (SGA, OR = 0.60, 95% CI: 0.45-0.79). Pregnant women with insufficient GWG had a higher frequency of SGA (OR = 1.68, 95% CI: 1.32-2.13) and a lower rate of LGA (OR = 0.51, 95% CI: 0.27-0.96). Interestingly, significant associations of GWG categories in relation to low birth weight (LBW), macrosomia, and SGA were only suggested among pregnant women with MTHFR A1298C AA genotype. Among pregnant women with insufficient GWG group, an increased risk of 3.96 (95% CI: 1.57-10.01) for LBW was observed among subjects with the A1298C AA genotype, compared to the AC+CC genotype group. GWG categories are closely related to LBW, macrosomia, SGA and LGA, and the associations were modified by the polymorphism of MTHFR A1298C.
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Background: Ovarian cancer (OC) is the most lethal malignancy among gynecological cancers worldwide. It is urgent to identify effective biomarkers for the prognosis and diagnosis of OC. Methods: We analyzed 4 OC Gene Expression Omnibus (GEO) data sets to detect differentially expressed genes (DEGs). To explore potential correlations between the gene sets and clinical features, we conducted weighted gene co-expression network analysis (WGCNA). Hub genes were identified from the key modules by univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses and risk scores were calculated based on the expressions of the hub genes. Univariate and multivariate Cox regression analyses were conducted to determine the values of the diagnoses for OC patients. We also determined the predictive value of the long non-coding RNA (lncRNA) score in response to immunotherapy and chemotherapeutic drugs. Results: DEGs were analyzed between the OC and normal ovarian tissues and prognostic modules were identified by a WGCNA. Nine hub genes chose from the prognostic modules were determined the prognostic values in OC. The risk scores were calculated based on the expression of hub genes, and patients with high-risk scores had poor survival. Univariate and multivariate Cox regression analyses showed that the risk score was an independent prognostic factor for OC. Additionally, the levels of hub genes were also found to be related to immune cell inï¬ltration in OC microenvironments. An immunotherapy cohort showed that high-risk scores enhanced the response to anti-programmed death-ligand 1 (PD-L1) immunotherapy and was remarkably correlated with the inflamed immune phenotype, and had significant therapeutic advantages and clinical benefits. Further, patients with high-risk scores were more sensitive to midostaurin. Conclusions: We identiï¬ed the risk score including protein phosphatase, Mg2+/Mn2+ dependent 1K (PPM1K), protein phosphatase 1 catalytic subunit alpha (PPP1CA), exostosin glycosyltransferase 1 (EXT1), RAB GTPase activating protein 1 like (RABGAP1L), mitotic arrest deficient 2 like 1 (MAD2L1), xeroderma pigmentosum complementation group C (XPC), Egl-9 family hypoxia inducible factor 3 (EGLN3), cyclin D1 binding protein 1 (CCNDBP1), and zinc finger protein 25 (ZNF25), and validated their prognostic and predicted values for OC.
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As an important second messenger, calcium (Ca2+) regulates a wide variety of physiological processes. Disturbance of intracellular calcium homeostasis implicated in the occurrence of multiple types of diseases. Orai1 is the major player in mediating store-operated calcium entry (SOCE) and regulates calcium homeostasis in non-excitable cells. Over-expression and activation of Orai1 have been reported in breast cancer. However, its molecular mechanisms are still not very clear. Here, we demonstrated that Nucleolin (NCL) was a novel interacting partner of Orai1. NCL is a multifunctional nucleocytoplasmic protein and is upregulated in human breast tumors. The binding of C-termini of NCL (NCL-CT) to N-termini of Orai1 (Orai1-NT) is critical for mediating calcium influx and proliferation of breast cancer cells. Blocking the NCL-Orai1 interaction by synthesized Orai1 peptide can effectively reduce the intracellular calcium influx and suppress the proliferation of breast cancer cells in vitro and in vivo. Our findings reveal a novel activation mechanism of Orai1 via direct interaction with NCL, which may lead to calcium homeostasis imbalance and promote the proliferation of breast cancer cells. Blocking NCL-Orai1 interaction might be an effective treatment of breast cancer.
RESUMO
PURPOSE: Cervical cancer is the fourth most common cancer in women worldwide and is the main cause of cancer-related deaths in women. Cisplatin (DDP) is one of the major chemotherapeutic drugs for cervical cancer patients. But, drug resistance limits the effectiveness of cancer therapy. Nucleolin (NCL) is a nucleocytoplasmic multifunctional protein involved in the development of cancer. It has been reported that NCL may be a potential target for modulation of drug resistance. However, the precise molecular mechanisms are poorly understood. MATERIALS AND METHODS: Human cervical cancer Hela cells and their cisplatin-resistant cell line Hela/DDP were used in this study. The protein level of NCL in cervical cancer cells was measured by western blot analysis. Hela cells and Hela/DDP cells were transfected with NCL overexpression plasmid or NCL siRNA separately. MTT and EdU assay were performed to evaluate the cell viability and sensitivity to cisplatin. The drug efflux function of MDR1 protein was assessed by intracellular rhodamine-123 accumulation assay.The promoter activity of MDR1 was assessed by using a dual-luciferase reporter assay. RESULTS: We found that the protein level of NCL was elevated in Hela/DDP cells. Overexpression of NCL increased cervical cancer cell proliferation and attenuated the sensitivity to cisplatin. Overexpression of NCL increased Multidrug resistance (MDR1) gene expression and drug efflux. Our results demonstrated that NCL was highly related with cisplatin resistance in cervical cancer. NCL played an important role in MDR1 gene transcription through regulation of the transcription factor YB1. CONCLUSION: Our findings revealed the novel role of NCL in cisplatin-resistant cervical cancer and NCL may be a potential therapeutic target for chemoresistance.