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BACKGROUND: Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgical resection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Results from landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinical practice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT). METHODS: In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative OSCC patients. Eligible patients had AJCC stage III-IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin ß1 (ITGB1) expression was analyzed as a biomarker for efficacy. RESULTS: After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm (p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT. CONCLUSIONS: This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients, with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . NCT02923258 (date of registration: October 4, 2016).
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Cisplatino , Docetaxel , Integrina beta1 , Neoplasias de la Boca , Humanos , Docetaxel/uso terapéutico , Docetaxel/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/terapia , Anciano , Adulto , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/terapia , Biomarcadores de Tumor , Antineoplásicos/uso terapéutico , Resultado del TratamientoRESUMEN
Introduction: This study explored the causal connections between gut microbiota (GM), urinary tract infection (UTI), and potential metabolite mediators using Mendelian randomization (MR). Methods: We utilized summary statistics from the most comprehensive and extensive genome-wide association studies (GWAS) available to date, including 196 bacterial traits for GM, 1,091 blood metabolites, 309 metabolite ratios, alongside UTI data from ukb-b-8814 and ebi-a-GCST90013890. Bidirectional MR analyses were conducted to investigate the causal links between GM and UTI. Subsequently, two MR analyses were performed to identify the potential mediating metabolites, followed by a two-step MR analysis to quantify the mediation proportion. Results: Our findings revealed that out of the total 15 bacterial traits, significant associations with UTI risk were observed across both datasets. Particularly, taxon g_Ruminococcaceae UCG010 displayed a causal link with a diminished UTI risk in both datasets (ukb-b-8814: odds ratio [OR] = 0.9964, 95% confidence interval [CI] = 0.9930-0.9997, P = 0.036; GCST90013890: OR = 0.8252, 95% CI = 0.7217-0.9436, P = 0.005). However, no substantial changes in g_Ruminococcaceae UCG010 due to UTI were noted (ukb-b-8814: ß = 0.51, P = 0.87; ebi-a-GCST90013890: ß = -0.02, P = 0.77). Additionally, variations in 56 specific metabolites were induced by g_Ruminococcaceae UCG010, with N-acetylkynurenine (NAK) exhibiting a causal correlation with UTI. A negative association was found between g_Ruminococcaceae UCG010 and NAK (OR: 0.8128, 95% CI: 0.6647-0.9941, P = 0.044), while NAK was positively associated with UTI risk (OR: 1.0009; 95% CI: 1.0002-1.0016; P = 0.0173). Mediation analysis revealed that the association between g_Ruminococcaceae UCG010 and UTI was mediated by NAK with a mediation proportion of 5.07%. Discussion: This MR study provides compelling evidence supporting the existence of causal relationships between specific GM taxa and UTI, along with potential mediating metabolites.
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Human DDX3X, an important member of the DEAD-box family RNA helicases, plays a crucial role in RNA metabolism and is involved in cancer development, viral infection, and neurodegenerative disease. Although there have been many studies on the physiological functions of human DDX3X, issues regarding its exact targets and mechanisms of action remain unclear. In this study, we systematically characterized the biochemical activities and substrate specificity of DDX3X. The results demonstrate that DDX3X is a bidirectional RNA helicase to unwind RNA duplex and RNA-DNA hybrid driven by ATP. DDX3X also has nucleic acid annealing activity, especially for DNA. More importantly, it can function as a typical nucleic acid chaperone which destabilizes highly structured DNA and RNA in an ATP-independent manner and promotes their annealing to form a more stable structure. Further truncation mutations confirmed that the highly disordered N-tail and C-tail are critical for the biochemical activities of DDX3X. They are functionally complementary, with the N-tail being crucial. These results will shed new light on our understanding of the molecular mechanism of DDX3X in RNA metabolism and DNA repair, and have potential significance for the development of antiviral/anticancer drugs targeting DDX3X.
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Adenosina Trifosfato , ARN Helicasas DEAD-box , Chaperonas Moleculares , Humanos , Adenosina Trifosfato/metabolismo , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , ADN/metabolismo , ADN/química , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , ARN/metabolismo , ARN/química , ARN/genética , Especificidad por SustratoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus mongholicus Bunge (AM, recorded in http://www.worldfloraonline.org, 2023-08-03) is a kind of medicine food homology plant with a long medicinal history in China. Astragaloside III (AS-III) has immunomodulatory effects and is one of the most active components in AM. However, its underlying mechanism of action is still not fully explained. AIM OF THE STUDY: The research was designed to discuss the protective effects of AS-III on immunosuppression and to elucidate its prospective mechanism. MATERIALS AND METHODS: Molecular docking methods and network pharmacology analysis were used to comprehensively investigate potential targets and relative pathways for AS-III and immunosuppression. In order to study and verify the pharmacological activity and mechanism of AS-III in alleviating immunosuppression, immunosuppression mouse model induced by cyclophosphamide (CTX) in vivo and macrophage RAW264.7 cell model induced by hypoxia/lipopolysaccharide (LPS) in vitro were used. RESULTS: A total of 105 common targets were obtained from the AS-III-related and immunosuppression-related target networks. The results of network pharmacology and molecular docking demonstrate that AS-III may treat immunosuppression through by regulating glucose metabolism-related pathways such as regulation of lipolysis in adipocytes, carbohydrate digestion and absorption, cGMP-PKG signaling pathway, central carbon metabolism in cancer together with HIF-1 pathway. The results of molecular docking showed that AS-III has good binding relationship with LDHA, AKT1 and HIF1A. In CTX-induced immunosuppressive mouse model, AS-III had a significant protective effect on the reduction of body weight, immune organ index and hematological indices. It can also protect immune organs from damage. In addition, AS-III could significantly improve the expression of key proteins involved in energy metabolism and serum inflammatory factors. To further validate the animal results, an initial inflammatory/immune response model of macrophage RAW264.7 cells was constructed through hypoxia and LPS. AS-III improved the immune function of macrophages, reduced the release of NO, TNF-α, IL-1ß, PDHK-1, LDH, lactate, HK, PK and GLUT-1, and restored the decrease of ATP caused by hypoxia. Besides, AS-III was also demonstrated that it could inhibit the increase of HIF-1α, PDHK-1 and LDH by adding inhibitors and agonists. CONCLUSIONS: In this study, the main targets of AS-III for immunosuppressive therapy were initially analyzed. AS-III was systematically confirmed to attenuates immunosuppressive state through the HIF-1α/PDHK-1 pathway. These findings offer an experimental foundation for the use of AS-III as a potential candidate for the treatment of immunosuppression.
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Simulación del Acoplamiento Molecular , Farmacología en Red , Saponinas , Animales , Ratones , Células RAW 264.7 , Saponinas/farmacología , Lipopolisacáridos , Masculino , Ciclofosfamida/farmacología , Inmunosupresores/farmacología , Triterpenos/farmacología , Transducción de Señal/efectos de los fármacos , Planta del Astrágalo/químicaRESUMEN
This study utilized high-throughput sequencing and SEM observation to elucidate the microbial composition of a Tibetan herder's homemade kefir grain named TKG-Y. Subsequently, S. warneri KYS-164 was isolated from TKG-Y, which can produce mixed protein substances with antibacterial activity, namely bacteriocin-like inhibitory substances (BLIS). BLIS can significantly reduce the growth rate of Escherichia coli 366-a, Staphylococcus aureus CICC 10384 and mixed strains at low concentrations (1 × MIC). The presence of the warnericin-centered gene cluster in KYS-164 may explain the antibacterial properties of the BLIS. Pepsin and an acidic environment can reduce the number of colonies of KYS-164 by 2.5 Log10 CFU mL-1 within 1 h, and reduce the antibacterial activity of BLIS by 21.48%. S. warneri KYS-164 showed no antibiotic resistance and biological toxicity after 80 subcultures, while BLIS produced by 40 generations of the strain retained their inhibitory efficacy against pathogenic bacteria. After 48-hour fermentation of milk with KYS-164, volatile compounds such as aldehydes, phenols, esters, and alcohols, giving it a floral, fruity, milky, oily, and nutty aroma, were released, enriching the sensory characteristics of dairy products. This study not only revealed the bacterial colony composition information of home-made kefir grain TKG-Y but also discovered and proved that S. warneri KYS-164 has the potential to inhibit bacteria and ferment dairy products. This will provide a basis for subsequent applied research on KYS-164.
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Antibacterianos , Fermentación , Kéfir , Leche , Kéfir/microbiología , Leche/microbiología , Antibacterianos/farmacología , Animales , Tibet , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Bacteriocinas/farmacologíaRESUMEN
BACKGROUND: The metabolic benefits of bariatric surgery that contribute to the alleviation of metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. However, the processes and mechanisms underlying the contribution of lipid metabolic reprogramming after bariatric surgery to attenuating MASLD remain elusive. METHODS: A case-control study was designed to evaluate the impact of three of the most common adipokines (Nrg4, leptin, and adiponectin) on hepatic steatosis in the early recovery phase following sleeve gastrectomy (SG). A series of rodent and cell line experiments were subsequently used to determine the role and mechanism of secreted adipokines following SG in the alleviation of MASLD. RESULTS: In morbidly obese patients, an increase in circulating Nrg4 levels is associated with the alleviation of hepatic steatosis in the early recovery phase following SG before remarkable weight loss. The temporal parameters of the mice confirmed that an increase in circulating Nrg4 levels was initially stimulated by SG and contributed to the beneficial effect of SG on hepatic lipid deposition. Moreover, this occurred early following bariatric surgery. Mechanistically, gain- and loss-of-function studies in mice or cell lines revealed that circulating Nrg4 activates ErbB4, which could positively regulate fatty acid oxidation in hepatocytes to reduce intracellular lipid deposition. CONCLUSIONS: This study demonstrated that the rapid effect of SG on hepatic lipid metabolic reprogramming mediated by circulating Nrg4 alleviates MASLD.
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Hígado Graso , Metabolismo de los Lípidos , Enfermedades Metabólicas , Reprogramación Metabólica , Neurregulinas , Obesidad Mórbida , Animales , Humanos , Ratones , Adipoquinas , Estudios de Casos y Controles , Gastrectomía/efectos adversos , Lípidos , Hepatopatías , Enfermedades Metabólicas/complicaciones , Reprogramación Metabólica/genética , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Neurregulinas/genética , Neurregulinas/metabolismoRESUMEN
This study reports the rational engineering of the S1' substrate-binding pocket of a thermally-stable keratinase from Pseudomonas aeruginosa 4-3 (4-3Ker) to improve substrate specificity to typical keratinase (K/C > 0.5) and catalytic activity without compromising thermal stability for efficient keratin degradation. Of 10 chosen mutation hotspots in the S1' substrate-binding pocket, the top three mutations M128R, A138V, and V142I showing the best catalytic activity and substrate specificity were identified. Their double and triple combinatorial mutants synergistically overcame limitations of single mutants, fabricating an excellent M128R/A138V/V142I triple mutant which displayed a 1.21-fold increase in keratin catalytic activity, 1.10-fold enhancement in keratin/casein activity ratio, and a 3.13 °C increase in half-inactivation temperature compared to 4-3Ker. Molecular dynamics simulations revealed enhanced flexibility of critical amino acid residues at the substrate access tunnel, improved global protein rigidity, and heightened hydrophobicity within the active site likely underpinned the increased catalytic activity and substrate specificity. Additionally, the triple mutant improved the feather degradation rate by 32.86 % over the wild-type, far exceeding commercial keratinase in substrate specificity and thermal stability. This study exemplified engineering a typical keratinase with enhanced substrate specificity, catalytic activity, and thermal stability from thermally-stable 4-3Ker, providing a more robust tool for feather degradation.
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Queratinas , Péptido Hidrolasas , Queratinas/metabolismo , Especificidad por Sustrato , Péptido Hidrolasas/metabolismo , Temperatura , Concentración de Iones de HidrógenoRESUMEN
BACKGROUND AND PURPOSE: Collateral circulation plays an important role in steno-occlusive internal carotid artery disease (ICAD) to reduce the risk of stroke. We aimed to investigate the utility of planning-free random vessel-encoded arterial spin-labeling (rVE-ASL) in assessing collateral flows in patients with ICAD. MATERIALS AND METHODS: Forty patients with ICAD were prospectively recruited. The presence and extent of collateral flow were assessed and compared between rVE-ASL and DSA by using Contingency (C) and Cramer V (V) coefficients. The differences in flow territory alterations stratified by stenosis ratio and symptoms, respectively, were compared between symptomatic (n = 19) and asymptomatic (n = 21) patients by using the Fisher exact test. RESULTS: Good agreement was observed between rVE-ASL and DSA in assessing collateral flow (C = 0.762, V = 0.833, both P < .001). Patients with ICA stenosis of ≥90% were more likely to have flow alterations (P < .001). Symptomatic patients showed a higher prevalence of flow alterations in the territory of the MCA on the same side of ICAD (63.2%), compared with asymptomatic patients (23.8%, P = .012), while the flow alterations in the territory of anterior cerebral artery did not differ (P = .442). The collateral flow to MCA territory was developed primarily from the contralateral internal carotid artery (70.6%) and vertebrobasilar artery to a lesser extent (47.1%). CONCLUSIONS: rVE-ASL provides comparable information with DSA on the assessment of collateral flow. The flow alterations in the MCA territory may be attributed to symptomatic ICAD.
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Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Humanos , Estenosis Carotídea/diagnóstico por imagen , Constricción Patológica , Marcadores de Spin , Angiografía de Substracción Digital , Arteria Carótida Interna/diagnóstico por imagen , Circulación Colateral , Circulación Cerebrovascular , Angiografía por Resonancia MagnéticaRESUMEN
BACKGROUND: The causes of vitamin B12 (B12) deficiency are varied and mainly related to gastric disorders. Glossitis is a common oral manifestation of B12 deficiency and is often first seen by dentists. This study aimed to investigate the correlation between B12 deficiency-related glossitis (B12-def glossitis) and gastric serum biomarkers [gastrin-17(G17), pepsinogen I (PGI), pepsinogen II (PGII), and anti-Helicobacter pylori (H. pylori) antibodies], and preliminarily discuss the etiology of B12-def glossitis. METHODS: A cross-sectional study was conducted in patients complaining of glossodynia, burning sensation, or severe recurrent oral ulcers, but patients with a history of gastrectomy were excluded. All subjects underwent a uniform oral examination and hematological tests. RESULTS: Of 243 patients, 133 with B12-def glossitis were in the case group, and 110 with other oral mucosal diseases (non-glossitis) and normal B12 levels were in the control group. In the case group, 84.2% (112/133) showed high G17 and low PGI levels (G17hi PGIlow ). Univariate logistic regression showed that G17hi PGIlow was a high-risk factor for B12-def glossitis (OR: 92.44; 95% CI: 35.91, 238.02). Subgroup analyses in the case group showed that the G17hi PGIlow group presented with lower B12 levels and a lower positive rate of anti-H. pylori antibodies compared to the non-G17hi PGIlow group. CONCLUSION: Gastric serum biomarkers in patients with B12-def glossitis generally showed G17hi PGIlow , suggesting possible atrophy of gastric corpus and fundus mucosa. The G17hi PGIlow and non-G17hi PGIlow groups may represent different etiologies of B12 deficiency.
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Gastrinas , Glositis , Infecciones por Helicobacter , Humanos , Pepsinógeno A , Mucosa Gástrica/patología , Estudios Transversales , Biomarcadores , Glositis/etiología , Glositis/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/diagnósticoRESUMEN
STUDY OBJECTIVES: This study aimed to evaluate the safety and short-term effect of contemporaneous surgeries (bariatric surgery plus uvulopalatopharyngoplasty [UPPP]) in the treatment of morbid obesity comorbid with severe obstructive sleep apnea (OSA). METHODS: A retrospective cohort study was performed to identify patients with obesity and severe OSA who underwent laparoscopic sleeve gastrectomy (LSG) with or without UPPP surgeries between December 2019 and December 2021 in our center. Patients were divided into 2 groups according to different surgical methods (contemporaneous group [LSG with UPPP] vs LSG-only group). Data about surgical safety, OSA remission, and effectiveness of weight loss were collected and analyzed between the 2 groups before and 12 months after surgery. RESULTS: A total of 101 patients were included in this study (contemporaneous group [LSG with UPPP], n = 42 vs LSG only group, n = 59). There was no significant difference in surgical safety between the 2 groups, and both OSA and obesity were significantly improved at 12.5 ± 2.1 months postoperative follow-up. The apnea-hypopnea index decreased from 68.7 ± 30.4 events/h to 10.2 ± 7.0 events/h in the contemporaneous group (P < .001) and from 64.7 ± 26.2 events/h to 18.9 ± 9.8 events/h in the LSG group (P < .001). Moreover, the apnea-hypopnea index decreased to below 5 events/h in 50% of patients (21/42) in the contemporaneous group but only in 13.5% of patients in the LSG group (P < .001). In the LSG group 20 (34%) patients achieved a reduction in apnea-hypopnea index < 15 events/h and resolution of daytime sleepiness. CONCLUSIONS: Contemporaneous surgery (concurrent bariatric and UPPP surgeries) is feasible and an effective option for patients with obesity and severe OSA. However, our finding suggests that approximately a third of patients undergoing LSG with UPPP may not derive significant benefit from the UPPP portion of the contemporaneous surgical approach. CITATION: Yang C, Yu W, Yao K, et al. Concurrent laparoscopic sleeve gastrectomy with uvulopalatopharyngoplasty in the treatment of morbid obesity comorbid with severe obstructive sleep apnea: a retrospective cohort study. J Clin Sleep Med. 2024;20(4):555-564.
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Laparoscopía , Obesidad Mórbida , Apnea Obstructiva del Sueño , Humanos , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Estudios Retrospectivos , Resultado del Tratamiento , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/cirugía , Gastrectomía/métodos , Laparoscopía/métodosRESUMEN
Reactive oxygen species (ROS) are crucial for signal transduction and the maintenance of cellular homeostasis. However, superfluous ROS may engender chronic pathologies. Feather keratin is a promising new source of antioxidant peptides that can eliminate excess ROS and potentially treat oxidative stress-related diseases, but the underlying mechanisms have remained elusive. This study investigated the antioxidant effects and mechanisms against H2O2-induced oxidative damage in HepG2 cells of the two latest discovered antioxidant peptides, CRPCGPTP (CP-8) and ANSCNEPCVR (AR-10), first decrypted from feather keratin. The results revealed that CP-8 and AR-10 did not exhibit cytotoxicity to HepG2 cells while reducing intracellular ROS accumulation. Simultaneously, they enhanced the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), thus alleviating H2O2-induced cell apoptosis. Molecular docking analysis demonstrated that CP-8, AR-10 interacted well with the key amino acids in the Kelch domain of Keap1, thereby directly disrupting the Keap1-Nrf2 interaction. The peptides' biosafety and antioxidant activity via Keap1/Nrf2 signaling lay the groundwork for further animal studies and applications as functional food additives.
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Antioxidantes , Factor 2 Relacionado con NF-E2 , Animales , Humanos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Peróxido de Hidrógeno/toxicidad , Peróxido de Hidrógeno/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Queratinas , Plumas , Células Hep G2 , Simulación del Acoplamiento Molecular , Estrés OxidativoRESUMEN
BACKGROUND: This study aimed to find out the characteristics in relation to tumor recurrence in diffused-tenosynovial giant cell tumor of temporomandibular joint and to develop and validate the prognostic model for personalized prediction. METHODS: From April 2009 to January 2021, patients with diffused-tenosynovial giant cell tumor of temporomandibular joint at a single center were included in this study. The clinical features and local recurrence-free survival were assessed through the expression of the Ki-67 index and colony-stimulating factor 1 receptor expression. Both univariate and multivariate analyses were performed on the prognostic factors for local recurrence-free survival. An independent predictor nomogram and pertinent tumor characteristics were included. RESULTS: The retrospective study enrolling seventy eligible patients at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. During the follow-up time, eleven patients suffered tumor recurrence. Age was an independent risk factor for local recurrence-free survival (P = 0.032). The Ki-67 index varied significantly in different sites (P = 0.034) and tumor volume (P = 0.017). Multivariate logistic regression was used to develop the prediction model using both statistical significance and prognostic indicators. The C-index of the nomogram based on age, site, Ki-67, and colony-stimulating factor 1 receptor was 0.833. These variates provided good predicted accuracy for a nomogram on local recurrence-free survival. Diffused-tenosynovial giant cell tumor from the temporomandibular joint is extremely uncommon, and certain clinical traits are linked to the tumor proliferation index. CONCLUSIONS: We identified the risk indicators and developed a nomogram in this study to forecast the likelihood of local recurrence-free survival in patients with diffused-tenosynovial giant cell tumor from temporomandibular joint.
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Tumor de Células Gigantes de las Vainas Tendinosas , Recurrencia Local de Neoplasia , Humanos , Estudios Retrospectivos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Factor Estimulante de Colonias de Macrófagos , Antígeno Ki-67 , China , Tumor de Células Gigantes de las Vainas Tendinosas/patología , Articulación Temporomandibular/patologíaRESUMEN
Heat stress can cause testicular damage and affect male fertility. Tanshinone IIA (TSA) is a monomer substance derived from plants, with antioxidant and anti-apoptotic effects. Whether it can repair testicular damage caused by heat stress is unclear. This study aims to construct a mouse testicular heat stress injury model and intervene with TSA. Various methods such as histopathology, high-throughput sequencing, bioinformatics analysis, and molecular biology were used to investigate whether TSA can alleviate heat stress-induced testicular injury and its mechanism. Results showed that heat stress significantly reduced the diameter of the mouse seminiferous tubules, increased cell apoptosis in the testicular tissue, and significantly decreased testosterone levels. After TSA intervention, testicular morphology and cell apoptosis improved significantly, and testosterone secretion function was restored. High-throughput transcriptome sequencing found that key differentially expressed genes between the HS group and the control and TSA groups clustered in the apoptosis and TGFß signaling pathways. Using western blot technology, we found that the HS group upregulated TGFß1/Smad2/Smad3 pathway protein expression, causing cell apoptosis, testicular tissue organic lesions, and affecting testicular secretion function. Through TSA intervention, we found that it can inhibit TGFß1/Smad2/Smad3 pathway protein expression, thereby restoring testicular damage caused by heat stress. This study confirms that TSA can effectively restore testicular damage caused by heat stress in mice, possibly by inhibiting the TGFß1/Smad2/Smad3 pathway to suppress apoptosis.
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Transducción de Señal , Testículo , Animales , Masculino , Ratones , Apoptosis , Respuesta al Choque Térmico , Testosterona/metabolismoRESUMEN
BACKGROUND: To analyze the clinicopathological features of different histological subtypes of epulis, and evaluate the risk factors associated with recurrence. MATERIALS AND METHODS: A retrospective study including 2971 patients was performed. The patients' sex, age, location, size, histological subtypes, recurrence information, oral hygiene habits, periodontitis symptoms and smoking history were retrieved from the patient medical records and follow-up information. RESULTS: Among the 2971 cases, focal fibrous hyperplasia (FFH) was the most common lesion (60.92%), followed by peripheral ossifying fibroma (POF) (29.32%), pyogenic granuloma (PG) (8.08%) and peripheral giant cell granuloma (PGCG) (1.68%). The peak incidence of epulis was in the third and fourth decade of life, with a mean age of 45.55 years. Female predominance was found in all types of lesions with a female to male ratio of 1.71:1. PG had the highest recurrence rate (17.18%), followed by POF (12.98%), FFH (9.55%) and PGCG (8.82%). Histological subtypes were significantly correlated with the recurrence of epulis (P = 0.013). Regular supportive periodontal therapy (P = 0.050) had a negative correlation with recurrence, whereas symptoms of periodontitis (P < 0.001) had a positive correlation with the recurrence of epulis. CONCLUSIONS: Controlling the periodontal inflammation and regular supportive periodontal therapy might help reduce the recurrence of epulis.
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Calcinosis , Fibroma Osificante , Enfermedades de las Encías , Neoplasias Gingivales , Granuloma de Células Gigantes , Granuloma Piogénico , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios de Cohortes , Estudios Retrospectivos , Enfermedades de las Encías/epidemiología , Neoplasias Gingivales/patología , Fibroma Osificante/diagnóstico , Fibroma Osificante/epidemiología , Fibroma Osificante/patología , Granuloma de Células Gigantes/epidemiología , Granuloma de Células Gigantes/patología , Factores de Riesgo , Granuloma Piogénico/epidemiología , Granuloma Piogénico/patología , HiperplasiaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Myelosuppression, also known as bone marrow suppression (BMS), is a pathological phenomenon of the decrease in the production of blood cells and further lead to immune homeostasis disorder. Astragalus mongholicus Bunge (AM, checked with The World Flora Online, http://www.worldfloraonline.org, updated on January 30, 2023) is a traditional Chinese medicine with efficacy of tonifying Qi and strengthening body immunity in thousands of years of clinical practice in China. Astragaloside IV (AS-IV) is a major active ingredient of AM, which plays an important role in regulating immune system through different ways. AIM OF THE STUDY: This study was aimed to investigate the protective effect and mechanism of AS-IV on macrophages in vitro and cyclophosphamide (CTX)-induced immunosuppressive mice in vivo, and to provide experimental basis for the prevention and treatment of AS-IV in myelosuppression. MATERIALS AND METHODS: Based on network pharmacology and molecular docking technology, the core targets and signaling pathways of saponins of AM against myelosuppression were screened. And then, the immunoregulatory effect of AS-IV on RAW264.7 cells was investigated by cellular immune activity and cellular secretion analysis in vitro. In this way, the effects of AS-IV on the main potential targets of HIF-1α/NF-κB signaling pathway were analyzed by qRT-PCR and Western blot methods. Furthermore, comprehensive analysis of the effects of AS-IV against CTX-induced mice were conducted on the basis of immune organs indices analysis, histopathological analysis, hematological analysis, natural killer cell activity analysis and spleen lymphocyte transformation activity analysis. In order to further verify the relationship between active ingredients and action targets, drug inhibitor experiments were finally conducted. RESULTS: AS-IV, as a potential anti-myelosuppressive compound, was screened by systematic pharmacological methods to act on target genes including HIF1A and RELA together with the HIF-1α/NF-κB signaling pathway. Further studies by molecular docking technology showed that AS-IV had good binding activity with HIF1A, RELA, TNF, IL6, IL1B and other core targets. Besides, cellular and animal experiments validation results showed that AS-IV could enhance the migration and phagocytosis of RAW264.7 cells, and protect the immune organs such as spleen and thymus together with bone tissues from damage. By this means, immune cell function including spleen natural killer cell and lymphocyte transformation activity were also enhanced. In addition, white blood cells, red blood cells, hemoglobin, platelets and bone marrow cells were also significantly improved in the suppressed bone marrow microenvironment (BMM). In kinetic experiments, the secretion of cytokines such as TNF-α, IL-6 and IL-1ß were increased, and IL-10, TGF-ß1 were decreased. The key regulatory proteins such as HIF-1α, NF-κB, PHD3 in HIF-1α/NF-κB signaling pathway were also regulated in the results of upregulated expression of HIF-1α, p-NF-κB p65 and PHD3 at the protein or mRNA level. Finally, the inhibition experiment results suggested that AS-IV could significantly improve protein response in immunity and inflammation such as HIF-1α, NF-κB and PHD3. CONCLUSION: AS-IV could significantly relieve CTX-induced immunosuppressive and might improve the immune activity of macrophages by activating HIF-1α/NF-κB signaling pathway, and provide a reliable basis for the clinical application of AS-IV as a potentially valuable regulator of BMM.
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FN-kappa B , Saponinas , Ratones , Animales , FN-kappa B/metabolismo , Farmacología en Red , Simulación del Acoplamiento Molecular , Saponinas/farmacología , Ciclofosfamida/toxicidadRESUMEN
Background: The relative efficacy of 5 sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and 4 glucagon-like peptide-1 (GLP-1) receptor agonists for non-alcoholic fatty liver disease (NAFLD) therapy has not been sufficiently investigated. Methods: Randomized controlled trials (RCTs) in which patients with NAFLD were treated with SGLT-2 inhibitors or GLP-1 receptor agonists were included. Primary outcomes were improvements in liver enzymes and liver fat parameters, while secondary outcomes included anthropometric measures, blood lipids and glycemic parameters. The frequentist method was used to perform a network meta-analysis. Evidence certainty was assessed using the grading of recommendations assessment, development, and evaluation (GRADE). Results: The criteria were satisfied by 37 RCTs with 9 interventions (5 SGLT-2 inhibitors and 4 GLP-1 receptor agonists). Based on high certainty evidence, in patients with NAFLD (or comorbid with type 2 diabetes), semaglutide could lower alanine aminotransferase as well as aspartate aminotransferase, γ-glutamyl transferase, controlled attenuation parameter, liver stiffness measurement, body weight, systolic blood pressure, triglycerides, high-density lipoprotein-cholesterol, glycosylated hemoglobin. Liraglutide could lower alanine aminotransferase as well as subcutaneous adipose tissue, body mass index, fasting blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment, while dapagliflozin could lower alanine aminotransferase as well as body weight, fasting blood glucose, postprandial blood glucose, glycosylated hemoglobin, glucose and homeostasis model assessment. Conclusion: Semaglutide, liraglutide, and dapagliflozin all have a certain effect on NAFLD (or comorbid with type 2 diabetes) based on high confidence evidence from indirect comparisons, and semaglutide appears to have a therapeutic advantage over the other included medicines. Head-to-head studies are needed to provide more confidence in clinical decision-making.
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Preterm prelabor rupture of membranes (PPROM) is a major cause of spontaneous preterm birth (sPTB), one of the greatest challenges facing obstetrics with complicated pathogenesis. This case-cohort study investigated the association between vaginal bacteriome of singleton pregnant females in the early second trimester and PPROM. The study included 35,255 and 180 pregnant females with PPROM as cases and term-birth without prelabor rupture of membranes (TWPROM) and term prelabor rupture of membranes (TPROM) pregnant females as controls, respectively. Using 16S rRNA sequencing, the vaginal microbiome traits were analyzed. Females with PPROM had higher alpha and beta diversity (P < 0.05) than TWPROM and TPROM. The presence of L. mulieris was associated with a decreased risk of PPROM (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI]: 0.17-0.72) compared with TWPROM. Meanwhile, the presence of Megasphaera genus (aOR = 2.27; 95% CI: 1.09-4.70), Faecalibacterium genus (aOR = 3.29; 95% CI: 1.52-7.13), Bifidobacterium genus (aOR = 3.26; 95% CI: 1.47-7.24), Xanthomonadales genus (aOR = 2.76; 95% CI: 1.27-6.01), Gammaproteobacteria class (aOR = 2.36; 95% CI: 1.09-5.14), and Alphaproteobacteria class (aOR = 2.45; 95% CI: 1.14-5.26) was associated with an increased risk of PPROM compared with TWPROM. Our results indicated that the risk of PPROM can decrease with vaginal L. mulieris but increase with high alpha or beta diversity, and several vaginal bacteria in pregnant females may be involved in the occurrence of PPROM.
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Rotura Prematura de Membranas Fetales , Nacimiento Prematuro , Embarazo , Humanos , Recién Nacido , Femenino , Segundo Trimestre del Embarazo , Estudios de Cohortes , ARN Ribosómico 16S/genéticaRESUMEN
Background: Anti-TNF therapy has been found to exert an influence on long-term nutritional status and even reverse malnutrition in patients with Crohn's disease. Aims: to observe the effect of anti-TNF therapy on nutritional status in patients with Crohn's disease, investigate the correlation between the timing of anti-TNF therapy and the human body composition and examine independent body composition factors for predicting malnutrition in these patients. Methods: This was a retrospective study of 115 patients with Crohn's disease. Body composition parameters were assessed by bioelectrical impedance analysis. The nutritional status of the patients was determined by NRS2002 and MNA. Results: The BMI, BFMI, FFMI, BCMI, SMI, BMC, intracellular water, protein and BMR were significantly lower in patients without any biologic agents (p < 0.05). Negative correlations were found between BMC, intracellular water, extracellular water, protein and BMR and the interval between the first symptom and first dose by Spearman's correlation analysis (r < 0, p < 0.05). Low BMI (OR 0.602, 95% CI 0.434-0.836, p = 0.002), low FFMI (OR 0.678, 95% CI 0.507-0.906, p = 0.009), and low BCMI (OR 0.564, 95% CI 0.367-0.868, p = 0.009) were independent risk factors for malnutrition in Crohn's disease patients. Anti-TNF therapy tended to reduce the malnutrition probability as assessed by Cox regression analysis (OR: 0.217, 95% CI 0.057-0.821, p = 0.024). Conclusion: Body composition analysis is predictive of malnutrition in patients with Crohn's disease. Early application of anti-TNF therapy significantly affected skeletal muscle mass, fat mass and bone mineral content, supporting their long-term nutritional status and reducing their probability of malnutrition.
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INTRODUCTION: There is no conclusive evidence comparing the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists to the other guidelines recommended pharmacotherapy for nonalcoholic fatty liver disease (NAFLD). Therefore, we aim to compare the effects of GLP-1 receptor agonists, pioglitazone and vitamin E in patients with NAFLD. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library up to 11 April 2022. Randomized clinical trials (RCTs) comparing GLP-1 receptor agonists, pioglitazone and vitamin E against placebo or other active controls in patients with NAFLD were included. RESULTS: Nine RCTs including 1482 patients proved eligible. GLP-1 receptor agonists ranked first in steatosis, ballooning necrosis, γ-glutamyl transferase, body weight, body mass index, and triglycerides. Administration of GLP-1 receptor agonists, as compared with placebo, was associated with improvement in liver histology [steatosis (OR = 4.11, 95% CI: 2.83, 5.96), ballooning necrosis (OR = 3.07, 95% CI: 2.14, 4.41), lobular inflammation (OR = 1.86, 95% CI: 1.29, 2.68), fibrosis (OR = 1.52, 95% CI: 1.06, 2.20)]. CONCLUSIONS: GLP-1 receptor agonists were as effective as pioglitazone and vitamin E for liver histology among patients with NAFLD. GLP-1 receptor agonists might be considered as an alternative or complementary treatment in the future clinical practice. [Figure: see text].
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/uso terapéutico , Hipoglucemiantes/efectos adversos , Necrosis/tratamiento farmacológico , Metaanálisis en Red , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Pioglitazona/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Vitamina E/efectos adversos , Proyectos PilotoRESUMEN
Objective: The effect of vaginal microbiota on spontaneous preterm birth (sPTB) has not been fully addressed, and few studies have explored the associations between vaginal taxa and sPTB in the gestational diabetes mellitus (GDM) and non-GDM groups, respectively. Study Design. To minimize external interference, a total of 41 pregnant women with sPTB and 308 controls (pregnant women without sPTB) from same regain were enrolled in this case-cohort study. Controls were randomly selected at baseline. With the exception of GDM, other characteristics were not significantly different between the two groups. Vaginal swabs were collected at early second trimester. Using 16S amplicon sequencing, the main bioinformatics analysis was performed on the platform of QIIME 2. Vaginal microbiota traits of the sPTB group were compared with controls. Finally, the effects of binary taxa on sPTB in the GDM group and the non-GDM group were analyzed, respectively. Results: The proportion of GDM in the sPTB (19.51%) was higher than the controls (7.47%, P = 0.018). The vaginal microbiota of pregnant women with sPTB exhibited higher alpha diversity metrics (observed features, P = 0.001; Faith's phylogenetic diversity, P = 0.013) and different beta diversity metrics (unweighted UniFrac, P = 0.006; Jaccard's distance, P = 0.004), compared with controls. The presence of Lactobacillus paragasseri/gasseri (aOR: 3.12, 95% CI: 1.24-7.84), Streptococcus (aOR: 3.58, 95% CI: 1.68-7.65), or Proteobacteria (aOR: 3.39, 95% CI: 1.55-7.39) was associated with an increased risk of sPTB in the non-GDM group (P < 0.05). However, the relative abundance of novel L. mulieris (a new species of the L. delbrueckii group) was associated with a decreased risk of sPTB (false discovery rate, 0.10) in all pregnant women. Conclusion: GDM may modify the association of vaginal taxa with sPTB, suggesting that maternal GDM should be considered when using vaginal taxa to identify pregnant women at high risk of sPTB.