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Cholangiocarcinoma (CCA) is a prevalent and highly lethal form of cancer globally. Although microRNAs (miRNAs) have been implicated in the advancement of CCA, their potential influence on 5-fluorouracil (5-Fu) resistance in CCA remains to be fully elucidated. Here, in this study, we investigated the impact of miR-22-3p on CCA resistance. Our investigation involved bioinformatics analysis, which revealed an association between miR-22-3p and the progression, diagnosis, and patient survival of CCA. Furthermore, we validated a notable downregulation of miR-22-3p expression in CCA cell lines. Elevated levels of miR-22-3p inhibit the activity and proliferation of 5-Fu-resistant CCA cell lines. In addition, we confirmed that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a target gene of miR-22-3p, and its expression correlates with the survival of CCA patients. Reduced PTEN expression enhances apoptosis in 5-Fu-resistant CCA cells. Meanwhile, we verified the existence of the miR-22-3p/PTEN/phosphatidylinositol-3 kinase (PI3K)/Protein kinase B (AKT) regulatory networks in CCA, influencing the sensitivity of CCA cells to 5-Fu. In conclusion, our findings suggest that miR-22-3p acts as a tumor suppressor. Its overexpression inhibits the PTEN/PI3K/AKT axis, promoting cell apoptosis and enhancing CCA sensitivity to 5-Fu.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Resistencia a Antineoplásicos , Fluorouracilo , MicroARNs , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Colangiocarcinoma/metabolismo , Fluorouracilo/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antimetabolitos Antineoplásicos/farmacología , Línea Celular TumoralRESUMEN
Purpose: This study aims to explore the value of clinical features, CT imaging signs, and radiomics features in differentiating between adults and children with Mycoplasma pneumonia and seeking quantitative radiomic representations of CT imaging signs. Materials and methods: In a retrospective analysis of 981 cases of mycoplasmal pneumonia patients from November 2021 to December 2023, 590 internal data (adults:450, children: 140) randomly divided into a training set and a validation set with an 8:2 ratio and 391 external test data (adults:121; children:270) were included. Using univariate analysis, CT imaging signs and clinical features with significant differences (p < 0.05) were selected. After segmenting the lesion area on the CT image as the region of interest, 1,904 radiomic features were extracted. Then, Pearson correlation analysis (PCC) and the least absolute shrinkage and selection operator (LASSO) were used to select the radiomic features. Based on the selected features, multivariable logistic regression analysis was used to establish the clinical model, CT image model, radiomic model, and combined model. The predictive performance of each model was evaluated using ROC curves, AUC, sensitivity, specificity, accuracy, and precision. The AUC between each model was compared using the Delong test. Importantly, the radiomics features and quantitative and qualitative CT image features were analyzed using Pearson correlation analysis and analysis of variance, respectively. Results: For the individual model, the radiomics model, which was built using 45 selected features, achieved the highest AUCs in the training set, validation set, and external test set, which were 0.995 (0.992, 0.998), 0.952 (0.921, 0.978), and 0.969 (0.953, 0.982), respectively. In all models, the combined model achieved the highest AUCs, which were 0.996 (0.993, 0.998), 0.972 (0.942, 0.995), and 0.986 (0.976, 0.993) in the training set, validation set, and test set, respectively. In addition, we selected 11 radiomics features and CT image features with a correlation coefficient r greater than 0.35. Conclusion: The combined model has good diagnostic performance for differentiating between adults and children with mycoplasmal pneumonia, and different CT imaging signs are quantitatively represented by radiomics.
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OBJECTIVE: Several studies have demonstrated a significant association between the presence of the ear lobe crease (ELC) and cardiovascular disease. Advanced glycation end-products (AGEs) can affect the structures and functions of proteins and contribute to the development of diabetic complications. However, few studies have reported the relationship between AGEs and ELC. The purpose of this study was to investigate the correlation of skin autofluorescence (SAF)-AGEage (SAF-AGEs × age/100) with ELC. METHODS: This cross-sectional study enrolled 6500 eligible participants from two communities in Beijing. Skin autofluorescence (SAF) was used to measure skin AGEs (SAF-AGEs). SAF-AGEage was defined as AGEs × age/100. Binary logistic regression analysis and linear regression analysis nested in logistic models were applied to test outcomes. RESULTS: The overall prevalence of ELC with an average age of 62.7 years participants was 57.1% (n = 3714). Age, fasting blood glucose, systolic blood pressure, and lipoprotein cholesterol were all greater in participants with ELC. ELC-positive participants had higher prevalence of coronary heart disease. Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGEage and ELC (odds ratio [OR] 1.526, 95% CI 1.324-1.759; OR 2.072, CI 1.791-2.396; and OR 2.983, CI 2.551-3.489) for the multivariate-adjusted models, respectively. Stratified research revealed that those with a history of diabetes, hypertension, or coronary heart disease experienced the connection between SAF-AGEage and ELC. CONCLUSION: ELC is associated with coronary heart disease, and the SAF-AGE has a potential role in ELC development in elder people.
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Enfermedad Coronaria , Diabetes Mellitus , Humanos , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Estudios Transversales , Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Piel/metabolismoRESUMEN
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT.
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Carcinoma de Células Pequeñas , Hipercalcemia , Inmunoterapia , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/terapia , Neoplasias Ováricas/tratamiento farmacológico , Carcinoma de Células Pequeñas/terapia , Carcinoma de Células Pequeñas/tratamiento farmacológico , Hipercalcemia/terapia , Hipercalcemia/etiología , Inmunoterapia/métodos , Persona de Mediana Edad , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: To investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) in the short-term prognosis of elderly patients with severe sepsis combined with diabetes mellitus (DM). METHODS: The clinical data of 162 elderly patients with severe sepsis combined with DM from January 2018 to December 2022 were retrospectively collected. These patients were divided into a survival group (n = 104) and a death group (n = 58) according to 90-day prognosis. The number of neutrophils, lymphocytes, and NLR were compared. The optimal cut-off value for NLR to predict 90-day prognosis in elderly patients with severe sepsis combined with DM was determined using Receiver Operator Characteristic (ROC) curves, and the patients were divided into high and low NLR groups depending on the optimal cut-off value. The Kaplan-Meier method was used to plot the survival curves of the high and low NLR groups. Risk factors for the 90-day death in elderly patients with severe sepsis combined with DM were analyzed by a multivariate cox regression model. RESULTS: There were no significant differences in gender, age, history of hypertension and hyperlipidemia, intensive care unit (ICU) stay, duration of mechanical ventilation, and oxygenation index between the survival group and death group (p > 0.05). However, acute physiological and chronic health evaluation II (APACHE II) scores, and sepsis-related organ failure assessment (SOFA) scores were significantly lower in the survival group compared with the death group (p < 0.05). In the survival group, neutrophils counts and NLR were much lower than those in the death group, while lymphocytes counts were much higher (p < 0.05). ROC curves showed that the optimal cut-off value for NLR to predict 90-day mortality in elderly patients with severe sepsis combined with DM was 3.482. Patients were divided into high NLR and low NLR groups based on whether NLR was ≥ 3.482. In terms of the log-rank test results, patients in the low NLR group had a significantly higher 90-day survival rate than those in the high NLR group (Logrank χ2 = 8.635, p = 0.003). The multivariate cox regression model showed that the length of ICU stay longer than 15 days and NLR ≥ 3.482 were independent risk factors for 90-day prognosis in elderly patients with severe sepsis combined with DM. CONCLUSION: NLR ≥ 3.482 can be used to predict whether poor prognosis occurs in the short term after illness in elderly patients with severe sepsis combined with DM, and has good assessment value.
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Diabetes Mellitus , Sepsis , Humanos , Anciano , Neutrófilos , Estudios Retrospectivos , Linfocitos , Pronóstico , Sepsis/complicaciones , Sepsis/diagnóstico , Sepsis/terapia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Curva ROCRESUMEN
Objective: To compare the diagnostic value of adrenocorticotropic hormone (ACTH) stimulation test (AST) with different doses of ACTH combined with midnight administration of 1 mg dexamethasone for the determination of the subtypes of primary hyperaldosteronism (PA). Methods: This is a prospective observational study. Patients diagnosed with PA in the Department of Endocrinology, the First Medical Center of of Chinese PLA General Hospital from January 1, 2020 to September 30, 2022 underwent AST with different doses of ACTH. All patients received 1 mg dexamethasone at midnight for inhibition. Then, the patients were randomly assigned to 25-unit and 50-unit ACTH treatment groups by a ratio of 1:2. Subtype classification and diagnosis of aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) was made on the basis of adrenal venous blood samples and/or postoperative pathology and clinical follow-up findings. Receiver operating characteristics (ROC) curves were plotted to examine the diagnostic efficacy and the difference of AST by varying doses of ACTH in distinguishing APA and IHA. Results: A total of 82 patients, including 49 patients with APA (59.8%) and 33 patients with IHA (40.2%), were enrolled. There were 29 patients in the 25-unit ACTH group (35.4%) and 53 patients in the 50-unit ACTH group (64.6%). There were no significant differences in age, sex, blood pressure, minimum serum potassium, and biochemical parameters between the 25-unit and 50-unit groups. After ACTH stimulation, plasma aldosterone concentration (PAC), cortisol (F), and PAC/F at different points of time showed no statistical difference between the two groups (P>0.05). The area under the curve (AUC) of PAC in the 25-unit group was higher than that of PAC/F. The AUC of PAC reached the maximum at 90 minutes (0.948, 95% confidence interval [CI]: 0870-1.000) and the optimal cutoff was 38.0 ng/dL, which had a sensitivity of 92.9% and a specificity of 86.7% for differentiating APA and IHA. Similar to the 25-unit group, the maximum AUC of PAC in the 50-unit group was greater than that of PAC/F. The AUC of PAC reached the maximum 90 minutes (0.930, 95% CI: 0.840-0.994) and the optimal cutoff was 39.6 ng/dL, which had a sensitivity of 91.2% and a specificity of 83.3%. The AUC of PAC at different points of time in the 25-unit ACTH group (0.862-0.948) was greater than that of 50-unit ACTH group (0.823-0.930), but the difference was not statistical significance. Conclusion: AST with 25-unit or 50-unit ACTH combined with small-dose dexamethasone can be used in PA subtype determination, ie, differentiation between APA and IHA. The optimal PAC cut-off values for 25-unit or 50-unit ACTH are similar, being 38.0 ng/dL and 39.6 ng/dL, respectively, and both cutoff values show higher sensitivity and specificity at 90 min. The AST with 25-unit ACTH has the smaller dose and the better safety. Therefore, it is recommended for the diagnosis of PA subtypes.
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Hormona Adrenocorticotrópica , Hiperaldosteronismo , Hipertensión , Humanos , Hormona Adrenocorticotrópica/administración & dosificación , Aldosterona , Dexametasona , Hiperaldosteronismo/diagnóstico , Sensibilidad y EspecificidadRESUMEN
PURPOSE: Prostate cancer (PCa) is often considered as a "cold" tumor with low responsiveness to immunotherapy. Recent evidence suggests the activation of specific immune cells, such as tumor-associated macrophages (TAMs), could potentially influence the efficacy of immunotherapy in PCa. However, the relationship between TAMs and PD-L1, a significant regulator in immunotherapy, within PCa remains unexplored. METHODS: In this study, we assessed TAM infiltration and PD-L1 expression levels in a local cohort of 95 PCa tissue samples and two publicly available PCa datasets. We employed a combination of bioinformatics and experimental techniques, including gene set enrichment analysis, CIBERSORTx, tissue microarray, immunohistochemistry staining, and analysis of single-cell sequencing datasets, to provide a comprehensive understanding of the association between PD-L1 and TAMs in the PCa microenvironment. RESULTS: The study showed that CD68+ TAMs and CD163+ TAMs (M2-TAMs) were more abundant in the tumor microenvironment than in non-cancerous surrounding tissues. The infiltration of CD163+ TAMs was significantly associated with the Gleason score and risk stratification of PCa. Importantly, elevated PD-L1 expression correlated significantly with high infiltration of CD163+ TAMs. Furthermore, patients displaying high levels of CD163+ TAMs and PD-L1 expression exhibited shorter times to biochemical recurrence-free survival. CONCLUSION: Our study suggests that CD163+ TAMs are closely associated with PD-L1 expression and can act as a valuable prognostic indicator for PCa. The high infiltration of M2-TAMs, coupled with the overexpression of PD-L1, may contribute to immune escape mechanisms in PCa, thereby influencing disease prognosis.
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Neoplasias de la Próstata , Macrófagos Asociados a Tumores , Humanos , Masculino , Antígeno B7-H1/metabolismo , Inmunoterapia , Macrófagos/metabolismo , Pronóstico , Neoplasias de la Próstata/patología , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismoRESUMEN
BACKGROUND: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.
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Diabetes Mellitus Tipo 2 , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , Masculino , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina Glucada , Cordón Umbilical , Resultado del Tratamiento , Células Madre Mesenquimatosas/fisiologíaRESUMEN
Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been proved a promising clinical strategy for the treatment of diabetes, and time in range (TIR) has been demonstrated a new metric of glycemic control links to diabetes complications. To further assess the therapeutic effect of UC-MSCs on TIR, a phase II study investigating the efficacy of UC-MSCs in Chinese adults with type 2 diabetes (T2D) assessed by retrospective continuous glucose monitoring (CGM) was conducted. In this randomized and placebo-controlled trial, a total of 73 patients were randomly assigned to receive intravenous infusion of UC-MSCs (nâ =â 37) or placebo (nâ =â 36) 3 times at 4-week intervals and followed up for 48 weeks. The primary endpoint was the changes in TIR and glycosylated hemoglobin (HbA1c). TIR and HbA1c were both significantly improved in UC-MSCs and placebo groups after 48 weeks of therapy compared with baseline. Compared with placebo group, UC-MSCs group exhibited more pronounced changes at 9 and 48 weeks from baseline in TIR (26.54 vs. 15.84 and 21.36 vs. 6.32) and HbA1c (-1.79 vs. -0.96 and -1.36 vs. -0.51). More patients in UC-MSCs group achieved the glycemic control target of TIRâ ≥â 70% and HbA1câ <â 7% at 9 and 48 weeks than in placebo group (59.5% vs. 27.8% and 43.2% vs. 11.1%). The C-peptide area under the curve (AUCC-pep) was an independent risk factor associated with efficacy in T2D undergoing UC-MSCs intervention. These results illustrate that UC-MSCs administration via intravenous infusion is an effective approach for ameliorating TIR.
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Diabetes Mellitus Tipo 2 , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Adulto , Humanos , Diabetes Mellitus Tipo 2/terapia , Hemoglobina Glucada , Glucemia , Automonitorización de la Glucosa Sanguínea , Monitoreo Continuo de Glucosa , Estudios Retrospectivos , Cordón Umbilical , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
Upstream-stimulating factor 1 (USF1) is a ubiquitously expressed transcription factor implicated in multiple cellular processes, including metabolism and proliferation. This study focused on the function of USF1 in glycolysis and the malignant development of prostate adenocarcinoma (PRAD). Bioinformatics predictions suggested that USF1 is poorly expressed in PRAD. The clinical PRAD samples revealed a low level of USF1, which was correlated with an unfavorable prognosis. Artificial upregulation of USF1 significantly repressed glycolytic activity in PRAD cells and reduced cell growth and metastasis in vitro and in vivo. Potential downstream genes of USF1 were probed by integrated bioinformatics analyses. The chromatin immunoprecipitation and luciferase assays indicated that USF1 bound to the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) promoter for transcription activation. Flightless I (FLII) was identified as the gene showing the highest degree of correlation with ALKBH5. As an m6A demethylase, ALKBH5 enhanced FLII mRNA stability by inducing m6A demethylation in an m6A-YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2)-dependent manner. Either silencing of ALKBH5 or FLII blocked the role of USF1 in PARD cells and restored glycolysis, cell proliferation, and invasion. This study demonstrates that USF1 activates ALKBH5 to stabilize FLII mRNA in an m6A-YTHDF2-dependent manner, thereby repressing glycolysis processes and the progression of PRAD.
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Adenocarcinoma , Próstata , Masculino , Humanos , Factores de Transcripción , Activación Transcripcional , Adenocarcinoma/genética , Anticuerpos , Glucólisis/genética , Proteínas de Microfilamentos , Transactivadores , Factores Estimuladores hacia 5'/genética , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Proteínas de Unión al ARNRESUMEN
BACKGROUND: The brachial-ankle pulse-wave velocity (baPWV) is regarded as the gold standard in the evaluation of arterial stiffness. Its prognostic significance for major adverse cardiovascular events (MACE) has been demonstrated. However, the factors influencing the association between baPWV and MACE risk have not been determined. In this study, we investigated the association of baPWV and MACE risk and whether it is affected by the risk factors for different cardiovascular diseases (CVDs). METHODS: This was a prospective cohort study that initially enrolled 6850 participants from 12 communities in Beijing. The participants were divided into three subgroups according to their baPWV values. The primary outcome was the first occurrence of MACE, defined as hospitalization from cardiovascular diseases, first occurrence of a nonfatal myocardial infarction, or nonfatal stroke. Cox proportional hazards regression and restricted cubic spline analyses were used to examine the association between baPWV and MACE. The effect of CVD risk factors on the relationship between baPWV and MACE was explored in subgroup analyses. RESULTS: The final study population consisted of 5719 participants. During a median follow-up of 34.73âmonths, MACE occurred in 169 participants. The restricted cubic spline analysis indicated a positive linear relationship between baPWV and MACE risk. After adjustment for cardiovascular risk factors, the hazard ratio (HR) for MACE risk per SD increase in baPWV was 1.272 [95% confidence interval (CI): 1.149-1.407, P â<â0.001], and the HR for MACE in the high-baPWV vs. the low-baPWV group was 1.965 (95% CI: 1.296-2.979, P â=â0.001). Adding baPWV to the conventional cardiovascular risk factors significantly improved the model's prediction performance and the net reclassification (NRI) [NRI: 0.379 (95% CI: 0.072-0.710), P â=â0.025] in MACE discrimination. However, in the subgroup analysis, two CVD risk factors, stable coronary heart disease and hypertension, showed significant interaction effects ( Pinteraction both < 0.05). This result indicated that the effect of CVD risk factors must be taken into account when assessing the relationship between baPWV and MACE. CONCLUSION: baPWV is a potential marker to improve the identification of MACE risk in the general population. A positive linear correlation was firstly determined between baPWV and MACE risk, but it may not be valid in participants with stable coronary heart disease and hypertension.
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Enfermedades Cardiovasculares , Hipertensión , Infarto del Miocardio , Rigidez Vascular , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Tobillo , Índice Tobillo Braquial , Factores de Riesgo , Análisis de la Onda del PulsoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tenuigenin (TEN) is a main pharmacologically active component of Polygala tenuifolia Willd. (Polygalaceae), which has shown neuroprotective functions in Alzheimer's disease. Moreover, TEN also demonstrated an anti-oxidative impact in an in vitro model of Parkinson's disease, reducing damage and loss of dopaminergic neurons. AIM: This work focuses on the impact of TEN on locomotor recovery following spinal cord injury (SCI) and underpinning molecules involved. METHODS: A rat model of SCI was generated, and the rats were treated with TEN, oe-PTPN1 (PTP non-receptor type 1), a protein kinase B (Akt)/mammalian target of rapamycin (mTOR) antagonist LY294002, or an autophagy inhibitor 3-methyladenine (3-MA). Subsequently, locomotor function was detected. Pathological changes and neuronal activity in the spinal cord tissues were analyzed by hematoxylin and eosin staining, Nissl staining, and TUNEL assays. Protein expression of Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3B)-II/LC3B-I, PTPN1, IRS1, mTOR, and phosphorylated Akt (p-Akt) was analyzed by western blot assays. The LC3B expression was further examined by immunofluorescence staining. RESULTS: Treatment with TEN restored the locomotor function of SCI rats, reduced the cavity area and cell apoptosis, upregulated growth-associated protein 43 and neurofilament 200, and decreased the Beclin-1 and LC3B-II/LC3B-I levels in the spinal cord. TEN suppressed PTPN1 protein level, while PTPN1 suppressed IRS1 protein to reduce the p-Akt and mTOR levels. Either PTPN1 overexpression or LY294002 treatment blocked the promoting effect of TEN on SCI recovery. However, treatment with 3-MA suppressed autophagy, which consequently rescued the locomotor function and reduced neuron loss induced by PTPN1. CONCLUSION: This study demonstrates that TEN suppresses autophagy to promote function recovery in SCI rats by blocking PTPN1 and rescuing the IRS1/Akt/mTOR signaling.
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Proteínas Proto-Oncogénicas c-akt , Traumatismos de la Médula Espinal , Ratas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Beclina-1/metabolismo , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/patología , Médula Espinal , Apoptosis , Autofagia , Mamíferos/metabolismoRESUMEN
Background: Castleman Disease (CD) is a group of diseases with characteristic lymph node histopathology, characterized by marked enlargement of deep or superficial lymph nodes. Adrenal CD is rarely reported, and an accurate preoperative diagnosis of adrenal CD is difficult. Method: We report four cases of CD in the adrenal gland confirmed by pathology and review the characteristics of this rare disease, highlighting the necessity of diagnostic evaluation and follow-up of the patients. Results: All of the patients sought medical advice because of adrenal incidentalomas. No significant abnormalities were presented in the biochemistry or endocrine systems. The imaging suggested a moderate-to-large mass with uneven moderate contrast enhancement of the adrenal region, similar to a pheochromocytoma. All cases were misdiagnosed as pheochromocytomas before operation and finally confirmed by histopathology. Three cases were pathologically diagnosed as hyaline vascular CD, and one case was diagnosed as plasma cell CD. All the patients are alive without recurrence after a median follow-up of 8 years. Conclusion: The adrenal CD should be considered after excluding pheochromocytoma and malignancy in the adrenal region. The long-term prognosis of patients with complete resection of the mass is excellent.
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Neoplasias de las Glándulas Suprarrenales , Enfermedad de Castleman , Feocromocitoma , Humanos , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/cirugía , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/cirugía , Enfermedad de Castleman/patología , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Feocromocitoma/diagnóstico , Feocromocitoma/cirugía , PronósticoRESUMEN
BACKGROUND: Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia. METHODS: Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and erythrocyte sedimentation rate (ESR) were measured by standard assays. Ten-year CVD risk was calculated from the Framingham risk score (FRS) model. In vitro study, human cardiac microvascular endothelial cells (HCMECs) were incubated with normal or uremic serum, with or without exogenous MtDNA. Intracellular toll-like receptor 9 (TLR9), adhesion molecule 1 (ICAM-1), MCP-1 and tumor necrosis factor-α (TNF-α) and cytosolic MtDNA were detected by qPCR. RESULTS: Plasma MtDNA in MHD patients was significantly higher than healthy controls (4.74 vs. 2.41 × 105 copies/mL; p = 0.000). Subsequently, the MHD patients were classified into two groups based on the MtDNA median (4.34 × 105 copies/mL). In stratified analyses, the levels of Hs-CRP (5.02 vs. 3.73 mg/L; p = 0.042) and MCP-l (99.97 vs. 64.72 pg/mL; p = 0.008) and FRS (21.80 vs. 16.52; p = 0.016) in the high plasma MtDNA group were higher than those in the low plasma MtDNA group. In vitro study, we found that exogenous MtDNA aggravated uremic serum-induced microvascular inflammation (ICAM-1 and TNF-α) in HCMECs (all p < 0.05). Besides, the addition of MtDNA to the medium resulted in a further increase in cytosolic MtDNA and TLR9 levels in uremic serum-treated cells (all p < 0.05). In patients with MHD, MtDNA levels in plasma were significantly reduced after a single routine hemodialysis (pre 4.47 vs. post 3.45 × 105 copies/mL; p = 0.001) or hemodiafiltration (pre 4.85 vs. post 4.09 × 105 copies/mL; p = 0.001). These two approaches seem similar in terms of MtDNA clearance rate (21.26% vs. 11.94%; p = 0.172). CONCLUSIONS: Overall, the present study suggests that MtDNA released into the circulation under the uremic toxin environment may adversely affect the cardiovascular system by exacerbating microvascular inflammation, and that reducing circulating MtDNA might be a future therapeutic strategy for the prevention of MHD-related CVD.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/genética , Proteína C-Reactiva , Molécula 1 de Adhesión Intercelular , Receptor Toll-Like 9 , ADN Mitocondrial/genética , Factor de Necrosis Tumoral alfa , Células Endoteliales , Diálisis Renal/efectos adversos , Inflamación , Arritmias Cardíacas/etiología , BiomarcadoresRESUMEN
CONTEXT: Intraoperative hemodynamic instability (HI) deteriorates surgical outcomes of patients with normotensive pheochromocytoma (NP). OBJECTIVE: To characterize the hemodynamics of NP and develop and externally validate a prediction model for intraoperative HI. METHODS: Data on 117 patients with NP (derivation cohort) and 40 patients with normotensive adrenal myelolipoma (NAM) who underwent laparoscopic adrenalectomy from January 2011 to November 2021 were retrospectively collected. Data on 22 patients with NP (independent validation cohort) were collected from another hospital during the same period. The hemodynamic characteristics of patients with NP and NAM were compared. Machine learning models were used to identify risk factors associated with HI. The final model was visualized via a nomogram. RESULTS: Forty-eight (41%) out of 117 patients experienced HI, which was significantly more than that for NAM. A multivariate logistic regression including age, tumor size, fasting plasma glucose, and preoperative systolic blood pressure showed good discrimination measured by area under curve (0.8286; 95% CI 0.6875-0.9696 and 0.7667; 95% CI 0.5386-0.9947) for predicting HI in internal and independent validation cohorts, respectively. The sensitivities and positive predictive values were 0.6667 and 0.7692 for the internal and 0.9167 and 0.6111 for the independent validations, respectively. The final model was visualized via a nomogram and yielded net benefits across a wide range of risk thresholds in decision curve analysis. CONCLUSION: Patients with NP experienced HI during laparoscopic adrenalectomy. The nomogram can be used for individualized prediction of intraoperative HI in patients with NP.
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Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Enfermedades Vasculares , Humanos , Presión Sanguínea , Feocromocitoma/diagnóstico , Feocromocitoma/cirugía , Feocromocitoma/complicaciones , Nomogramas , Estudios Retrospectivos , Neoplasias de las Glándulas Suprarrenales/complicaciones , Hemodinámica/fisiologíaRESUMEN
Background: Gitelman Syndrome (GS) patients frequently exhibit disrupted glucose metabolism, attributed to hypokalemia, hypomagnesemia and heightened aldosterone. This study delved into the genetic underpinnings linked to insulin resistance and diabetes in a GS patient, contextualized within his family history. Methods: The hydrochlorothiazide and furosemide loading test were performed to ascertain the presence of GS. Oral glucose tolerance test (OGTT) evaluated glucose metabolism and insulin sensitivity. Whole-exome sequencing, validated by Sanger sequencing, was employed to confirm gene mutations, which were then tracked among the patient's relatives. Results: Symptoms and laboratory examination confirmed the clinical diagnosis of GS. Comprehensive whole-exome sequencing, augmented by Sanger sequencing validation, revealed a compound heterozygous mutation within the SLC12A3 gene (c.1108G>C in exon 9, c.676G>A in exon 5 and c.2398G>A in exon 20) in the patient. The OGTT affirmed diabetes and heightened insulin resistance, distinct from previous patients with GS we evaluated. Further genetic analysis identified a missense heterozygous mutation (c.97C>G in exon 1) within the PDX1 gene, inherited from the patient's diabetic mother without GS. Furthermore, the patient's brother, with impaired glucose tolerance but regular potassium levels, also bore this mutation, hinting at additional impacts of the PDX1 gene mutation on glucose metabolism regulation beyond the known impacts of GS. Conclusion: This study unveils unprecedented compound heterozygous mutations in the SLC12A3 and PDX1 genes in a GS patient. These findings illuminate the potential complex genetic factors influencing glucose metabolism disruptions in GS. Take-home message: This research uncovers a novel combination of SLC12A3 and PDX1 gene mutations in a Gitelman Syndrome patient, revealing intricate genetic factors that potentially disrupt glucose metabolism and shedding light on familial diabetes links.
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Diabetes Mellitus , Síndrome de Gitelman , Resistencia a la Insulina , Masculino , Humanos , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/genética , Resistencia a la Insulina/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Mutación , Diabetes Mellitus/genética , GlucosaRESUMEN
BACKGROUND: Ultrasonography (US) and 99m Technetium-sestamibi scintigraphy (99m Tc-MIBI) are currently first-line imaging modalities to localize parathyroid adenomas with sensitivities of 80% and 84%, respectively. Therefore, finding other modalities to further improve the diagnostic accuracy for preoperative localization is critically needed. PURPOSE: To evaluate the application value of contrast-enhanced ultrasound (CEUS) in the preoperative localization of microwave ablation (MWA) for primary hyperparathyroidism (PHPT). METHODS: Between December 2012 and May 2021, 100 PHPT patients (34 males and 66 females; mean age, 56.31 ± 13.43 years; age range, 25-85 years) with 130 suspected parathyroid nodules were enrolled. US, CEUS, and 99m Tc-MIBI were performed for the localization of pathological parathyroid glands. All patients were performed MWA under ultrasound guidance. All the suspected parathyroid nodules underwent core needle biopsy under ultrasound guidance during MWA to confirm the pathology. The diagnostic performance of all the imaging tests was analyzed in comparison with the pathological results. RESULTS: A total of 130 nodules suspected to be of parathyroid origin from preoperative localization images were confirmed by pathological results, of which 116 were of parathyroid origin, and 14 were not of parathyroid origin. The sensitivity, specificity, accuracy, and the area under receiver operating characteristic curve of CEUS in the localization of pathological parathyroid glands were 100%, 92.86%, 99.23%, and 0.964, which were significantly higher than those of US (93.10%, 42.86%, 87.69%, and 0.680) and 99m Tc-MIBI (81.90%, 42.86%, 77.69%, and 0.624) (p < 0.05). The sensitivity and accuracy of CEUS were 100% and 97.22%, which were higher than those of 99m Tc-MIBI (65.62% and 63.89%) or US (75.00% and 72.22%) in patients with multiple parathyroid glands (p < 0.05). For smaller parathyroid adenomas (≤2 cm in diameter), the sensitivities of CEUS in locating hyperfunctioning parathyroid glands were 100%, which was significantly higher than that of 99m Tc-MIBI (73.68% and 84.31%, p < 0.05). CONCLUSIONS: CEUS is a valuable preoperative localization method for PHPT patients performed MWA, especially for the patients with smaller pathological parathyroid gland and multiple glandular lesions.
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Hiperparatiroidismo Primario , Neoplasias de las Paratiroides , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neoplasias de las Paratiroides/diagnóstico por imagen , Neoplasias de las Paratiroides/cirugía , Hiperparatiroidismo Primario/diagnóstico por imagen , Hiperparatiroidismo Primario/cirugía , Hiperparatiroidismo Primario/patología , Microondas/uso terapéutico , Glándulas Paratiroides/diagnóstico por imagen , Glándulas Paratiroides/cirugía , Glándulas Paratiroides/patología , Tecnecio Tc 99m Sestamibi , Radiofármacos , Ultrasonografía/métodos , Sensibilidad y EspecificidadRESUMEN
The multi-attribute method (MAM) was conceived as a single assay to potentially replace multiple single-attribute assays that have long been used in process development and quality control (QC) for protein therapeutics. MAM is rooted in traditional peptide mapping methods; it leverages mass spectrometry (MS) detection for confident identification and quantitation of many types of protein attributes that may be targeted for monitoring. While MAM has been widely explored across the industry, it has yet to gain a strong foothold within QC laboratories as a replacement method for established orthogonal platforms. Members of the MAM consortium recently undertook an interlaboratory study to evaluate the industry-wide status of MAM. Here we present the results of this study as they pertain to the targeted attribute analytics component of MAM, including investigation into the sources of variability between laboratories and comparison of MAM data to orthogonal methods. These results are made available with an eye toward aiding the community in further optimizing the method to enable its more frequent use in the QC environment.
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Benchmarking , Proteínas , Espectrometría de Masas/métodos , Mapeo Peptídico/métodos , Control de CalidadRESUMEN
BACKGROUND: The coexistence of primary hyperparathyroidism (PHPT) and giant toxic nodular goiter is very rare. Moreover, PHPT could be easily overlooked because hyperthyroidism may also lead to hypercalcemia. A 99mTc-MIBI scan of the parathyroid glands is often negative when they are concomitant. CASE PRESENTATION: Here, we report a rare case of the coexistence of giant toxic nodular goiter and PHPT that had been ignored for many years but was successfully treated with an ultrasound-guided parathyroid adenoma microwave ablation (MWA). CONCLUSION: Reoperation for PHPT carries an increased risk of cure failure and complications. Thermal ablation has been proven effective in inactivating hyperfunctioning parathyroid lesions and in normalizing both serum parathyroid hormone (PTH) and calcium.
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Bocio Nodular , Hiperparatiroidismo Primario , Hipertiroidismo , Neoplasias de las Paratiroides , Bocio Nodular/complicaciones , Bocio Nodular/cirugía , Humanos , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/diagnóstico , Hipertiroidismo/complicaciones , Hormona Paratiroidea , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/cirugía , Tecnecio Tc 99m SestamibiRESUMEN
OBJECTIVE: Patients with hypoparathyroidism always present with recurrent tetany caused by hypocalcemia. These patients are usually misdiagnosed with epilepsy and incorrectly treated with anti-epileptic drugs. This research analyzed clinical data about 22 patients with hypoparathyroidism misdiagnosed as epilepsy and summarized the clinical experience for reducing misdiagnosis and incorrect therapy about hypoparathyroidism. METHOD: Totally 160 patients with hypoparathyroidism, administrated to the First Medical Center of Chinese PLA General Hospital from January 1st, 2008, to July 1st, 2021, were enrolled in this report. Clinical data about 22 patients initially misdiagnosed with epilepsy were analyzed. RESULTS: Of the 160 cases with hypoparathyroidism, 22 patients (12 males and 10 females) were misdiagnosed with epilepsy in local hospitals. The misdiagnosis rate was 13.75% and the median duration of misdiagnosis was 8.0 (2.0, 14.8) years. The clinical manifestations of the 22 patients misdiagnosed as epilepsy included tetany 81.8% (18/22), disturbance of consciousness 27.3% (6/22), limb numbness 13.6% (3/22), limb weakness 27.3% (6/22), mental and behavioral abnormality 9.1% (2/22), and memory impairment 13.6% (3/22), etc. Electroencephalogram (EEG) was performed in 9 cases, which presented as slow wave and spike-slow complex wave in 3 cases, slowing down of θ and δ band background in 2 cases and normal EEG in 4 cases. Out of the 15 cases that underwent head computed tomography (CT) scan, in which 13 cases had intracranial calcification. Anti-epileptic drugs were used to treat 22 patients, of which 17 patients were treated with two kinds of drugs. With calcium and calcitriol supplement in all these 22 patients, the anti-epileptic drugs were gradually reduced and withdrawn in 17 cases. In the other 5 cases with secondary epilepsy, the type of anti-epileptic drugs was reduced to one and the clinical condition improved obviously. CONCLUSION: The clinical manifestations of hypoparathyroidism are complex and usually be misdiagnosed as primary epilepsy. Detection of serum calcium, phosphorus and parathyroid hormone is very important to avoid misdiagnosis and incorrect therapy about hypoparathyroidism.