Cell-Membrane-Coated Metal-Organic Framework Nanocarrier Combining Chemodynamic Therapy for the Inhibition of Hepatocellular Carcinoma Proliferation.

Chemodynamic therapy (CDT) employs hydrogen peroxide (H2O2) within the tumor microenvironment (TME) to initiate the Fenton reaction and catalyze the generation of hydroxyl radicals (·OH) for targeted therapy. Metal ion-based nanomaterials have garnered significant attention as catalysts due to their potent anti-tumor effects. Hypoxia in the TME is often associated with cancer cell development and metastasis, with HIF-1α being a pivotal factor in hypoxia adaptation. In this study, an organic framework called MIL-101 (Fe) was designed and synthesized to facilitate H2O2-induced ·OH production while also serving as a carrier for the HIF-1α inhibitor Acriflavine (ACF). A biomimetic nanomedical drug delivery system named MIL-101/ACF@CCM was constructed by encapsulating liver cancer cell membranes onto the framework. This delivery system utilized the homologous targeting of tumor cell membranes to transport ACF, inhibiting HIF-1α expression, alleviating tumor hypoxia, and catalyzing ·OH production for effective tumor eradication. Both in vivo and in vitro experiments confirmed that combining ACF with chemotherapy achieved remarkable tumor inhibition by enhancing ROS production and suppressing HIF-1α expression.

GLDC mitigated by miR-30e regulates cell proliferation and tumor immune infiltration in TNBC.

Background: TNBC, whose clinical prognosis is poorer than other subgroups of breast cancer, is a malignant tumor characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression. Due to the lack of specific targeted drugs, it is crucial to identify critical factors involved in regulating the progression of TNBC. Methods: We analyzed the expression profiles of TNBC in TCGA and the prognoses values of GLDC. Correlations of GLDC and tumor immune infiltration were also identified. CCK8 and BrdU incorporation assays were utilized to determine cell proliferation. The mRNA and protein levels were examined by using Real-time PCR and Western blot analysis. Results: In the present study, we analyzed the mRNA expression profiles of TNBC in TCGA and found that GLDC, a key enzyme in glycine cleavage system, was significantly up-regulated in TNBC tissues and higher expression of GLDC was correlated with a worse prognosis in TNBC. Moreover, the expression of GLDC was negatively correlated with macrophage and monocyte and positively correlated with activated CD4 T cell and type 2 T helper cell in TNBC. Overexpression of GLDC facilitated the proliferation of TNBC cells, whereas GLDC knockdown had the opposite effects. Additionally, miR-30e acts as a functional upstream regulator of GLDC and the inhibitory effects of miR-30e on cell proliferation were mitigated by the reintroduction of GLDC. Conclusions: These results imply that miR-30e-depressed GLDC acts as a tumor suppressive pathway in TNBC and provides potential targets for the treatment of TNBC.

Diffusion-weighted MRI and 18F-FDG PET/CT in assessing the response to neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a currently widely used strategy for locally advanced esophageal cancer (EC). However, the conventional imaging methods have certain deficiencies in the evaluation and prediction of the efficacy of nCRT. This study aimed to explore the value of functional imaging in predicting the response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Fifty-four patients diagnosed with locally advanced ESCC from August 2017 to September 2019 and treated with nCRT were retrospectively analyzed. DW-MRI scanning was performed before nCRT, at 10-15 fractions of radiotherapy, and 4-6 weeks after the completion of nCRT. 18F-FDG PET/CT scans were performed before nCRT and 4-6 weeks after the completion of nCRT. These 18F-FDG PET/CT and DW-MRI parameters and relative changes were compared between patients with pathological complete response (pCR) and non-pCR. RESULTS: A total of 8 of 54 patients (14.8%) were evaluated as disease progression in the preoperative assessment. The remaining forty-six patients underwent operations, and the pathological assessments of the surgical resection specimens demonstrated pathological complete response (pCR) in 10 patients (21.7%) and complete response of primary tumor (pCR-T) in 16 patients (34.8%). The change of metabolic tumor volume (∆MTV) and change of total lesion glycolysis (∆TLG) were significantly different between patients with pCR and non-pCR. The SUVmax-Tpost, MTV-Tpost, and TLG-Tpost of esophageal tumors in 18F-FDG PET/CT scans after neoadjuvant chemoradiotherapy and the ∆ SUVmax-T and ∆MTV-T were significantly different between pCR-T versus non-pCR-T patients. The esophageal tumor apparent diffusion coefficient (ADC) increased after nCRT; the ADCduring, ADCpost and ∆ADCduring were significantly different between pCR-T and non-pCR-T groups. ROC analyses showed that the model that combined ADCduring with TLG-Tpost had the highest AUC (0.914) for pCR-T prediction, with 90.0% and 86.4% sensitivity and specificity, respectively. CONCLUSION: 18F-FDG PET/CT is useful for re-staging after nCRT and for surgical decision. Integrating parameters of 18F-FDG PET/CT and DW-MRI can identify pathological response of primary tumor to nCRT more accurately in ESCC.

A retrospective analysis of the risk factors affecting recurrence time in patients with recurrent glioblastoma.

BACKGROUND: This study explored the related factors that influence the recurrence time of glioblastomas (GBM). METHODS: A retrospective study of recurrent GBM patients with surgical resection was performed. Recurrence time was analyzed using Kaplan-Meier survival curves. The Cox regression model was used to investigate the possible factors associated with recurrence time. RESULTS: A total of 176 patients (113 males and 63 females) were enrolled in the study, with a median age of 57 years (range, 19-76 years). From this cohort, 18 patients (10.2%) had gross total resection (GTR), 53 patients (30.1%) had subtotal resection (STR), and 105 patients (59.7%) had partial resection (PR). Postoperatively, all patients received radiotherapy (RT), with 55.1% administered concurrent chemotherapy (CTh) and 59.7% administered adjuvant CTh. The median recurrence time was 10.0 months (range, 1.0-75.0 months). Patients with PR (P=0.004), gliomas that contacted the subventricular zone (SVZ) (P=0.004), isocitrate dehydrogenase 1 (IDH1) wild-type (P=0.048), telomerase reverse transcriptase (TERT) C228T wild-type (P=0.012), and positive glial fibrillary acidic protein (GFAP) expression (P=0.044) had a shortened time to recurrence. Cox regression analysis revealed that PR (P=0.036), SVZ contact (P=0.008), and TERT C228T wild type (P=0.023) were significantly associated with a shortened recurrence time. CONCLUSIONS: PR, tumor contacting the SVZ, and TERT C228T wild type were independent risk factors for tumor recurrence in patients with GBM.

Splenic irradiation combined with tumor irradiation promotes T cell infiltration in the tumor microenvironment and helps in tumor control.

Locally applied radiation to the tumor is reported to stimulate systemic immune response. During radiotherapy to the abdominal cancer, spleen often receives certain dose, though as an important immune organ, little is known about the impact of splenic irradiation (SI) on systemic immune and local tumor control. Through a mice model, we found that the combination of SI with tumor irradiation (TI) helped in local control. The analysis of the tumor infiltrating leucocytes demonstrated that SI plus TI brought more T cell aggregation in the tumor microenvironment (TME), which helped in tumor control. Increased T cell infiltration may be partly due to higher expression of T cell chemokine in the TME and more expression of CXCR3 on the T cells in the spleen after SI. SI produced more IL-1ß in the spleen, IL-1ß stimulated the expression of CXCR3 on the T cells, and enhanced their migration ability. Taken together, radiation to the spleen combined with TI helped in local control through promoting T cell infiltration, and may be a considerable means to enhance the immunomodulatory of radiotherapy.

ROS-dependent Atg4 upregulation mediated autophagy plays an important role in Cd-induced proliferation and invasion in A549 cells.

Cadmium (Cd) is a toxic heavy metal that is widely used in industry and agriculture. In this study the role of autophagy in Cd-induced proliferation, migration and invasion was investigated in A549 cells. Exposure to Cd (2 µM) significantly increased reactive oxygen species (ROS) production, induced autophagy and enhanced cell growth, migration and invasion in A549 cells. Western blot analysis showed that the expression of autophagy-related proteins, LC3-II, Beclin-1 and Atg4 and invasion-related protein MMP-9 were upregulated in Cd-treated cells. N-acetyl cysteine (NAC) markedly prevented Cd-induced proliferation of A549 cells and the increasing protein level of LC3-II and Atg4. Blocking Atg4 expression by siRNA strongly reduced Beclin-1 and LC3-II protein expression and the number of autophagosome positive cells induced by Cd. Furthermore, Atg4 siRNA increased the number of cells at G0/G1 phase, reduced the number of S and G2/M phase cells, and inhibited Cd-induced cell growth significantly compared with that of Cd-treated Control siRNA cells. 3-MA pretreatment increased the percentage of G0/G1 phase cells, decreased S phase and G2/M phase percentage, and inhibited Cd-induced cell growth remarkably compared with that of only Cd-treated cells. Knocking down Atg4 reduced the number of cells that migrated and invaded through the Matrigel matrix significantly and led to a significant decrease of MMP-9 expression. In addition, in lung tissues of Cd-treated BALB/c mice, the increased expression of LC3-II, Beclin-1 and Atg4 were observed. Taken together, our results demonstrated that ROS-dependent Atg4-mediated autophagy plays an important role in Cd-induced cell growth, migration and invasion in A549 cells.

Comparison and Prognostic Analysis of Adjuvant Radiotherapy versus Salvage Radiotherapy for Treatment of Radically Resected Locally Advanced Esophageal Squamous Cell Carcinoma.

Objective. To compare adjuvant radiotherapy and salvage radiotherapy after radical resection for treatment of esophageal squamous cell carcinoma (ESCC). Methods. Data from 155 patients with locally advanced ESCC who underwent radical resection and received postoperative radiotherapy from 2005 to 2011 were reviewed. Seventy-nine patients received adjuvant radiotherapy and 76 received salvage radiotherapy after locoregional recurrence. Results. The median disease-free survival (DFS) and overall survival (OS) were significantly higher in the adjuvant radiotherapy group than the salvage radiotherapy group (DFS 25.73 months versus 10.73 months, P < 0.001; OS 33.33 months versus 26.22 months, P = 0.006). The independent prognostic factors for DFS were performance status (PS) before radiotherapy and pathological stage in the adjuvant radiotherapy group, compared with lymph node metastasis, tumor location, and adjuvant chemotherapy in the salvage radiotherapy group. The independent prognostic factors for OS were age and PS in both groups. No differences in median DFS and OS between the groups were observed in patients aged > 65 years or with PS ≥ 2. Conclusion. Compared to salvage radiotherapy, postoperative adjuvant radiotherapy can prolong DFS and OS for patients with radically resected local advanced ESCC but cannot improve survival for patients aged > 65 years or with PS ≥ 2.

ROS-dependent HMGA2 upregulation mediates Cd-induced proliferation in MRC-5 cells.

Cadmium (Cd) is a heavy metal widely found in a number of environmental matrices, and the exposure to Cd is increasing nowadays. In this study, the role of high mobility group A2 (HMGA2) in Cd-induced proliferation was investigated in MRC-5 cells. Exposure to Cd (2µM) for 48h significantly enhanced the growth of MRC-5 cells, increased reactive oxygen species (ROS) production, and induced both mRNA and protein expression of HMGA2. Evidence for Cd-induced reduction of the number of G0/G1 phase cells and an increase in the number of cells in S phase and G2/M phase was sought by flow cytometric analysis. Western blot analysis showed that cyclin D1, cyclin B1, and cyclin E were upregulated in Cd-treated cells. Further study revealed that N-acetyl cysteine (NAC) markedly prevented Cd-induced proliferation of MRC-5 cells, ROS generation, and the increasing protein level of HMGA2. Silencing of HMGA2 gene by siRNA blocked Cd-induced cyclin D1, cyclin B1, and cyclin E expression and reduction of the number of G0/G1 phase cells. Combining, our data showed that Cd-induced ROS formation provoked HMGA2 upregulation, caused cell cycle changes, and led to cell proliferation. This suggests that HMGA2 might be an important biomarker in Cd-induced cell proliferation.

Effects of medication methods after simple and effective probing of lacrimal passage.

AIM: To evaluate the effect of reducing the use of antibiotics in the treatment of infant bacterial dacryocystitis after probing of the lacrimal duct. METHODS: A total of 542 cases of children under one year old and accepting nasolacrimal duct probing treatment were divided into two groups, which were treated with topical and oral antibiotics, respectively. Conjunctival sac secretions were used as a control index of bacterial infection, whereas the disappearance of epiphora symptoms and lacrimal passage patency were used as cure indexes. The χ (2) test was used to compare enumeration and measurement data, and a statistical significance was set at P<0.05. The therapeutic effect on the two groups of postoperative patients was investigated. RESULTS: In the two study groups, no significant differences in gender, age and postoperative control of lacrimal sac infection were observed. The cure rates after three probing operations also showed no significant difference. CONCLUSION: After probing of the lacrimal passage, results of this study confirmed that postoperative medication without oral antibiotics but an ophthalmic dosage of antibiotics was a simple and effective treatment method.

Esophageal perforation during or after conformal radiotherapy for esophageal carcinoma.

The aim of this study was to analyze the risk factors and prognosis for patients with esophageal perforation occurring during or after radiotherapy for esophageal carcinoma. We retrospectively analyzed 322 patients with esophageal carcinoma. These patients received radiotherapy for unresectable esophageal tumors, residual tumors after operation, or local recurrence. Of these, 12 had radiotherapy to the esophagus before being admitted, 68 patients had concurrent chemoradiotherapy (CRT), and 18 patients had esophageal perforation after RT (5.8%). Covered self-expandable metallic stents were placed in 11 patients. Two patients continued RT after stenting and control of infection; one of these suffered a new perforation, and the other had a massive hemorrhage. The median overall survival was 2 months (0-3 months) compared with 17 months in the non-perforation group. In univariate analysis, the Karnofsky performance status (KPS) being ≤ 70, age younger than 60, T4 stage, a second course of radiotherapy to the esophagus, extracapsular lymph nodes (LN) involving the esophagus, a total dose >100 Gy (biologically effective dose-10), and CRT were risk factors for perforation. In multivariate analysis, age younger than 60, extracapsular LN involving the esophagus, T4 stage, and a second course of radiotherapy to the esophagus were risk factors. In conclusion, patients with T4 stage, extracapsular LN involving the esophagus, and those receiving a second course of RT should be given particular care to avoid perforation. The prognosis after perforation was poor.

Effectiveness and toxicities of intensity-modulated radiotherapy for patients with locally recurrent nasopharyngeal carcinoma.

PURPOSE: To analyze the effectiveness and toxicities in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT). METHODS: This is a retrospective analysis of 54 NPC patients with local recurrence re-irradiated with IMRT. The re-staging for rT1, rT2, rT3, rT4 were 3 (5.6%), 8 (14.8%), 9 (16.7%), 34 (63%) respectively. The average dose to GTV was 69.95 Gy (49.8-76.58 Gy), the average BED(3Gy) was 116.8 Gy (83.5-127.9 Gy). V95 was 96%, and D95 was 65.75 Gy. 33.3% of them received concurrent chemoradiotherapy. RESULTS: Median overall survival (OS) was 21 months (1-93 mon). The 1-, 2-year local progression free survival (LPFS) rate was 84.5%, 64% and OS rate was 71.7%, 44.3%. Severe late adverse events (SLAE) occurred in 48.1% of patients, including 31.5% with ulcer or necrosis of the nasopharyngeal mucosa, 20.4% with difficulty in feeding, 18.5% with temporal lobe necrosis, 11.1% with massive hemorrhage. 15.4% died of local regional progression, 5.8% died of distant metastasis, 25% died of SLAE, 9.6% died of both local regional progression and SLAE that could not be differentiated, 5.8% died of other medical complications. Concurrent chemoradiotherapy was the independent negative prognostic factors for LPFS; PTV>100 ml was a predictive factor of poor OS; patients with invasion of post-styloid space were at higher risk of SLAE. CONCLUSIONS: The present study demonstrated that IMRT with 70Gy was efficient for local tumor control. However, we observed a high frequency of serious late complications. More optimized combination treatment and patient selection are required to achieve excellent local control without significant late morbidities in locally recurrent NPC.

[Analysis on the result of retinopathy of prematurity screening in 1225 premature infants].

OBJECTIVE: To investigate the factors involved in the development of retinopathy of prematurity (ROP), and to provide the preliminary data for the evaluation of current criteria for ROP screening. METHOD: Premature infants with birth body weight (BBW) ≤ 2000 g or gestational age (GA) ≤ 34 weeks in the two hospitals in Zhejiang between March 2005 and November 2008 were recruited and examined by indirect ophthalmoscopy. The records were analyzed. RESULT: One thousand two hundred and twenty-five premature infants were included. Of them, 713 were male and 512 female. There were 179 twins and 21 triplets in the premature infants. The incidence of ROP was 10.8% (132 in 1225 patients). There were 12 cases (0.98%) to the point of pre threshold ROP. 4 cases (0.3%) developed threshold ROP. Only one case developed pre threshold ROP of low risk among 65 cases without history of oxygen treatment (1.5%). The percentage has significant difference compared to that of cases with history of oxygen (χ(2) = 5.115, P < 0.01).Between ROP and Non-ROP groups, there was significant difference in BBW(F = 26.39, P < 0.001), gestational age (F = 19.73, P < 0.001), but there was no significant difference in sex (χ(2) = 0.279, P > 0.05) or twins and triplets (χ(2) = 3.449, P > 0.05). The incidence of ROP among premature infants with BBW ≤ 1000 g was more than three times of that with BBW > 1000 g, and the incidence of ROP among premature infants with GA ≤ 28 weeks was about 2.5 times of that with GA > 28 weeks. Logistic regression analysis indicated that less BBW or shorter GA or undulation of blood oxygen concentration was a significant risk factor involved in the development of ROP (r = 0.57, P < 0.05). All ROP patients were cured. CONCLUSION: Less BBW, shorter GA and undulation of blood oxygen concentration are the important risk factors for the development of ROP. Premature infants with BBW ≤ 1000 g or GA ≤ 28 weeks, who had oxygen history, should be given very special attention in the ROP screening. The current criteria for ROP screening should be narrowed. In general, the ROP screening has lowered the incidence of blindness among children by investigating and treating ROP timely.