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OBJECTIVE: To determine the association between maternal blood glucose patterns throughout pregnancy and neonatal amino acids and acylcarnitines. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study involving 11,457 singleton pregnant women without preexisting diabetes from the Beijing Birth Cohort Study, along with their neonates born between July 2021 and October 2022 in Beijing, China. Distinct maternal glucose trajectories were identified using a latent class model based on blood glucose levels across the three trimesters, and their association with neonatal circulating metabolites, including 11 amino acids and 33 acylcarnitines, was examined, adjusting for potential confounding factors. RESULTS: Three distinct groups of maternal glucose trajectories were identified: consistent normoglycemia (n = 8,648), mid-to-late gestational hyperglycemia (n = 2,540), and early-onset hyperglycemia (n = 269). Mid-to-late gestational hyperglycemia was associated with decreased levels of amino acids (alanine, arginine, ornithine, and proline) involved in the arginine and proline metabolism and urea cycle pathway, as well as increased levels of C4DC+C5-OH and decreased level of C6DC and C10:1. Early-onset hyperglycemia was associated with elevated levels of free acylcarnitine and C4DC+C5-OH and a decreased level of C10:1, involved in the fatty acid oxidation pathway. However, these associations were primarily observed in male neonates rather than in female neonates. CONCLUSIONS: Our findings revealed a significant link between maternal glucose trajectories throughout pregnancy and neonatal arginine and proline metabolism, urea cycle pathway, and fatty acid oxidation pathway. These results highlight the importance of maintaining optimal blood glucose levels throughout pregnancy to promote healthy neonatal metabolic outcomes.
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The development of new electromagnetic absorbing materials is the main strategy to address electromagnetic radiation. Once traditional electromagnetic wave-absorbing materials are prepared, it is difficult to dynamically change their electromagnetic wave-absorbing performance. Facing the complexity of the information age and the rapid development of modern radar, it is significant to develop intelligent modulation of electromagnetic wave-absorbing materials. Here, CNTs/VO2/ANF composite aerogels with dynamic frequency tunability and switchable absorption on/off were synthesized. Based on the phase change behavior of VO2, the degree of polarization and interfacial effects of multiple heterogeneous interfaces between VO2 and CNTs and aramid nanofibers (ANFs) were modulated at different temperatures. With the increase in temperature (from 25 to 200 °C), the maximum absorption frequency of the frequency tunable aerogel is modulated from 12.24 to 8.56 GHz in the X-band, and the absorption intensity remains stable. The maximum effective switching bandwidth (ΔEAB) of the wave-absorbing switchable aerogel is 3.70 GHz. This study provides insights into intelligent electromagnetic wave absorption performance and paves the way for temperature-driven application of intelligent modulation of electromagnetic absorbers.
Subject(s)
Brain Stem , COVID-19 , Humans , COVID-19/complications , Brain Stem/diagnostic imaging , Brain Stem/pathology , Spinal Cord/diagnostic imaging , Spinal Cord/blood supply , SARS-CoV-2 , Male , Infarction/etiology , Infarction/diagnostic imaging , Brain Stem Infarctions/etiology , Brain Stem Infarctions/diagnostic imaging , Middle Aged , Magnetic Resonance ImagingABSTRACT
PURPOSE: Cerebral edema (CE) is the main secondary injury following traumatic brain injury (TBI) caused by road traffic accidents (RTAs). It is challenging to be predicted timely. In this study, we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries. METHODS: This case-control study included 218 patients with TBI caused by RTAs. The cohort was divided into CE and non-CE groups, according to CT results within 7 days. Demographic data, imaging data, and clinical data were collected and analyzed. Quantitative variables that follow normal distribution were presented as mean ± standard deviation, those that do not follow normal distribution were presented as median (Q1, Q3). Categorical variables were expressed as percentages. The Chi-square test and logistic regression analysis were used to identify risk factors for CE. Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries. The efficacy of the model was evaluated using the receiver operator characteristic curve. RESULTS: According to the study, almost half (47.3%) of the patients were found to have CE. The risk factors associated with CE were bilateral frontal lobe contusion, unilateral frontal lobe contusion, cerebral contusion, subarachnoid hemorrhage, and abbreviated injury scale (AIS). The odds ratio values for these factors were 7.27 (95% confidence interval (CI): 2.08 - 25.42, p = 0.002), 2.85 (95% CI: 1.11 - 7.31, p = 0.030), 2.62 (95% CI: 1.12 - 6.13, p = 0.027), 2.44 (95% CI: 1.25 - 4.76, p = 0.009), and 1.5 (95% CI: 1.10 - 2.04, p = 0.009), respectively. We also observed that patients with mild/moderate TBI (AIS ≤ 3) had a 50% probability of developing CE 19.7 h after injury (χ2 = 13.82, adjusted R2 = 0.51), while patients with severe TBI (AIS > 3) developed CE after 12.5 h (χ2 = 18.48, adjusted R2 = 0.54). Finally, we conducted a receiver operator characteristic curve analysis of CE time, which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI, respectively. CONCLUSION: Our study found that the onset of CE in individuals with TBI resulting from RTAs was correlated with the severity of the injury. Specifically, those with more severe injuries experienced an earlier onset of CE. These findings suggest that there is a critical time window for clinical intervention in cases of CE secondary to TBI.
Subject(s)
Accidents, Traffic , Brain Edema , Brain Injuries, Traumatic , Humans , Brain Injuries, Traumatic/complications , Risk Factors , Male , Female , Case-Control Studies , Brain Edema/etiology , Brain Edema/diagnostic imaging , Adult , Middle Aged , Logistic ModelsABSTRACT
Encapsulating nanomaterials in carbon is one of the main ways to increase the cathode stability, but it is difficult to simultaneously optimize the rate capacity and enhance durability derived from the insufficient ion transport channels and deficient ion adsorption sites that constipate the ion transport and pseudocapacitive reaction. Herein, we develop the ligand-confined growth strategy to encapsulate the nano-Na3V2(PO4)3 cathode material in various carbon channels (microporous, mesoporous, and macroporous) to discriminate the optimal carbon channels for synchronously improving rate capacity and holding the high-rate cycle stability. Benefiting from the unobstructed ion/charge transport channels and flexible maskant created by the interconnected mesoporous carbon channels, the prepared Na3V2(PO4)3 nanoparticles confined in mesoporous carbon channel (Mes-NVP/C) achieve a discharge-specific capacity of 70 mAh g-1 even at the ultrahigh rate of 100 C, higher than those of the Na3V2(PO4)3 nanoparticles confined in microporous and macroporous carbon channel (Micr-NVP/C and Macr-NVP/C), respectively. Significantly, the capacity retention rate of Mes-NVP/C after 5000 cycles at 20 C is as high as 90.48%, exceeding most of the reported work. These findings hold great promise for traditional cathode materials to synergistically realize fast charging ability and long cycle life.
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OBJECTIVES: To investigate if spatial recurrence pattern is associated with patient prognosis, and whether MRI vascular habitats can predict spatial pattern. METHODS: In this retrospective study, 69 patients with locally recurrent high-grade gliomas (HGGs) were included. The cohort was divided into intra-resection cavity recurrence (ICR) and extra-resection cavity recurrence (ECR) patterns, according to the distance between the location of the recurrent tumor and the resection cavity or surgical region. Four vascular habitats, high angiogenic tumor, low angiogenic tumor, infiltrated peripheral edema, and vasogenic peripheral edema, were segmented and vascular heterogeneity parameters were analyzed. The survival and diagnostic performance under different spatial recurrence patterns were analyzed by Kaplan-Meier and ROC. A nomogram model was constructed by regression analysis and validated by bootstrapping technique. RESULTS: Progression-free survival (PFS) and overall survival (OS) were longer for ICR (n = 32) than those for ECR (n = 37) (median PFS: 8 vs. 5 months, median OS: 17 vs. 13 months, p < 0.05). MRI vascular habitat analyses showed ECR had higher median relative cerebral blood volume (rCBVmedian) at each habitat than ICR (all p < 0.01). The rCBVmedian at IPE had good diagnostic performance (AUC: 0.727, 95%CI: 0.607, 0.828). The AUC of the nomogram based on MRI vascular habitats and clinical factors was 0.834 (95%CI: 0.726, 0.913) and was confirmed as 0.833 (95%CI: 0.830, 0.836) by bootstrapping validation. CONCLUSIONS: The spatial pattern of locally recurrent HGGs is associated with prognosis. MRI vascular heterogeneity parameter could be used as a non-invasive imaging marker to predict spatial recurrence pattern. CLINICAL RELEVANCE STATEMENT: Vascular heterogeneity parameters based on MRI vascular habitat analyses can non-invasively predict the spatial patterns of locally recurrent high-grade gliomas, providing a new diagnostic basis for clinicians to develop the extent of surgical resection and postoperative radiotherapy planning. KEY POINTS: ⢠Intra-resection cavity pattern was associated with longer progression-free survival and overall survival in locally recurrent high-grade gliomas. ⢠Higher vascular heterogeneities in extra-resection cavity recurrence than in intra-resection cavity recurrence and the vascular heterogeneity parameters had good diagnostic performance in discriminating spatial recurrence pattern. ⢠A nomogram model based on MRI vascular habitats and clinical factors had good performance in predicting spatial recurrence pattern.
Subject(s)
Brain Neoplasms , Glioma , Humans , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Retrospective Studies , Glioma/diagnostic imaging , Glioma/surgery , Magnetic Resonance Imaging/methods , EdemaABSTRACT
Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of mature T-cell malignancies. The efficacy of current first-line treatment is dismal, and novel agents are urgently needed to improve patient outcomes. A close association between the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and tumor promotion exists, revealing prospective therapeutic targets. This study, investigates the role of the cGAS-STING pathway and its underlying mechanisms in PTCL progression. Single-cell RNA sequencing showes that the cGAS-STING pathway is highly expressed and closely associated with PTCL proliferation. cGAS inhibition suppresses tumor growth and impaires DNA damage repair. Moreover, Cdc2-like kinase 1 (CLK1) is critical for residual tumor cell survival after treatment with cGAS inhibitors, and CLK1 suppression enhances sensitivity to cGAS inhibitors. Single-cell dynamic transcriptomic analysis indicates reduced proliferation-associated nascent RNAs as the underlying mechanism. In first-line therapy, chemotherapy-triggered DNA damage activates the cGAS-STING pathway, and cGAS inhibitors can synergize with chemotherapeutic agents to kill tumors. The cGAS-STING pathway is oncogenic in PTCL, whereas targeting cGAS suppresses tumor growth, and CLK1 may be a sensitivity indicator for cGAS inhibitors. These findings provide a theoretical foundation for optimizing therapeutic strategies for PTCL, especially in patients with relapsed/refractory disease.
Subject(s)
Lymphoma, T-Cell, Peripheral , Humans , Nucleotidyltransferases , Cell Survival , Cell Transformation, Neoplastic , DNA DamageABSTRACT
[This corrects the article DOI: 10.7150/thno.44427.].
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Bromochloroacetamide (BCAcAm) is the main haloacetamide (HAcAm) detected in drinking water in different regions and exhibits strong cytotoxicity and genotoxicity. However, there is no appropriate method for detecting BCAcAm in urine or other biological samples, and thus, the internal exposure level in the population cannot be accurately assessed. In this study, a gas chromatography-electron capture detector (GC-ECD) was combined with salting-out assisted dispersive liquid-liquid microextraction (SA-DLLME) to develop a rapid and robust method for BCAcAm detection in urine of mice continuously exposed to BCAcAm. The factors influencing the pre-treatment procedure, including the type and volume of extraction and disperser solvents, extraction and standing time, and the amount of salt, were evaluated systematically. Under the optimised conditions, the analyte achieved good linearity in the spiked concentration range of 1.00-400.00 µg L-1, and the correlation coefficient was higher than 0.999. The limit of detection (LOD) and the limit of quantification (LOQ) were 0.17 µg L-1 and 0.50 µg L-1, respectively. The recoveries ranged from 84.20% to 92.17%. The detection of BCAcAm at three different calibration levels using this method afforded an intra-day precision of 1.95-4.29%, while the inter-day precision range was 5.54-9.82% (n = 6). This method has been successfully applied to monitor the concentration of BCAcAm in mouse urine in toxicity experiments and can provide technical support for assessing human internal exposure levels and health risks in later studies.
Subject(s)
Liquid Phase Microextraction , Humans , Mice , Animals , Liquid Phase Microextraction/methods , Solvents/chemistry , Chromatography, Gas/methods , Limit of Detection , Sodium ChlorideABSTRACT
BACKGROUND: The intratumoral heterogeneity of high-grade gliomas (HGGs) is associated with isocitrate dehydrogenase (IDH) status and prognosis, which can be established by quantitative radioanalysis of spatial tumor habitats. Therefore, we designed a framework for tackling tumors based on spatial metabolism using the hemodynamic tissue signature (HTS), focusing on metabolic changes in tumor habitat to predict IDH status and assess prognosis in patients with HGG. METHODS: Preoperative data for 121 patients with HGG with subsequent histologic confirmation of HGG were prospectively collected (January 2016 to December 2020). The HTS was mapped from the image data, chemical shift imaging voxels were selected from the HTS habitat as the region of interest, and the metabolic ratio of the HTS was calculated using weighted least square method fitting. The metabolic rate of the tumor enhancement area was used as a control to analyze the efficacy of each HTS metabolic rate in predicting the IDH status and prognosis of HGG. RESULTS: Total choline (Cho)/total creatine and Cho/N-acetyl-aspartate showed significant differences between IDH-wildtype and IDH-mutant in high- and low-angiogenic enhanced tumor sites (P < 0.05); Cho/total creatine was an independent risk factor for prognosis of HGG patients in high-angiogenic enhanced tumor habitats, with significant differences in survival time between groups (P < 0.05). The metabolic ratio in the tumor enhanced area could not predict IDH status or evaluate prognosis. CONCLUSIONS: Spectral analysis based on hemodynamic habitat imaging can clearly distinguish IDH mutations and the prognosis assessment is more accurate, rendering it superior to traditional spectral analysis in tumor enhancement areas.
Subject(s)
Brain Neoplasms , Glioma , Humans , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Creatine , Glioma/diagnostic imaging , Glioma/genetics , Glioma/metabolism , Prognosis , Magnetic Resonance Imaging/methods , Mutation , HemodynamicsABSTRACT
Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive amino acid metabolic disease. This study is to identify the pathogenic genetic factors of six cases of MUSD and evaluates the application value of high-throughput sequencing technology in the early diagnosis of MUSD. Methods: Clinical examination was carried out for patients and used blood tandem mass spectrometry (MS/MS), urine gas chromatography-mass spectrometry (GC/MS), and the application of high-throughput sequencing technology for detection. Validate candidate mutations by polymerase chain reaction (PCR)-Sanger sequencing technology. Bioinformatics software analyzed the variants' pathogenicity. Using Swiss PDB Viewer software to predict the effect of mutation on the structure of BCKDHA and BCKDHB proteins. Result: A total of six MSUD patients were diagnosed, including four males and two females. Nine variants were found in three genes of six MSUD families by high-throughput sequencing, including four missense mutations: c.659C>T(p.A220V), c.818C>T(p.T273I), c.1134C>G(p.D378E), and c.1006G>A(p.G336S); two non-sense mutations: c.1291C>T(p.R431*) and c.331C>T(p.R111*); three deletion mutations: c.550delT (p.S184Pfs*46), c.718delC (p.P240Lfs*14), and c.795delG (p.N266Tfs*64). Sanger sequencing's results were consistent with the high-throughput sequencing. The bioinformatics software revealed that the mutations were harmful, and the prediction results of Swiss PDB Viewer suggest that variation affects protein conformation. Conclusion: This study identified nine pathogenic variants in the BCKDHA, BCKDHB, and DBT genes in six MSUD families, including two novel pathogenic variants in the BCKDHB gene, which enriched the genetic mutational spectrum of the disease. High-throughput sequencing is essential for the MSUD's differential diagnosis, early treatment, and prenatal diagnosis.
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BACKGROUND: The currently preferred minimally invasive approaches have substantially improved outcomes of infected walled-off pancreatic necrosis (iWON). However, iWON with deep extension (iWONde) still poses a tricky challenge for sufficient necrosis evacuation by one stand-alone approach, often requiring repeated interventions. The aim of this study was to assess the effectiveness and safety of a minimal-access video-assisted retroperitoneal and/or transperitoneal debridement (hereafter called VARTD) in the management of iWONde. METHODS: Patients who had developed an iWONde were recruited to receive the VARTD in this prospective single-arm study. The primary efficacy endpoint was clinical improvement up to day 28 after the VARTD, defined as a ≥ 75% reduction in size of necrotic collection (in any axis) on CT and clinical resolution of sepsis or organ dysfunction. The primary safety endpoint was a composite of major complications or death during follow-up. Six-month postdischarge follow-up was available. RESULTS: Between July 18, 2018, and November 12, 2020, we screened 95 patients with necrotizing pancreatitis; of these, 21 iWONde patients (mean [SD] age, 42.9 [11.7] years; 10 [48%] women) were finally enrolled. The primary efficacy endpoint was achieved by most participants (14/21, 67%). No participants required repeated interventions. The primary safety endpoint occurred in six patients (29%). Except one in-hospital death attributable to repeated intra-abdominal hemorrhage, others were discharged without any major complication. CONCLUSIONS: The VARTD approach appears to have a reasonable efficacy with acceptable complication rates and thus might be an option for improving clinical management of iWONde. TRIAL REGISTRATION: This study is registered with Chinese Clinical Trial Registry (chictr.org.cn number, ChiCTR1800016950).
Subject(s)
Pancreatitis, Acute Necrotizing , Adult , Female , Humans , Male , Aftercare , Debridement , Drainage , Hospital Mortality , Pancreatitis, Acute Necrotizing/surgery , Patient Discharge , Prospective Studies , Treatment Outcome , Video-Assisted SurgeryABSTRACT
S-adenosyl-L-methionine (SAM), used in diverse pharmaceutical applications, was biosynthesized from L-methionine (L-met) and adenosine triphosphate (ATP). This study aims to increase the accumulation of SAM in Saccharomyces cerevisiae by promoting ATP availability. Strain ΔSOD1 was obtained from the parent strain WT15-33 (CCTCC M 2021915) by deleting gene sod1, which improved the supply of ATP. The SAM content in strain ΔSOD1 exhibited a 22.3% improvement compared to the parent strain, which reached 93.6 mg g-1. The transformation of NADH (reduced nicotinamide adenine dinucleotide) and the relative expression of ATPase essential genes were investigated, respectively. The results showed that the lack of gene sod1 benefited the generation of ATP, which positively regulated the synthesis of SAM. Besides that, the production of SAM was further enhanced by improving substrate assimilation. With the infusion of 1.44 g L-1L-met and 0.60 g L-1 adenosine at 24 h (h) and 0 h following fermentation, the optimum medium could produce 1.54 g L-1 SAM. Based on the regulations mentioned above, the SAM concentration of strain ΔSOD1 enhanced from 7.3 g L-1 to 10.1 g L-1 in a 5-L fermenter in 118 h. This work introduces a novel idea for the biosynthesis of ATP and SAM, and the strain ΔSOD1 has the potential for industrial production.
Subject(s)
S-Adenosylmethionine , Saccharomyces cerevisiae , Adenosine Triphosphate/metabolism , Fermentation , Methionine/metabolism , S-Adenosylmethionine/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Superoxide Dismutase-1ABSTRACT
Phytoextraction in phytoremediation is one of the environmentally friendly methods used for restoring soils contaminated by heavy metals (HMs). The screening and identification of HM-resistant plants and their regulatory genes associated with HM ion transport are the key research aims in this field. In this study, a plant cadmium (Cd) resistance (PCR) gene family member, SlPCR6, was identified in roots of Salix linearistipularis, which exhibits strong HM resistance. The results revealed that SlPCR6 expression was induced in S. linearistipularis roots in response to Cd stress. Furthermore, SlPCR6 was mainly localized on the plasma membrane. Compared with the wild type, SlPCR6 overexpression reduced the Cd and copper (Cu) contents in the transgenic poplar (84 K) and increased its Cd and Cu resistance. The roots of transgenic poplar seedlings had lower net Cd and Cu uptake rates than wild type roots. Further investigation revealed that the transcript levels of multiple HM ion transporters were not significantly different between the roots of the wild type and those of the transgenic poplar. These results suggest that SlPCR6 is directly involved in Cd and Cu transport in S. linearistipularis roots. Therefore, SlPCR6 can serve as a candidate gene to improve the phytoextraction of the HMs Cd and Cu through genetic engineering.
Subject(s)
Metals, Heavy , Populus , Salix , Soil Pollutants , Biodegradation, Environmental , Cadmium/metabolism , Copper/analysis , Metals, Heavy/analysis , Plant Roots/metabolism , Populus/genetics , Populus/metabolism , Salix/genetics , Salix/metabolism , Soil , Soil Pollutants/analysisSubject(s)
Encephalitis , Herpesvirus 1, Suid , Pseudorabies , Animals , Encephalitis/complications , Encephalitis/diagnostic imaging , HumansABSTRACT
This study aims to study the effects of extra arginine (Arg) supplementation during the suckling period on the weaning stress and intestinal barrier function of breastfed piglets. Forty 7-day-old breastfed piglets divided into the control group (CON) and Arg group (Arg) were fed with extra saline or Arg (250 mg per kg per d body weight), respectively. All piglets were weaned when they were 21 days old. Eight piglets from each group were sacrificed before weaning and on the 3rd-day after weaning, respectively. The results showed that Arg improved the average daily weight gain of piglets before weaning (P < 0.01) and decreased the average daily weight loss after weaning (P < 0.05). Weaning decreased the ratio of the villus length versus crypt depth (V/C) in the SI (P < 0.001), while Arg increased the V/C of the jejunum (P < 0.05). Arg increased the levels of immunoglobulins in the serum and SI (P < 0.05), decreased pro-inflammatory cytokines and increased anti-inflammatory cytokines in the SI (P < 0.05). In addition, Arg supplementation increased the numbers of SWC3a+CD40+ (P < 0.01) and SWC3a+SLAII+ DCs (P < 0.05), down-regulated Notch2 expression and up-regulated Jagged1 expression in the ilea of weaning piglets (P < 0.05). In conclusion, Arg supplementation during the suckling period decreased the LDH leakage in the SI, improved the intestinal morphology, down-regulated the contents of pro-inflammatory cytokines, accelerated the accumulation of DC precursors before weaning and increased the number of mature DCs after weaning, and thus improved the growth performance and reduced the weaning stress of piglets, and this might be associated with the regulation of Notch2 signaling.
Subject(s)
Arginine , Dietary Supplements , Animals , Arginine/metabolism , Arginine/pharmacology , Cytokines/metabolism , Dendritic Cells/metabolism , Diet , Intestinal Mucosa/metabolism , Swine , Weaning , Weight GainABSTRACT
Background: A tumor occurs because of abnormal cell multiplication caused by many variables like a significant disturbance in the regulation of cell growth and the instability of chromosome mitosis. Budding uninhibited by benzimidazoles 1 (BUB1), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), and budding uninhibited by benzimidazoles 3 (BUB3) are key regulators of mitosis, and their abnormal expression is highly correlated with breast cancer (BrCa), sarcoma, hepatic carcinoma, and other malignant tumors. However, the occurrence of BUBs (BUB1, BUB1B, and BUB3) and the development of BrCa have not been systematically explained. Methods: Find out the target gene by looking up literature on PubMed and CNKI. Using the R software, TCGA, GEO, Kaplan-Meier Plotter, TIMER, and other databases, we studied the level of transcription, genetic changes, and physiological functions of BUBs in BrCa patients and their relationship with the origin, development, prognosis, immunity, and drug resistance of BrCa patients. Findings. We found that the high expression level of BUBs in BrCa tissues proposed a poor prognosis. The multivariate Cox regression analysis suggested that BUB1B and BUB3 might be independent prognostic factors of BrCa. In addition, the Metascape functional enrichment analysis showed that BUBs may be involved in the composition of the spindle, chromosome, and other structures and play a role in mitosis, sister chromatid separation, and other processes. Pathway enrichment suggests that BUBs may affect the cell cycle and lead to abnormal proliferation. Meanwhile, we also found that BUB3 can negatively regulate B lymphocytes, and BUB1 and BUB1B inhibit immune responses by promoting the secretion level of checkpoint molecules of the immune system, leading to immune escape of tumor cells. Conclusion: We speculate that BUB1, BUB1B, and BUB3 may be therapeutic targets for BrCa patients and also provide new therapeutic strategies for BrCa treatment.
Subject(s)
Breast Neoplasms , Cell Cycle Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Benzimidazoles , Biomarkers , Breast Neoplasms/genetics , Carcinogenesis , Cell Cycle Proteins/genetics , Cell Transformation, Neoplastic , Female , Humans , Prognosis , Protein Serine-Threonine Kinases/geneticsABSTRACT
BACKGROUND: Childhood obesity places a major burden on global public health. We aimed to identify and characterize potential factors, both individually and jointly, in association with overweight and obesity in Chinese preschool-aged children. METHODS: We cross-sectionally recruited 9501 preschool-aged children from 30 kindergartens in Beijing and Tangshan. Overweight and obesity are defined according to the World Health Organization (WHO), International Obesity Task Force (IOTF), and China criteria. RESULTS: After multivariable adjustment, eating speed, sleep duration, birthweight, and paternal body mass index (BMI) were consistently and significantly associated with childhood overweight and obesity under three growth criteria at a significance level of 5%. Additional fast food intake frequency, maternal BMI, gestational weight gain (GWG) and maternal pre-pregnancy BMI were significant factors for overweight (WHO criteria) and obesity (both IOTF and China criteria). Importantly, there were significant interactions between parental obesity and eating speed for childhood obesity. Finally, for practical reasons, risk nomogram models were constructed for childhood overweight and obesity based on significant factors under each criterion, with good prediction accuracy. CONCLUSION: Our findings indicated a synergistic association of lifestyle, fetal and neonatal, and family-related factors with the risk of experiencing overweight and obesity among preschool-aged children.
Subject(s)
Gestational Weight Gain , Pediatric Obesity , Body Mass Index , Child , Child, Preschool , China/epidemiology , Female , Humans , Infant, Newborn , Overweight/epidemiology , Overweight/etiology , Pediatric Obesity/epidemiology , Pediatric Obesity/etiology , Pregnancy , Risk FactorsABSTRACT
BACKGROUND: Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease (AD). However, there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology. We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans. METHODS: We enrolled a group of cognitively normal patients (median age: 64 years) with unilateral chronic cerebral hypoperfusion. Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion. 11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient. RESULTS: The median age of the 10 participants, consisting of 4 males and 6 females, was 64 years (47-76 years). We found that there were no differences in standard uptake ratios of the cortex (volume of interest [VOI]: Pâ=â0.721, region of interest [ROI]: Pâ=â0.241) and grey/white ratio (VOI: Pâ=â0.333, ROI: Pâ=â0.445) and brain atrophy indices (Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular index, Pâ>â0.05) between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion. CONCLUSION: Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebral ß-amyloid deposition and neurodegeneration in humans.
Subject(s)
Alzheimer Disease , Cerebrovascular Circulation , Aged , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Arteries , Atrophy , Brain/metabolism , Cerebral Cortex/metabolism , Constriction, Pathologic/pathology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Positron-Emission Tomography/methodsABSTRACT
Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146Rin vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.