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Re-irradiation with intensity-modulated radiotherapy (IMRT) remains the primary treatment modality for inoperable locally recurrent nasopharyngeal carcinoma (NPC). However, the rate of radiation-related late adverse effects is often substantially high. Therefore, we aimed to explore failure patterns and individualized treatment plans of re-irradiation for inoperable locally recurrent NPC. Ninety-seven patients who underwent IMRT were retrospectively analyzed. Sixty-two patients had clinical target volume of recurrence (rCTV) delineated, and thirty-five patients had only gross tumor volume of recurrence (rGTV) delineated. Twenty-nine patients developed second local failures after re-irradiation with IMRT (28 cases available). Among those patients, 64.3% (18/28) of patients and 35.7% (10/28) developed in-field or out-field, respectively. No statistical correlation was observed between target volume (rGTV or rCTV) and the local recurrence rate, local failure patterns, grade ≥ 3 toxicity, and survival. Multivariate analysis showed that recurrent T (rT) stage (HR 2.62, P = 0.019) and rGTV volume (HR 1.73, P = 0.037) were independent prognostic factors for overall survival (OS). Risk stratification based on rT stage and rGTV volume revealed that low risk group had a longer 3-year OS rate (66.7% vs. 23.4%), lower total grade ≥ 3 toxicity (P = 0.004), and lower re-radiation associated mortality rates (HR 0.45, P = 0.03) than high risk group. This study demonstrates that the delineation of rCTV may not be beneficial for re-irradiation using IMRT in locally recurrent NPC. Patients with low risk were most suitable for re-irradiation, with maximizing local salvage and minimizing radiation-related toxicities. More precise and individualized plans of re-irradiation are warranted.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Recurrencia Local de Neoplasia , Radioterapia de Intensidad Modulada , Reirradiación , Humanos , Masculino , Persona de Mediana Edad , Femenino , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/patología , Recurrencia Local de Neoplasia/radioterapia , Reirradiación/métodos , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Adulto , Radioterapia de Intensidad Modulada/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Anciano , Estudios Retrospectivos , Insuficiencia del Tratamiento , Medicina de Precisión/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Cytolethal distending toxin (CDT) belongs to the genotoxin family and is closely related to Campylobacter jejuni-associated gastroenteritis. We recently reported that CDT triggers the danger-associated molecular pattern (DAMP) signaling to exert deleterious effects on host cells. However, how CDT traffics in cells and the mechanism of CDT intoxication remain to be elucidated. METHODS: Recombinant CDT subunits (CdtA, CdtB, and CdtC) were purified, and their activity was characterized in gastrointestinal cells. Molecular approaches and image tracking were employed to analyze the delivery of CDT in host cells. RESULTS: In this study, we found that CDT interacts with the receptor of advanced glycation end products (RAGE) and high mobility group box 1 (HMGB1) to enter the cells. Our results further showed that CdtB transport in cells through the dynamin-dependent endocytic pathway and lysosome is involved in this process. Conversely, blockage of RAGE signaling resulted in a reduction in CDT-arrested cell cycles, indicating that RAGE is involved in CDT intracellular transport and its subsequent pathogenesis. CONCLUSION: Our results demonstrate that RAGE is important for CDT trafficking in the cells. These findings expand our understanding of important issues related to host cell intoxication by C. jejuni CDT.
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The inhibitory properties and underlying mechanism of chlorine dioxide (ClO2) fumigation on the pathogen Ceratocystis fimbriata (C. fimbriata) and resultant sweetpotato black rot were investigated in vitro and in vivo. Results revealed that the ClO2 fumigation effectively inhibited fungal growth and induced obvious morphological variation of C. fimbriata mycelia. Furthermore, the mycelial membrane suffered damage, as evidenced by a significant increase in malondialdehyde content and the leakage of protein and nucleic acid from mycelia cells, accompanied by a marked decrease in ergosterol content. Additionally, ClO2 fumigation caused spores cell membrane damage, a notable decrease in spore viability, and induced cell apoptosis as indicated by reductions in spore germination rate, two fluorescence staining observations, and flow cytometry analysis. Moreover, the decay diameter of sweetpotato black rot lesions decreased significantly after ClO2 fumigation, and the growth of C. fimbriata was also inhibited. These findings present a novel and effective technology for inhibiting the progression of sweetpotato black rot.
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Background: The effect of polyphenol subclasses on prostate cancer (PCA) is controversial. Therefore, the purpose of this study was to investigate the relationship between polyphenol subclasses and PCA incidence. Methods: From the establishment of the database to December 2023, a systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library to identify relevant observational studies. The adjusted odds ratio (OR) and corresponding 95% confidence interval (95% CI) were used to assess the association. Results: A total of 38 studies (11 were cohort studies and 27 were case-control studies), composing 824,933 participants, were included in this meta-analysis after excluding irrelevant records. The findings of the study revealed that men who consumed dietary polyphenols had a significantly higher risk of PCA compared to those who never or rarely consumed dietary polyphenols (OR = 1.01, p = 0.023), especially dietary flavonol (OR = 1.05, p = 0.042), flavanol (OR = 1.03, p = 0.026) and anthocyanin (OR = 1.06, p = 0.001). Neither total nor subclasses of dietary polyphenols have an effect on non-localized or high-grade PCA (OR = 1.01, p = 0.518). Dietary isoflavones tended to reduce the incidence of local or low-grade PCA, although there was no statistically significant difference (OR = 1.00, p = 0.081). Regarding serum/plasma polyphenol, total polyphenol (OR = 0.95, p = 0.002), genistein (OR = 0.92, p = 0.029) and enterolactone (OR = 0.92, p = 0.022) can reduce the incidence of PCA. No association was observed between total/subclasses of urinary polyphenols and PCA risk. Conclusion: Polyphenols seem to generally increase the risk of PCA in the male population. The effect of polyphenols on PCA is affected by factors such as polyphenol subclasses, their forms (serum/plasma, urinary, dietary), and PCA-related factors (like PCA stage). Systematic review registration: identifier: CRD42022322699.
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Phenethyl isothiocyanate (PEITC), a natural product, exists in biological activities, including anticancer activity in many human cancer cells. No information shows that PEITC affects DNA damage in human retinoblastoma (RB) cells in vitro. In this study, the aim of experiments was to determine whether PEITC decreased total viable cell number or not by inducing protein expressions involved in DNA damage and repair in Y79 RB cells in vitro. Total cell viability was measured by PI exclusion assay, and PEITC reduced the total Y79 viable cell numbers in a dose-dependent manner. DNA condensation and DNA impairment were conducted by DAPI staining and comet assays, respectively, in Y79 cells. The findings show that PEITC induced DNA condensation dose-dependently based on the brighter fluorescence of cell nuclei stained by DAPI staining. PEITC-induced DNA damage showed a more extended DNA migration smears than that of the control, which was performed by a comet assay. Western blotting was performed to measure the protein expressions involved in DNA damage and repair, which showed that PEITC at 2.5-10 µM increased NRF2, HO-1, SOD (Mn), and catalase; however, it decreased SOD (Cu/Zn) except 10 µM PEITC treatment, and decreased glutathione, which were associated with oxidative stress. Furthermore, PEITC increased DNA-PK, MDC1, H2A.XpSer139, ATMpSer1981, p53, p53pSer15, PARP, HSP70, and HSP90, but decreased TOPIIα, TOPIIß, and MDM2pSer166 that were associated with DNA damage and repair mechanism in Y79 cells. The examination from confocal laser microscopy shows that PEITC increased H2A.XpSer139 and p53pSer15, and decreased glutathione and TOPIIα in Y79 cells. In conclusion, the cytotoxic effects of PEITC on reducing the number of viable cells may be due to the induction of DNA damage and the alteration of DNA repair proteins in Y79 cells in vitro.
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BACKGROUND: Accurately assessing 5-year recurrence rates is crucial for managing non-muscle-invasive bladder carcinoma (NMIBC). However, the European Organization for Research and Treatment of Cancer (EORTC) model exhibits poor performance. PURPOSE: To investigate whether integrating multiparametric MRI (mp-MRI) with clinical factors improves NMIBC 5-year recurrence risk assessment. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-one patients (median age, 65 years; age range, 54-73 years; 27 females) underwent mp-MRI between 2011 and 2017, and received ≥5-year follow-ups. They were divided into a training cohort (N = 115) and validation/testing cohorts (N = 38 in each). Recurrence rates were 23.5% (27/115) in the training cohort and 23.7% (9/38) in both validation and testing cohorts. FIELD STRENGTH/SEQUENCE: 3-T, fast spin echo T2-weighted imaging (T2WI), single-shot echo planar diffusion-weighted imaging (DWI), and volumetric spoiled gradient echo dynamic contrast-enhanced (DCE) sequences. ASSESSMENT: Radiomics and deep learning (DL) features were extracted from the combined region of interest (cROI) including intratumoral and peritumoral areas on mp-MRI. Four models were developed, including clinical, cROI-based radiomics, DL, and clinical-radiomics-DL (CRDL) models. STATISTICAL TESTS: Student's t-tests, DeLong's tests with Bonferroni correction, receiver operating characteristics with the area under the curves (AUCs), Cox proportional hazard analyses, Kaplan-Meier plots, SHapley Additive ExPlanations (SHAP) values, and Akaike information criterion for clinical usefulness. A P-value <0.05 was considered statistically significant. RESULTS: The cROI-based CRDL model showed superior performance (AUC 0.909; 95% CI: 0.792-0.985) compared to other models in the testing cohort for assessing 5-year recurrence in NMIBC. It achieved the highest Harrell's concordance index (0.804; 95% CI: 0.749-0.859) for estimating recurrence-free survival. SHAP analysis further highlighted the substantial role (22%) of the radiomics features in NMIBC recurrence assessment. DATA CONCLUSION: Integrating cROI-based radiomics and DL features from preoperative mp-MRI with clinical factors could improve 5-year recurrence risk assessment in NMIBC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.
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Treatment strategies for hard tissue defects aim to establish a mineralized microenvironment that facilitates tissue remodeling. As a mineralized tissue, cementum shares a similar structure with bone and exhibits an excellent capacity to resist resorption under compression. Macrophages are crucial for mineralized remodeling; however, their functional alterations in the microenvironment of cementum remain poorly understood. Therefore, this study explores the mechanisms by which cementum resists resorption under compression and the regulatory roles of cementoblasts in macrophage functions. As a result, extracellular vesicles from compression-loaded cementoblasts (Comp-EVs) promote macrophage M2 polarization and enhance the clearance of apoptotic cells (efferocytosis) by 2- to 3-fold. Local injection of Comp-EVs relieves cementum destruction in mouse root resorption model by activating the tissue repair function of macrophages. Moreover, Comp-EV-loaded hydrogels achieve significant bone healing in calvarial bone defect. Unexpectedly, under compression, EV secretion in cementoblasts is reduced by half. RNA-Seq analysis and verification reveal that Rab35 expression decreases by 60% under compression, thereby hampering the release of EVs. Rab35 overexpression is proposed as a modification of cementoblasts to boost the yield of Comp-EVs. Collectively, Comp-EVs activate the repair function of macrophages, which will be a potential therapeutic strategy for hard tissue repair and regeneration.
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Objective: To examine the clinical features and synovial pathologies in rheumatoid arthritis (RA) patients across varying titers of circulating anti-citrullinated protein antibodies (ACPA). Methodology: We devised a negative pressure suction and rebound synovial biopsy tool to enhance the yield of synovial biopsies, noted for its ease and safety of use. This research involved a retrospective examination of 60 active RA patients who underwent synovial biopsies with this tool from June to November 2013 at our institution. A range of disease activity markers were collected, including DAS28-CRP, ESR, CRP, count of swollen and tender joints, VAS pain scale, and so forth. Synovial tissue underwent HE staining and immunohistochemistry, including synovitis grading (GSS) and counting of B cells (CD20), T cells (CD3), macrophages (CD68), and plasma cells (CD138). Participants: were categorized into three groups as per ACPA titers: ACPA-negative (0-5U/mL), low-titer (5-20U/mL), and high-titer (above 20U/mL). The study compared the clinical features and synovial pathologies across these groups. Results: Of the 60 RA patients, they were segregated into three groups based on ACPA titers: 20 in ACPA-negative, 9 in the low-titer group, and 31 in the high-titer group. No significant differences were observed in GSS scores, synovial cell proliferation and loss, matrix activation, inflammatory infiltration, and neovascularization among these groups (P > 0.05). The high-titer ACPA group demonstrated significantly increased counts of CD3+ T cells, CD20+ B cells, and CD68+ macrophages in synovial tissues compared to the ACPA-negative and low-titer groups (p < 0.05), along with a higher incidence of ectopic lymphoid neogenesis (p < 0.05). Ordinal logistic regression revealed that rheumatoid factor (RF), and counts of synovial T cells, B cells, macrophages, and ectopic lymphoid neogenesis correlated with ACPA titers (P < 0.05), particularly lymphoid neogenesis (OR = 3.63, P = 0.023). Conclusion: RA patients with high-titer ACPA demonstrate elevated levels of inflammatory cell infiltration in synovial tissues, with ectopic lymphoid neogenesis showing a strong correlation with high ACPA positivity.
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Spinal cystic echinococcosis (CE) is a rare but malignant zoonosis that can cause disability or even death in more than half of patients. Due to the complex pathological features, it is not curable by conventional drugs and surgery, so new therapeutic targets urgently need to be discovered. In this study, we clarify the occurrence of the phenomenon of spinal encapsulation angiogenesis and explore its underlying molecular mechanisms. A co-culture system was established by protoscoleces (PSCs) with human umbilical vein endothelial cells (HUVECs) which showed a high expression level of Nrf2. A short hairpin RNA (shRNA) and Sulforaphane (SFN) affecting the expression of Nrf2 were used to treat HUVECs. The results showed that Nrf2 could promote the tube formation of HUVECs. Nrf2 also exerts a protective effect against HUVECs, which is achieved by promoting NQO1 expression to stabilize ROS levels. Furthermore, autophagy activation significantly promotes angiogenesis in the spinal echinococcosis model (SEM) as a result of Nrf2 regulation of oxidative stress. These results suggest that the ROS/Nrf2/autophagy axis can induce angiogenesis and may be a potential target for the treatment of spinal cystic echinococcosis.
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Autofagia , Equinococosis , Células Endoteliales de la Vena Umbilical Humana , Factor 2 Relacionado con NF-E2 , Neovascularización Patológica , Estrés Oxidativo , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Humanos , Autofagia/efectos de los fármacos , Autofagia/fisiología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Animales , Neovascularización Patológica/metabolismo , Equinococosis/metabolismo , Ratones , Técnicas de Cocultivo , Masculino , AngiogénesisRESUMEN
BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using KaplanâMeier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.
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Neoplasias Nasofaríngeas , Reirradiación , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/cirugía , Estudios Retrospectivos , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Pronóstico , Ganglios Linfáticos/patologíaRESUMEN
Graphene oxide (GO) with its atomic thickness and abundant functional groups holds great potential in molecular-scale membrane separation. However, constructing high-speed and highly selective water transport channels within GO membranes remains a key challenge. Herein, sulfonato calix[n]arenes (SCn) molecules with a cavity structure, hydrophilic entrance, and hydrophobic wall were incorporated into GO interlayer channels through a layer-by-layer assembly approach to facilitate water permeation in a water/ethanol separation process. The hydrophilic entrance enables preferential access of water molecules to the cavity over ethanol molecules, while the high hydrophobicity of the cavity wall confers low resistance for water diffusion. After incorporating SCn molecules, the membrane shows a remarkable increase in the water/ethanol separation factor from 732 to 1260, while the permeate flux also increases by about 50%. In addition, the strong electrostatic interactions between the building blocks endow the membrane with excellent swelling resistance even under a high water content. This work provides an effective strategy of constructing high-efficiency water transport channels in membrane.
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OBJECTIVES: To create a MRI-derived radiomics nomogram that combined clinicopathological factors and radiomics signature (Rad-score) for predicting disease-free survival (DFS) in patients with bladder cancer (BCa) following partial resection (PR) or radical cystectomy (RC), including lymphadenectomy (LAE). METHODS: Finally, 80 patients with BCa after PR or RC with LAE were enrolled. Patients were randomly split into training (n = 56) and internal validation (n = 24) cohorts. Radiomic features were extracted from T2-weighted, dynamic contrast-enhanced, diffusion-weighted imaging, and apparent diffusion coefficient sequence. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was applied to choose the valuable features and construct the Rad-score. The DFS prediction model was built using the Cox proportional hazards model. The relationship between the Rad-score and DFS was assessed using Kaplan-Meier analysis. A radiomics nomogram that combined the Rad-score and clinicopathological factors was created for individualized DFS estimation. RESULTS: In both the training and validation cohorts, the Rad-score was positively correlated with DFS (P < .001). In the validation cohort, the radiomics nomogram combining the Rad-score, tumour pathologic stage (pT stage), and lymphovascular invasion (LVI) achieved better performance in DFS prediction (C-index, 0.807; 95% CI, 0.713-0.901) than either the clinicopathological (C-index, 0.654; 95% CI, 0.467-0.841) or Rad-score-only model (C-index, 0.770; 95% CI, 0.702-0.837). CONCLUSION: The Rad-score was an independent predictor of DFS for patients with BCa after PR or RC with LAE, and the radiomics nomogram that combined the Rad-score, pT stage, and LVI achieved better performance in individual DFS prediction. ADVANCES IN KNOWLEDGE: This study provided a non-invasive and simple method for personalized and accurate prediction of DFS in BCa patients after PR or RC.
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Cistectomía , Neoplasias de la Vejiga Urinaria , Humanos , Supervivencia sin Enfermedad , Nomogramas , RadiómicaRESUMEN
An unprecedented one-pot route to achieve highly regioselective 1-sulfur-functionalized 2-nitrogen-functionalized alkenes and 2-thiocyanate indolines from unsymmetrical ynamides (readily and generally available amides) using the commercially available inexpensive iodobenzene diacetate (PIDA) as the oxidant and potassium thiocyanate (KSCN) as the thiocyanate (SCN) source has been developed. The interconversion of thiocyanate (SCN) and isothiocyanate (NCS) groups simultaneously forms C-N and C-S bonds in this metal-free approach, while introducing important functional groups into homemade alkynes. A radical-chain mechanism, involving competing kinetically controlled chain transfer at the S atom and sterically-controlled chain transfer at the N atom of the thiocyanogen molecule in this mild approach, is proposed.
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PW06 [(E)-3-(9-ethyl-9H-carbazol-3-yl)-1-(2,5-dimethoxyphenyl) prop-2-en-1-one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1-0.8 µM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa-2 cells in vitro. Wound healing assay shows PW06 at 0.2 µM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 µM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1-0.2 µM) suppressed the cell migration (decreased 26.67-35.42%) and invasion (decreased 48.51-68.66%). Atomic force microscopy assay shows PW06 (0.2 µM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p-JNK, p-ERK, and p-p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/ß, and E-cadherin. Nevertheless, results also show PW06 decreased p-Akt, mTOR, NF-κB, p-GSK3ß, ß-catenin, Snail, N-cadherin, and vimentin in MIA PaCa-2 cells. The confocal laser microscopy examination shows PW06 increased E-cadherin but decreased vimentin in MIA PaCa-2 cells. Together, our findings strongly suggest that PW06 inhibited the p-Akt/mTOR/NF-κB/MMPs pathways, increased E-cadherin, and decreased N-cadherin/vimentin, suppressing the migration and invasion in MIA PaCa-2 cells in vitro.
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FN-kappa B , Neoplasias Pancreáticas , Humanos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vimentina/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Línea Celular Tumoral , Transducción de Señal , Cadherinas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Movimiento Celular , Proliferación CelularRESUMEN
Irinotecan (IRI), an anticancer drug to treat colon cancer patients, causes cytotoxic effects on normal cells. Phenethyl isothiocyanate (PEITC), rich in common cruciferous plants, has anticancer activities (induction of cell apoptosis) in many human cancer cells, including colon cancer cells. However, the anticancer effects of IRI combined with PEITC on human colon cancer cells in vitro were unavailable. Herein, the aim of this study is to focus on the apoptotic effects of the combination of IRI and PEITC on human colon cancer HCT 116 cells in vitro. Propidium iodide (PI) exclusion and Annexin V/PI staining assays showed that IRI combined with PEITC decreased viable cell number and induced higher cell apoptosis than that of IRI or PEITC only in HCT 116 cells. Moreover, combined treatment induced higher levels of reactive oxygen species (ROS) and Ca2+ than that of IRI or PEITC only. Cells pre-treated with N-acetyl-l-cysteine (scavenger of ROS) and then treated with IRI, PEITC, or IRI combined with PEITC showed increased viable cell numbers than that of IRI or PEITC only. IRI combined with PEITC increased higher caspase-3, -8, and -9 activities than that of IRI or PEITC only by flow cytometer assay. IRI combined with PEITC induced higher levels of ER stress-, mitochondria-, and caspase-associated proteins than that of IRI or PEITC treatment only in HCT 116 cells. Based on these observations, PEITC potentiates IRI anticancer activity by promoting cell apoptosis in the human colon HCT 116 cells. Thus, PEITC may be a potential enhancer for IRI in humans as an anticolon cancer drug in the future.
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Apoptosis , Neoplasias del Colon , Humanos , Irinotecán/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células HCT116 , Línea Celular Tumoral , Isotiocianatos/farmacología , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
BACKGROUND: Periodontal ligament cells (PDLCs) are key mechanosensory cells involved in extracellular matrix (ECM) remodeling during orthodontic tooth movement (OTM). Mechanical force changes the ECM components, such as collagens and matrix metalloproteinases. However, the associations between the changes in ECM molecules and cellular dynamics during OTM remain largely uncharacterized. OBJECTIVES: To investigate the influence of mechanical force on the morphology and migration of PDLCs and explore the interaction between ECM remodeling and cellular dynamics, including the detailed mechanisms involved. METHODS: Human PDLCs (hPDLCs) were subjected to a static mechanical compression to mimic the compression state of OTM in vitro. A mouse OTM model was used to mimic the OTM procedure in vivo. The migration of hPDLCs was compared by wound healing and transwell migration assays. Moreover, expression levels of ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) and fibronectin (FN) in hPDLCs were determined via western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assays. Expression levels of ADAMTS9 and FN in mice were assessed via immunohistochemical staining. Additionally, the relative expression of long non-coding RNA (lncRNA) ADAMTS9-antisense RNA 2 (ADAMTS9-AS2) was assessed via quantitative real-time polymerase chain reaction. ADAMTS9-AS2 knockdown was performed to confirm its function in hPDLCs. RESULTS: Mechanical compression induced changes in the morphology of hPDLCs. It also promoted migration and simultaneous upregulation of FN and downregulation of ADAMTS9, a fibronectinase. The mouse OTM model showed the same expression patterns of the two proteins on the compression side of the periodontium of the moved teeth. RNA sequencing revealed that lncRNA ADAMTS9-AS2 expression was significantly upregulated in hPDLCs under mechanical compression. After knocking down ADAMTS9-AS2, hPDLCs migration was significantly inhibited. ADAMTS9 expression was increased as FN expression decreased compared to that in the control group. Moreover, knockdown of ADAMTS9-AS2 reduced the effect of mechanical compression on hPDLCs migration and reversed the expression change of ADAMTS9 and FN. RNA immunoprecipitation revealed direct binding between ADAMTS9-AS2 and ADAMTS9 protein. CONCLUSION: Our study suggests that mechanical compression induces the expression of ADAMTS9-AS2, which directly binds to ADAMTS9 and inhibits its function, leading to the promotion of downstream FN expression and ECM remodeling to facilitate hPDLCs migration and maintain the stability of the periodontium.
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ARN Largo no Codificante , Humanos , Ratones , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ligamento Periodontal/metabolismo , Proteína ADAMTS9/genética , Proteína ADAMTS9/metabolismo , Fibronectinas , Movimiento Celular , Proliferación Celular/genéticaRESUMEN
INTRODUCTION: Primary brainstem hemorrhage (PBSH) is the most fatal subtype of intracerebral hemorrhage and is associated with poor prognosis. We aimed to develop a prediction model for predicting 30-day mortality and functional outcome in patients with PBSH. METHODS: We reviewed records of 642 consecutive patients with first-time PBSH from three hospitals between 2016 and 2021. Multivariate logistic regression was used to establish a nomogram in a training cohort. Cutoff points of the variables were determined by receiver operating characteristic curve analysis, and certain points were assigned to these predictors to produce the PBSH score. The nomogram and PBSH score were compared with other scoring systems for PBSH. RESULTS: Five independent predictors, comprised of temperature, pupillary light reflex, platelet-to-lymphocyte ratio, Glasgow Coma Scale (GCS) score on admission, and hematoma volume, were incorporated to construct the nomogram. The PBSH score consisted of 4 independent factors with individual points assigned as follows: temperature, ≥38°C (=1 point), <38°C (=0 points); pupillary light reflex, absence (=1 point), presence (=0 points); GCS score 3-4 (=2 points), 5-11 (=1 point), and 12-15 (=0 points); PBSH volume >10 mL (=2 points), 5-10 mL (=1 point), and <5 mL (=0 points). Results showed that the nomogram was discriminative in predicting both 30-day mortality (area under the ROC curve [AUC] of 0.924 in the training cohort, and 0.931 in the validation cohort) and 30-day functional outcome (AUC of 0.887). The PBSH score was discriminative in predicting both 30-day mortality (AUC of 0.923 in the training cohort and 0.923 in the validation cohort) and 30-day functional outcome (AUC of 0.887). The prediction performances of the nomogram and the PBSH score were superior to the intracranial hemorrhage (ICH) score, primary pontine hemorrhage (PPH) score, and new PPH score. CONCLUSIONS: We developed and validated two prediction models for 30-day mortality and functional outcome in patients with PBSH. The nomogram and PBSH score could predict 30-day mortality and functional outcome in PBSH patients.
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Hemorragia Cerebral , Hemorragias Intracraneales , Humanos , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/terapia , Hemorragias Intracraneales/diagnóstico , Hemorragias Intracraneales/terapia , Curva ROC , Nomogramas , Estudios Retrospectivos , Tronco Encefálico , PronósticoRESUMEN
Antimicrobial peptides (AMPs) are natural molecules that function within the innate immune system to counteract pathogenic invasion and minimize the detrimental consequences of infection. However, utilizing these molecules for medical applications has been challenging. In this study, we selected a model AMP with poor stability, Tilapia Piscidin 4 (TP4), and modified its sequence and chirality (TP4-γ) to improve its potential for clinical application. The strategy of chirality inversion was inspired by the cereulide peptide, which has a DDLL enantiomer pattern and exhibits exceptional stability. Sequential substitution of key residues and selective chirality inversion yielded a less toxic peptide with enhanced stability and notable antimicrobial activity. In addition to its superior stability profile and antimicrobial activity, TP4-γ treatment reduced the level of LPS-induced nitric oxide (NO) release in a macrophage cell line. This reduction in NO release may reflect anti-inflammatory properties, as NO is widely known to promote inflammatory processes. Hence, our heterochiral peptide construct shows a more suitable pharmacokinetic profile than its parental compound, and further studies are warranted to develop the molecule for potential clinical application.