RESUMO
Smooth muscle cell-specific myosin heavy chain, encoded by MYH11 , is selectively expressed in smooth muscle cells ( SMC s). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11 E1892D/E1892D mice. Wild-type ( WT ) and mutant mice underwent cardiovascular phenotyping and with transverse aortic constriction ( TAC ). Myh11 E1892D/E1892D and WT mice displayed similar growth, blood pressure, root and ascending aortic diameters, and cardiac function up to 13 months of age, along with similar contraction and relaxation on myographic testing. TAC induced hypertension similarly in Myh11 E1892D/E1892D and WT mice, but mutant mice showed augmented ascending aortic enlargement and increased elastic fragmentation on histology. Unexpectedly, male Myh11 E1892D/E1892D mice two weeks post-TAC had decreased ejection fraction, stroke volume, fractional shortening, and cardiac output compared to similarly treated male WT mice. Importantly, left ventricular mass increased significantly due to primarily posterior wall thickening, and cardiac histology confirmed cardiomyocyte hypertrophy and increased collagen deposition in the myocardium and surrounding arteries. These results further highlight the clinical heterogeneity associated with MYH11 rare variants. Given that MYH11 is selectively expressed in SMCs, these results implicate a role of vascular SMCs in the heart contributing to cardiac hypertrophy and failure with pressure overload. Author Summary: In this study, we explore the impact of a specific genetic variant, MYH11 p.Glu1892Asp, on the heart and blood vessels in mice. The MYH11 gene is crucial for smooth muscle cells, which are found in the walls of blood vessels and play an important role in various vascular diseases. We created mice with this genetic variant to see if it would lead to thoracic aortic disease, a condition affecting the main artery from the heart. We found that mice with the variant were similar to normal mice in many aspects, such as growth, blood pressure, and heart function, for up to 13 months. However, when we induced high blood pressure in the mice, the mutant mice showed more significant enlargement of the aorta and damage to the elastic fibers in the aortic walls. Interestingly, male mutant mice also developed heart problems, such as reduced heart pumping ability and increased heart muscle thickness, after the high blood pressure challenge. This was accompanied by signs of heart muscle cell enlargement and increased tissue stiffness. These findings suggest that this rare MYH11 variant can contribute to a range of heart and vascular issues, particularly under conditions of pressure overload, and highlight the importance of smooth muscle cells in the development of these problems.
RESUMO
Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) were found in complex forms of familial Parkinsonism. However, the Synj1-regulated molecular and cellular changes associated with dopaminergic dysfunction remain unknown. We now report a fast depletion of evoked dopamine and impaired maintenance of the axonal dopamine transporter (DAT) in the Synj1 haploinsufficient (Synj1+/-) neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we provide in vitro and in vivo evidence demonstrating that Synj1 haploinsufficiency results in an increase of total DAT but a reduction of the surface DAT. Synj1+/- neurons exhibit maladaptive DAT trafficking, which could contribute to the altered DA release. We showed that the loss of surface DAT is associated with the impaired 5'-phosphatase activity and the hyperactive PI(4,5)P2-PKCß pathway downstream of Synj1 deficiency. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling, which might be relevant to early Parkinsonism.
RESUMO
The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.
RESUMO
Objective: Recurrent pregnancy loss (RPL) presents a formidable challenge for individuals undergoing in vitro fertilization-embryo transfer (IVF-ET), forming both a clinical dilemma and a focal point for scientific inquiry. This study endeavors to investigate the intricate interplay between clinical features, such as age, body mass index (BMI), and waist-to-hip ratio (WHR), and routine laboratory parameters, including sex hormones, blood composition, liver and thyroid functions, thyroid antibodies, and coagulation indicators, in RPL patients undergoing IVF-ET. By meticulously analyzing these variables, we aim to uncover the latent risk factors predisposing individuals to RPL. Identifying potential factors such as advanced maternal age, obesity, and insulin resistance will provide clinicians with vital insights and empirical evidence to strengthen preventive strategies aimed at reducing miscarriage recurrence. Methods: This retrospective case-controlled study included RPL patients who underwent IVF-ET treatment at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2012 and March 2021 as the case cohort, compared with women receiving assisted reproductive treatment due to male infertility as the control cohort. The fasting peripheral blood was collected 5 days before the first menstrual cycle at least 12 weeks after the last abortion. The clinical characteristics and relevant laboratory indexes of the two groups were compared. Employing both univariate and multivariate logistic regression analyses, we sought to unearth potential high-risk factors underlying RPL. Additionally, a linear trend analysis was conducted to assess the linear relationship between total testosterone (TT) levels and the number of miscarriages. Results: In contrast to the control cohort, the RPL cohort exhibited significant increases in age, BMI, and WHR (P<0.05). Notably, TT levels were markedly lower in the RPL cohort (P=0.022), while no significant differences were observed between the two groups concerning basal follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin levels, and anti-Müllerian hormone levels (P>0.05). Moreover, fasting insulin (FINS) levels and HOMA-IR index were notably elevated in the RPL cohort relative to the control cohort (P<0.001), although no significant differences were observed in fasting blood glucose levels (P>0.05). Furthermore, the neutrophil (NEU) count and NEU-to-lymphocyte ratio were notably higher in the RPL cohort (P<0.01). Univariate logistic regression analysis identified several factors, including age≥35 years old, BMI≥25 kg/m2, WHR>0.8, FINS>10 mU/L, HOMA-IR>2.14, NEU count>6.3×109 Lï¼1, and an elevated NEU/lymphocyte ratio (NLR), as significantly increasing the risk of RPL (P<0.05). Although TT levels were within the normal range for both cohorts, higher TT levels were associated with a diminished RPL risk (odds ratio [OR]=0.67, 95% confidence interval [CI]: 0.510-0.890, P=0.005). After adjustments for confounding factors, age≥35 years old (OR=1.91, 95% CI: 1.06-3.43), WHR>0.8 (OR=2.30, 95% CI: 1.26-4.19), and FINS>10 mU/L (OR=4.50, 95% CI: 1.30-15.56) emerged as potent risk factors for RPL (P<0.05). Conversely, higher TT levels were associated with a reduced RPL risk (OR=0.59, 95% CI: 0.38-0.93, P=0.023). Furthermore, the linear trend analysis unveiled a discernible linear association between TT levels and the number of miscarriages (P trend=0.003), indicating a declining trend in TT levels with escalating miscarriage occurrences. Conclusion: In patients undergoing IVF-ET, advanced maternal age, lower TT levels, increased WHR, and elevated FINS levels emerged as potent risk factors for RPL. These findings provide clinicians with valuable insights and facilitate the identification of patients who are at high risks and the formulation of preventive strategies to reduce the recurrence of miscarriages.
Assuntos
Aborto Habitual , Transferência Embrionária , Fertilização in vitro , Humanos , Feminino , Fertilização in vitro/métodos , Aborto Habitual/etiologia , Aborto Habitual/sangue , Transferência Embrionária/métodos , Fatores de Risco , Estudos Retrospectivos , Gravidez , Estudos de Casos e Controles , Adulto , Índice de Massa Corporal , Resistência à Insulina , Obesidade , Idade Materna , MasculinoRESUMO
BACKGROUND: This study investigates the distribution and characteristics of linezolid and vancomycin susceptibilities among Enterococcus faecalis (E. faecalis) and Enterococcus faecium (E. faecium) and explores the underlying resistance mechanisms. METHODS: A total of 2842 Enterococcus clinical isolates from patients were retrospectively collected, and their clinical data were further analyzed. The minimum inhibitory concentrations (MICs) of vancomycin and linezolid were validated by broth dilution method. The resistance genes optrA, cfr, vanA, vanB and vanM were investigated using polymerase chain reaction (PCR). Housekeeping genes and resistance genes were obtianed through whole-genome sequencing (WGS). RESULTS: Of the 2842 Enterococcus isolates, 88.5% (2516) originated from urine, with E. faecium accounted for 60.1% of these. The vanA gene was identified in 27/28 vancomycin resistant Enterococcus (VRE) isolates, 4 of which carried both vanA and vanM genes. The remaining strain was vanM positive. The optrA gene was identified in all E. faecalis isolates among linezolid resistant Enterococcus (LRE). E. faecium showed a higher multiple antibiotic resistance index (MAR index) compared to E. faecalis. The multi-locus sequence typing (MLST) showed the sequence type of E. faecium mainly belongs to clonal complex (CC) 17, nearly E. faecalis isolates analyzed were differentiated into 7 characteristics of sequence types (STs), among which ST16 of CC16 were the major lineage. CONCLUSION: Urine was the primary source of VRE and LRE isolates in this study. E. faecium showed higher levels of resistance compared to E. faecalis. OptrA gene was detected in 91.6% of LRE, which could explain linezolid resistance, and van genes were detected in all vancomycin resistant Enterococcus strains, while vanA was a key resistance mechanism in VRE identified in this study.
Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Linezolida , Testes de Sensibilidade Microbiana , Linezolida/farmacologia , Humanos , China/epidemiologia , Enterococcus faecium/genética , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/isolamento & purificação , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Enterococcus faecalis/genética , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/isolamento & purificação , Feminino , Vancomicina/farmacologia , Antibacterianos/farmacologia , Epidemiologia Molecular , Adulto , Resistência a Vancomicina/genética , Idoso , Estudos Retrospectivos , Enterococos Resistentes à Vancomicina/genética , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/isolamento & purificação , Adulto Jovem , Enterococcus/genética , Enterococcus/efeitos dos fármacos , Enterococcus/isolamento & purificaçãoRESUMO
Background: Ovarian stimulation (OS) for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in women with PCOS often results in multiple follicular development, yet some individuals experience poor or suboptimal responses. Limited data exist regarding the impact of poor/suboptimal ovarian response on pregnancy outcomes in women with PCOS. Objectives: The aim of this study was to evaluate whether the live birth rate (LBR) per fresh embryo transfer and cumulative live birth rate (CLBR) per aspiration cycle differ in women with PCOS defined by the Patient-Oriented Strategy Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Methods: A retrospective study involving 2,377 women with PCOS who underwent their first IVF/ICSI cycle at Sun Yat-sen Memorial Hospital from January 2011 to December 2020 was used. Patients were categorized into four groups based on age, antral follicle count, and the number of oocytes retrieved, according to the POSEIDON criteria. The LBR and CLBR were compared among these groups. Logistic regression analysis was performed to assess whether the POSEIDON criteria served as independent risk factors and identify factors associated with POSEIDON. Results: For patients <35 years old, there was no significant difference in the clinical pregnancy rate between POSEIDON and non-POSEIDON patients, whereas POSEIDON patients exhibited lower rates of implantation and live birth. POSEIDON Group 1a displayed lower rates of implantation, clinical pregnancy, and live birth. However, no significant differences were observed in the rates of clinical pregnancy and live birth between POSEIDON Group 1b and non-POSEIDON groups. For patients ≥35 years old, there were no significant differences in the rates of implantation, clinical pregnancy, and live birth between POSEIDON and non-POSEIDON patients. CLBRs were significantly lower in POSEIDON Groups 1 and 2, compared with the non-POSEIDON groups. The levels of body mass index (BMI), follicle-stimulating hormone (FSH), and antral follicle count (AFC) were associated with POSEIDON hypo-response. POSEIDON was found to be associated with lower CLBR, but not LBR per fresh embryo transfer. Conclusions: In patients with PCOS, an unexpected suboptimal response can achieve a fair LBR per fresh embryo transfer. However, CLBR per aspirated cycle in POSEIDON patients was lower than that of normal responders. BMI, basal FSH level, and AFC were independent factors associated with POSEIDON. Our study provides data for decision-making in women with PCOS after an unexpected poor/suboptimal response to OS.
Assuntos
Coeficiente de Natalidade , Transferência Embrionária , Fertilização in vitro , Nascido Vivo , Indução da Ovulação , Síndrome do Ovário Policístico , Taxa de Gravidez , Humanos , Feminino , Estudos Retrospectivos , Adulto , Gravidez , Transferência Embrionária/métodos , Nascido Vivo/epidemiologia , Fertilização in vitro/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Resultado da Gravidez , Infertilidade Feminina/terapiaRESUMO
In brief: Ovarian aging results in reactive oxygen species accumulation and mitochondrial deterioration. During the aging process, GRSF1 deficiency attenuates mitochondrial function in aging granulosa cells. Abstract: Ovarian aging critically influences reproductive potential, with a marked decrease in oocyte quality and quantity and an increase in oxidative stress and mitochondrial dysfunction. This study elucidates the role of guanine-rich RNA sequence binding factor 1 (GRSF1) in the aging of ovarian granulosa cells (GCs). We observed a significant reduction in GRSF1 within GCs correlating with patient age, utilizing clinical samples from IVF patients. Using an siRNA-mediated knockdown technique, we established that diminished GRSF1 expression exacerbates mitochondrial dysfunction, elevates reactive oxygen species, and impairs ATP production. Furthermore, RNA immunoprecipitation revealed GRSF1's interaction with superoxide dismutase 2 (SOD2) mRNA, a key antioxidant enzyme, suggesting a mechanism whereby GRSF1 modulates oxidative stress. Downregulation of SOD2 reversed the protective effects of GRSF1 overexpression on mitochondrial function. These insights into the role of GRSF1 in ovarian aging may guide the development of interventions to improve fertility outcomes in advanced age.
Assuntos
Envelhecimento , Senescência Celular , Células da Granulosa , Mitocôndrias , Estresse Oxidativo , Espécies Reativas de Oxigênio , Feminino , Células da Granulosa/metabolismo , Humanos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/metabolismo , Adulto , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Células Cultivadas , Proteínas de Ligação a Poli(A)RESUMO
BACKGROUND: Malformations of cortical development (MCD) are a group of congenital disorders characterized by structural abnormalities in the brain cortex. The clinical manifestations include refractory epilepsy, mental retardation, and cognitive impairment. Genetic factors play a key role in the etiology of MCD. Currently, there is no curative treatment for MCD. Phenotypes such as epilepsy and cerebral palsy cannot be observed in the fetus. Therefore, the diagnosis of MCD is typically based on fetal brain magnetic resonance imaging (MRI), ultrasound, or genetic testing. The recent advances in neuroimaging have enabled the in-utero diagnosis of MCD using fetal ultrasound or MRI. METHODS: The present study retrospectively reviewed 32 cases of fetal MCD diagnosed by ultrasound or MRI. Then, the chromosome karyotype analysis, single nucleotide polymorphism array or copy number variation sequencing, and whole-exome sequencing (WES) findings were presented. RESULTS: Pathogenic copy number variants (CNVs) or single-nucleotide variants (SNVs) were detected in 22 fetuses (three pathogenic CNVs [9.4%, 3/32] and 19 SNVs [59.4%, 19/32]), corresponding to a total detection rate of 68.8% (22/32). CONCLUSION: The results suggest that genetic testing, especially WES, should be performed for fetal MCD, in order to evaluate the outcomes and prognosis, and predict the risk of recurrence in future pregnancies.
Assuntos
Variações do Número de Cópias de DNA , Diagnóstico Pré-Natal , Gravidez , Feminino , Humanos , Estudos Retrospectivos , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal/métodos , Testes Genéticos/métodosRESUMO
Background: Neuroimaging studies have suggested a pivotal role for the amygdala involvement in chronic low back pain (CLBP). However, the relationship between the amygdala subregions and CLBP has not yet been delineated. This study aimed to analyze whether the amygdala subregions were linked to the development of CLBP. Methods: A total of 45 patients with CLBP and 45 healthy controls (HCs) were included in this study. All subjects were asked to complete a three-dimensional T1-weighted magnetic resonance imaging (3D-T1 MRI) scan. FreeSurfer 7.3.2 was applied to preprocess the structural MRI images and segment the amygdala into nine subregions. Afterwards, comparisons were made between the two groups in terms of the volumes of the amygdala subregions. Correlation analysis is utilized to examine the relationship between the amygdala subregion and the scale scores, as well as the pain duration in patients with CLBP. Additionally, logistic regression was used to explore the risk of the amygdala and its subregions for CLBP. Results: In comparison to HCs, patients with CLBP exhibited a significant enlargement of the left central nucleus (Ce) and left cortical nucleus (Co). Furthermore, the increased volume of the left Ce was associated with a higher risk of CLBP. Conclusion: Our study suggests that the left Ce and left Co may be involved in the pathophysiological processes of CLBP. Moreover, the volume of the left Ce may be a biomarker for detecting the risk of CLBP.
RESUMO
Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the Synj1+/- neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured Synj1+/- neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity. We revealed that the loss of surface DAT is specifically associated with the impaired 5'-phosphatase activity of Synj1 and the hyperactive downstream PI(4,5)P2-PKCß pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling in early parkinsonism.
RESUMO
BACKGROUND: Despite regional brain structural changes having been reported in patients with chronic low back pain (CLBP), the topological properties of structural covariance networks (SCNs), which refer to the organization of the SCNs, remain unclear. This study applied graph theoretical analysis to explore the alterations of the topological properties of SCNs, aiming to comprehend the integration and separation of SCNs in patients with CLBP. METHODS: A total of 38 patients with CLBP and 38 healthy controls (HCs), balanced for age and sex, were scanned using three-dimensional T1-weighted magnetic resonance imaging. The cortical thickness was extracted from 68 brain regions, according to the Desikan-Killiany atlas, and used to reconstruct the SCNs. Subsequently, graph theoretical analysis was employed to evaluate the alterations of the topological properties in the SCNs of patients with CLBP. RESULTS: In comparison to HCs, patients with CLBP had less cortical thickness in the left superior frontal cortex. Additionally, the cortical thickness of the left superior frontal cortex was negatively correlated with the Visual Analogue Scale scores of patients with CLBP. Furthermore, patients with CLBP, relative to HCs, exhibited lower global efficiency and small-worldness, as well as a longer characteristic path length. This indicates a decline in the brain's capacity to transmit and process information, potentially impacting the processing of pain signals in patients with CLBP and contributing to the development of CLBP. In contrast, there were no significant differences in the clustering coefficient, local efficiency, nodal efficiency, nodal betweenness centrality, or nodal degree between the two groups. CONCLUSIONS: From the regional cortical thickness to the complex brain network level, our study demonstrated changes in the cortical thickness and topological properties of the SCNs in patients with CLBP, thus aiding in a better understanding of the pathophysiological mechanisms of CLBP.
Assuntos
Córtex Cerebral , Dor Crônica , Dor Lombar , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Dor Lombar/diagnóstico por imagem , Dor Lombar/patologia , Adulto , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Dor Crônica/diagnóstico por imagem , Dor Crônica/patologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologiaRESUMO
Background: Due to the complex histological type and anatomical structures, there has been considerable debate on the classification of adenocarcinoma of the esophagogastric junction (AEG), especially Siewert II AEG. Furthermore, neither the American Joint Committee on Cancer (AJCC) 7th tumor-node-metastasis (TNM) [esophageal adenocarcinoma (E) or gastric cancer (G)] nor the AJCC 8th TNM (E or G) accurately predicted the prognosis of patients with Siewert II AEG. Objective: This study aimed to investigate the factors influencing the survival and prognosis of patients with Siewert II AEG and establish a new and better prognostic predictive model. Design: A retrospective study. Methods: Patients with Siewert II AEG, retrieved from the Surveillance, Epidemiology, and End Results (SEER) databases, were assigned to the training set. Patients retrieved from a single tertiary medical center were assigned to the external validation set. Significant variables were selected using univariate and multivariate Cox regression analyses to construct the nomogram. Nomogram models were assessed using the concordance index (C-index), a calibration plot, decision curve analysis (DCA), and external validation. Results: Age, tumor grade, and size, as well as the T, N, and M stages, were included in the nomograms. For the SEER training set, the C-index of the nomogram was 0.683 (0.665-0.701). The C-index of the nomogram for the external validation set was 0.690 (0.653-0.727). The calibration curve showed good agreement between the nomogram estimations and actual observations in both the training and external validation sets. The DCA showed that the nomogram was clinically useful. Conclusion: The new predictive model showed significant accuracy in predicting the prognosis of Siewert II AEG.
RESUMO
Ecological stoichiometry is essential for understanding changes in ecosystem structure and nutrient cycling in forest ecosystems. However, the stoichiometric characteristics of carbon (C) and nitrogen (N) in different organs or layers, such as leaves, branches, trunks, roots, understory vegetation, litter, and soil within a forest ecosystem, have remained poorly understood. In this study, four age groups of Pinus massoniana natural forest including young, middle-aged, near-mature, and mature were selected as research subjects to illustrate the C and N stoichiometry interactions among different layers and organs in the forest ecosystem. The results showed that the average C and N concentrations in the leaves of the tree layer, shrub layer, and herb aboveground parts (HAP) were higher than that of other tree and shrub organs, as well as the herb underground parts (HUP), respectively. The N concentrations of tree branches and trunks showed a trend of increase first and decrease later from young to mature phases, but the C:N ratios presented an opposite trend. The C concentrations.in all tissues in shrubs showed a first decline and then a rise with age. As age progressed, the N concentration in each ecosystem layer increased gradually and demonstrated high synergy. The mineralization of organic matter in the soil was generally slow. The C concentrations in the understory vegetation layer were significantly positively correlated with the C concentrations in the litter layer but negatively correlated with the soil layer, and the C concentrations in the litter layer were also significantly negatively correlated with the C concentrations in the soil layer. The research findings can provide a reference basis for the formulation of nutrient regulation and sustainable management measures in the natural forests of P. massoniana in the study area.
Assuntos
Ecossistema , Pinus , Humanos , Pessoa de Meia-Idade , Carbono/análise , Solo/química , Nitrogênio/análise , Florestas , Árvores/química , ChinaRESUMO
PURPOSE: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC. METHODS AND MATERIALS: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 1011 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients. CONCLUSIONS: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia Viral Oncolítica , Radiocirurgia , Humanos , Radiocirurgia/efeitos adversos , Terapia Viral Oncolítica/efeitos adversos , Valaciclovir/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: With the rising prevalence of severe obesity, bariatric surgery has emerged as a crucial treatment option. As the number of surgeries performed worldwide increases, there has been growing interest in the impact of bariatric surgery on cancer incidence. While several studies have examined this relationship, the topic remains controversial. OBJECTIVES: We conducted this systematic review of cohort studies with meta-analysis to evaluate the effect of bariatric surgery versus nonsurgical treatment on overall cancer incidence. However, the effects may vary when focusing on specific cancer types, surgical procedures, or gender, so we conducted additional subgroup analyses. SETTING: A meta-analysis. University hospital. METHODS: The Cochrane, Embase, PubMed, and Web of Science databases were searched for studies from 1 January 2000 to 1 December 2022. Meta-analysis was conducted to evaluate the pooled effect and further implemented subgroup analysis stratified by cancer type, operation type, and sex. RESULTS: All cohort studies were included in this meta-analysis from 18,216 studies. The overall cancer incidence demonstrated a significant decrease in the group with bariatric surgery (odds ratios [OR] = .56, P = .000, 95% CI .46 to .68). In subgroup analysis, similar decrease effect was found in 9 cancers. Furthermore, the incidence of cancer decreased significantly in male (OR = .66, P = .001, 95% CI .51 to .85) and female patients (OR = .63, P = .000, 95% CI .57 to .69) and patients undergoing gastric bypass (OR = .46, P = .000, 95% CI .33 to .63) or sleeve gastrectomy (OR = .44, P = .001, 95% CI .27 to .70). CONCLUSIONS: In the overall analysis, bariatric surgery could reduce the incidence of cancer significantly. Further large-scale well-matched studies are needed to verify the protective effect of bariatric surgery on cancer incidence.
Assuntos
Cirurgia Bariátrica , Neoplasias , Obesidade Mórbida , Humanos , Cirurgia Bariátrica/efeitos adversos , Cirurgia Bariátrica/estatística & dados numéricos , Incidência , Neoplasias/epidemiologia , Neoplasias/cirurgia , Obesidade Mórbida/cirurgia , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/complicações , Masculino , Feminino , Estudos de CoortesRESUMO
Antibiotics are extensively applied in the pharmaceutical industry, while posing a tremendous hazard to the ecosystem and human health. In this study, the degradation performance of ciprofloxacin (CIP), one of the typical contaminants of antibiotics, in an oxidation system of peroxymonosulfate (PMS) activated by magnetic graphene oxide (MGO) was investigated. The effects of the MGO dosage, PMS concentration and pH on the degradation of CIP were evaluated, and under the optimal treatment conditions, the CIP degradation rate was up to 96.5% with a TOC removal rate of 63.4%. A kinetic model of pseudo-secondary adsorption indicated that it involves an adsorption process with progressively intensified chemical reactions. Furthermore, the MGO exhibited excellent recyclability and stability, maintaining strong catalytic activity after three regenerative cycles, with a CIP removal rate of 87.0%. EPR and LC-MS experiments suggested that â¢OH and SO4-⢠generated in the MGO/PMS system served as the main reactants contributing to the decomposition of the CIP, whereby the CIP molecule was effectively destroyed to produce other organic intermediates. Results of this study indicate that organic pollutants in the aqueous environment can be effectively removed in the MGO/PMS system, in which MGO has excellent catalytic activity and stabilization for being recycled to avoid secondary pollution, with definite research value and application prospects in the field of water treatment.
RESUMO
Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. In addition, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, whereas phosphorylation of proliferation regulators, for example, AKT, cyclin D1, and retinoblastoma protein, was decreased. Conversely, transcriptomic analysis showed LILRB3 activation by agonist antibodies may enhance leukemia survival through upregulation of cholesterol metabolism, which has been shown to promote leukemia cell survival. Moreover, LILRB3-targeted CAR T cells exhibited potent antitumor effects both in vitro and in vivo. Taken together, our results suggest that LILRB3 is a potentially potent target for multiple treatment modalities in AML. SIGNIFICANCE: LILRB3 regulates differentiation and proliferation in acute myeloid leukemia and can be targeted with monoclonal antibodies and CAR T cells to suppress leukemia growth.
Assuntos
Imunoterapia Adotiva , Leucemia Mieloide Aguda , Humanos , Imunoterapia Adotiva/métodos , Linfócitos T , Leucemia Mieloide Aguda/patologia , Receptores de Superfície Celular/metabolismo , Células Mieloides/metabolismo , Receptores Imunológicos/metabolismo , Antígenos CD/metabolismoRESUMO
Vegetation plays a critical role in the water and carbon cycling and energy flow, serving as an indicator for regulating land carbon balance and reflecting climate change and human activities. We analyzed the spatiotemporal variations of normalized difference vegetation index (NDVI) during the growing season in southern Jiangxi from 2000 to 2020, using statistical methods, including the Mann-Kendall test, Theil-Sen Median analysis, Hurst index, and coefficient of variation. We employed the geodetector model to comprehensively assess the impacts of climate, topography, soil and human factors on spatial differentiation of vegetation NDVI. The results showed NDVI exhibited an upward fluctuating trend with a rate of 0.003 per year from 2000 to 2020. The proportion of high-grade and medium-high-grade NDVI areas were 55.8% and 41.9%, respectively, while the areas with low and relatively low fluctuations accounted for 92.3%. The proportions of areas showing extremely significant improvement and significant improvement were 40.4% and 19.4%, respectively. In contrast, the combined proportion of areas displaying extremely significant degradation and significant degradation was only 2.2%. The proportions of areas demonstrating continuous improvement and future improvement were 28.0% and 60.2%, respectively. Elevation, precipitation, relative humidity, temperature, landform type, land use type, population density, and nighttime light were identified as the major factors for the vairations of NDVI in the study area, followed by slope, soil type, and GDP, while slope aspect and vegetation type had indirect influence. Throughout the study period, NDVI in southern Jiangxi was overall stable, with future changes primarily indicating improvement. Notably, human factors such as land use type, population density, and nighttime light index exhibited an upward trend in their impacts on NDVI.
Assuntos
Mudança Climática , Solo , Humanos , China , Temperatura , Carbono , EcossistemaRESUMO
Ultra-rapid cooling and rewarming rate is a critical technical approach to achieve ice-free cells during the freezing and melting process. A set of ultra-rapid solid surface freeze-thaw visualization system was developed based on a sapphire flim, and experiments on droplet freeze-thaw were carried out under different cryoprotectant components, volumes and laser energies. The results showed that the cooling rate of 1 µL mixed cryoprotectant [1.5 mol/L propylene glycol (PG) + 1.5 mol/L ethylene glycol (EG) + 0.5 mol/L trehalose (TRE)] could be 9.2×10 3 °C/min. The volume range of 1-8 µL droplets could be vitrified. After comparing the proportions of multiple cryoprotectants, the combination of equal proportion mixed permeability protectant and trehalose had the best vitrification freezing effect and more uniform crystallization characteristics. During the rewarming operation, the heating curve of glassy droplets containing gold nanoparticles was measured for the first time under the action of 400-1 200 W laser power, and the rewarming rate was up to the order of 10 6 °C/min. According to the droplet images of different power rewarming processes, the laser power range for ice-free rewarming with micron-level resolution was clarified to be 1 400-1 600 W. The work of this paper simultaneously realizes the ultra-high-speed temperature ramp-up, transient visual observation and temperature measurement of droplets, providing technical means for judging the ice free droplets during the freeze-thaw process. It is conducive to promoting the development of ultra-rapid freeze-thaw technology for biological cells and tissues.
Assuntos
Nanopartículas Metálicas , Vitrificação , Congelamento , Criopreservação/métodos , Trealose , Ouro , Reaquecimento , Crioprotetores , LasersRESUMO
Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.