Dacomitinib exhibits promising activity against the rare HER2 exon 20 insertion M774delinsWLV in lung cancer: A case report and literature review.

A775_G776insYVMA, the typical and predominant HER2 exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent HER2-targeted tyrosine kinase inhibitors. However, other less common insertions have shown better responses to HER2-targeted inhibitors. M774delinsWLV is a rare HER2 exon 20 insertion subtype and its clinical sensitivity to HER2-targeted inhibitors remains unclear. Furthermore, there is a lack of current studies to elucidate its structure and predict its sensitivity to HER2-targeted tyrosine kinase inhibitors. Herein, we presented a case of non-small cell lung cancer harboring M774delinsWLV who derived favorable response and significant survival benefit from HER2-targeted tyrosine kinase inhibitors. A 60-year-old male with metastatic lung adenocarcinoma carrying M774delinsWLV received pyrotinib monotherapy as first-line treatment. After rapid disease progression at three months, sequential combination therapy with pyrotinib and bevacizumab yielded promising antitumor activity and sustained progression-free survival benefits for nearly a year. Subsequent dacomitinib monotherapy displayed significant activity against this uncommon insertion, resulting in a rapid decrease in tumor markers and partial response, along with progression-free survival of one year. The molecular simulation revealed no significant differences in the overall protein structure and binding pocket region between M774delinsWLV and the HER2 wild type. Drug binding dynamics simulation indicated that dacomitinib exhibited the most potent binding activity compared to afatinib, pyrotinib and poziotinib. Conclusively, dacomitinib exhibited promising efficacy against the rare HER2 exon 20 insertion M774delinsWLV. Extensive investigation is needed to elucidate the effects of HER2-targeted tyrosine kinase inhibitors on non-small cell lung cancer with different HER2 insertion subtypes.

Phase I/II clinical trial of efficacy and safety of EGCG oxygen nebulization inhalation in the treatment of COVID-19 pneumonia patients with cancer.

BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.

Association between the surgical approach and prognosis of spontaneous supratentorial deep intracerebral hemorrhage.

The association between surgical approach and prognosis in patients with spontaneous supratentorial deep intracerebral hemorrhage is unclear. We aimed to explore the association between surgical approach and prognosis in these patients. A retrospective cohort of 311 patients from 3 centers who were treated with surgery 24 h after ictus was recruited. The surgical procedure involved removing the intracerebral hematoma using an aspirator through either the cortical approach or Sylvian fissure approach, assisted by an endoscope or microscope. The primary outcome was the one-year modified Rankin scale (mRS) score. The association between the surgical approach and the one-year mRS score was explored by using ordinal logistic regression and binary logistic regression. Baseline characteristics were balanced by propensity score matching and inverse propensity score weighting. In the adjusted analysis, compared with the cortex approach group, the Sylvian fissure approach group had better one-year mRS scores when analyzed as an ordinal variable (3.00 [2.00-4.00] vs. 4.00 [3.00-5.00]; adjusted odds ratio, 3.15; 95% CI, 1.78-5.58; p < 0.001) and a dichotomous variable (74.14% vs. 49.01%; adjusted odds ratio, 6.61; 95% CI, 2.75-15.88; p < 0.001). Surgical approach was not significantly associated with rebleeding (p = 0.88) or three-month mortality (p = 0.81). In univariate analysis after propensity score matching, there were significant differences in one-year mRS score between the two groups (p < 0.001), and there were no significant differences in rebleeding (Fisher's exact test, p > 0.999) or three-month mortality (Fisher's exact test, p > 0.999). Inverse probability weighted regression analysis showed better one-year mRS scores when analyzed as an ordinal variable (adjusted odds ratio, 3.03; 95% CI, 2.17-4.17; p < 0.001) and a dichotomous variable (adjusted odds ratio, 3.11; 95% CI, 2.16-4.77; p < 0.001) in the Sylvian fissure approach group; the surgical approach was not significantly associated with rebleeding (p = 0.50) or three-month mortality (p = 0.60). In the surgical treatment of patients with spontaneous supratentorial deep intracerebral hemorrhage, the Sylvian fissure approach may lead to a better functional outcome compared with the cortex approach. Future prospective studies are warranted to confirm this finding.

Surgical treatment of traumatic frontal hematoma: comparison of the endoscopic supraorbital approach with frontotemporal approach.

Background: The objective of this study was to compare the efficacy, safety, and outcomes of the endoscopic supraorbital approach and frontotemporal approach for the treatment of traumatic frontal hematoma, with the aim of demonstrating the feasibility of the endoscopic supraorbital approach. Methods: A total of 24 cases underwent hematoma evacuation, including 10 cases using the endoscopic supraorbital approach and 14 cases using the frontotemporal approach. Baseline demographic data, hematoma clearance rate, blood loss, postoperative complications, and 6-month outcomes were retrospectively analyzed. Results: Both approaches effectively evacuated the hematoma, with hematoma clearance rates of 90.97 ± 10.23% in the endoscopic supraorbital group and 85.29 ± 16.15% in the frontotemporal approach group (p > 0.05). The supraorbital approach group demonstrated significantly shorter operation times compared to the frontotemporal approach group (116.50 ± 28.19 min vs. 193.29 ± 72.55 min, p < 0.05), as well as significantly less blood loss (55.00 ± 33.08 mL vs. 685.71 ± 840.20 mL, p < 0.05). There was no significant difference in the rate of postoperative complications between the two groups, and the majority of patients achieved favorable outcomes with a Glasgow Outcome Scale score of 4 or 5 in both groups. Conclusion: Compared to the frontotemporal approach, the endoscopic supraorbital approach offers advantages such as shorter operation times, reduced blood loss, similar treatment effects, and comparable complication rates. Therefore, the endoscopic supraorbital approach may serve as a viable alternative for the treatment of traumatic frontal hematoma.

SDF-1 induces directional chemotaxis of BMSCs at the intervertebral fusion site and promotes osteogenic differentiation by regulating Wnt/ß-catenin in the bone marrow chimera spinal intervertebral fusion mouse model.

Clinical observations show that the current spinal fusion with internal fixation has a nonfusion rate of 5%-35%; however, methods to promote spinal fusion are limited. This study aimed to investigate the role of SDF-1-induced directional chemotaxis of BMSCs in bone marrow chimera spinal intervertebral fusion mouse model. BMSCs were isolated from bone marrow and identified by detecting CD44/CD34 positive cells. BMSCs (GFP-BMSCs) were labeled with GFP for tracking in vivo. Mice were inoculated with GFP-BMSCs to construct bone marrow chimera spinal intervertebral fusion model, which were divided into BM-SIF model, BM-SIF+SDF-1, BM-SIF+SDF-1-Anta group. The callus area of intervertebral fusion site was detected by radiology. HE staining was used to detect trabeculae formation. Expressions of osteogenic molecules and fibroblast markers were detected by RT-PCR and Western blotting. GFP-BMSCs showed obvious osteogenic and adipogenic differentiation ability, according to oil-red O and alizarin-red staining. Bone marrow chimera spinal intervertebral fusion mouse model was successfully established, with efficient localization of GFP-BMSCs at intervertebral fusion site. SDF-1 significantly promoted bone trabeculae formation in callus at intervertebral fusion site. SDF-1 significantly increased osteogenic molecules transcription/expression in callus at intervertebral bone graft fusion site of mice; however, SDF-1-Anta (AMD3100) significantly decreased osteogenic molecules transcrition/expression, compared to those of mice from the BM-SIF model group (p < 0.05). SDF-1 markedly induced and SDF-1-Anta significantly decreased fibroblast proliferations in the callus at the intervertebral fusion site of mice, compared to those of mice from the BM-SIF model group (p < 0.05). SDF-1 enhanced expression of Wnt10b and ß-catenin in callus at intervertebral fusion site of mice compared to mice of the BM-SIF model group (p < 0.05). In conclusion, SDF-1 induced directional chemotaxis of BMSCs to the intervertebral fusion site and promoted osteogenic differentiation in bone marrow chimera spinal intervertebral fusion mice by regulating Wnt/ß-catenin pathway and modulating the proliferation of BMSCs.

Role of consolidative thoracic radiation in extensive-stage small-cell lung cancer with first-line chemoimmunotherapy: a retrospective study from a single cancer center.

OBJECTIVE: To investigate the role of consolidative thoracic radiation (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy followed by immunotherapy maintenance. PATIENTS AND METHODS: Outcomes of patients without disease progression after first-line chemotherapy were retrospectively reviewed (January 2020 to December 2021). Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan-Meier method and compared by log-rank test. RESULTS: Of 100 patients, 47 received TRT and 53 non-TRT. The median follow-up was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months (p = 0.93) and 24.3 months (p = 0.63), respectively, in non-TRT. The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p = 0.38) while liver metastases did not. Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred. CONCLUSION: Consolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but associated with improved LRFS in ES-SCLC.

[Automatic modeling of the knee joint based on artificial intelligence].

Objective: To investigate an artificial intelligence (AI) automatic segmentation and modeling method for knee joints, aiming to improve the efficiency of knee joint modeling. Methods: Knee CT images of 3 volunteers were randomly selected. AI automatic segmentation and manual segmentation of images and modeling were performed in Mimics software. The AI-automated modeling time was recorded. The anatomical landmarks of the distal femur and proximal tibia were selected with reference to previous literature, and the indexes related to the surgical design were calculated. Pearson correlation coefficient ( r) was used to judge the correlation of the modeling results of the two methods; the consistency of the modeling results of the two methods were analyzed by DICE coefficient. Results: The three-dimensional model of the knee joint was successfully constructed by both automatic modeling and manual modeling. The time required for AI to reconstruct each knee model was 10.45, 9.50, and 10.20 minutes, respectively, which was shorter than the manual modeling [(64.73±17.07) minutes] in the previous literature. Pearson correlation analysis showed that there was a strong correlation between the models generated by manual and automatic segmentation ( r=0.999, P<0.001). The DICE coefficients of the 3 knee models were 0.990, 0.996, and 0.944 for the femur and 0.943, 0.978, and 0.981 for the tibia, respectively, verifying a high degree of consistency between automatic modeling and manual modeling. Conclusion: The AI segmentation method in Mimics software can be used to quickly reconstruct a valid knee model.

Application of Skin-stretching Device for Closing Scalp Defect.

BACKGROUND: The scalp defect was a clinical common constructive challenge. This research verified the efficacy of the skin-stretching device in the treatment of scalp defect and assessed the associated complications. METHODS: The clinical data of 12 patients with scalp defect treated with skin-stretching device from January 2020 to January 2021 were collected. We used EASApprox skin-stretching device for the treatment of scalp defect. We described a detailed reconstruction procedure for this treatment. We collected the site, distance from wound edge and other characteristics of the wound, and recorded the number of stretching cycles, operation time, closed state, healing time, and observed postoperative complications and wound healing status. RESULTS: In this research, the scalp defect was mainly caused by pressure ulcer, and mainly located in the parietooccipital site. The average distance from wound edge was 3.2 cm, the average stretching cycles was 4.2 times during the operation, and the average operation time was 43.5 minutes. Ten patients were directly sutured after stretching, and 2 patients underwent first-stage stretching to reduce the wound. The average time of wound healing was 13.5 days. Postoperative follow-up of 3 months, no patients had wound tear, necrosis, 1 patient suffered from wound exudation and infection due to poor nutrition. Skin function and final scar was acceptable. CONCLUSION: The treatment of skin-stretching device was effective for scalp defect and has the advantages of convenient operation, acceptable functional results, without severe complications. In addition to traditional treatment, this was a promising treatment. However, more clinical and preclinical research of the skin-stretching device were required.

Immunotherapy combined with chemotherapy improved clinical outcomes over bevacizumab combined with chemotherapy as first-line therapy in adenocarcinoma patients.

PURPOSE: No definite conclusion has yet to be reached for the first-line treatment combined with chemotherapy for advanced adenocarcinoma NSCLC patients with negative driver genes. This study sought to compare the clinical outcomes of Beva+ChT and IO+ChT as first-line treatment for this population and investigated whether the statuses of BM, PD-L1 expression, and KRAS and TP53 mutations could influence the results. PATIENTS AND METHODS: The clinical data of patients with adenocarcinoma NSCLC who received first-line therapy were retrospectively collected and the patients were assigned to the IO+ChT and Beva+ChT groups. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated between the two groups. The survival effects of BM, PD-L1 expression, and KRAS and TP53 mutations were also evaluated. RESULTS: From April 2018 to October 2020, a total of 105 patients with first-line therapy were included in our analysis; 54 (51.4%) patients were included in the IO+ChT group and 51 (48.6%) patients were included in the Beva+ChT group. The results showed that OS (NR vs. 18.3 m, p = 0.011) and PFS (14.9 m vs. 6.3 m, p < 0.001) were superior in patients in the IO+ChT group than in patients in the Beva+ChT group. Further analysis revealed that the OS (median OS: NR vs. 14.7 months, p = 0.039) and PFS (median PFS: 18.5 vs. 5.5 months, p < 0.001) advantages of the IO+ChT group were also seen in the PD-L1 > 1% subgroup but were not seen in the PD-L1 < 1%, BM or KRAS mutation subgroups. CONCLUSIONS: ICIs combined with ChT improved clinical outcomes over Beva combined with ChT as first-line therapy for adenocarcinoma patients without driver gene alterations, especially in patients with PD-L1 ≥ 1%.

Efficacy and safety of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer: a prospective, single-arm, phase II study in China.

PURPOSE: Although immune checkpoint inhibitor monotherapy has been used as a second-line treatment in advanced non-small cell lung cancer (NSCLC), the improvement in progression-free survival (PFS) remains unsatisfactory. We investigated the feasibility of sintilimab plus chemotherapy as a second-line treatment in advanced NSCLC. METHODS: This was a phase II, single-arm, prospective study in advanced NSCLC patients who had failed standard platinum-based chemotherapy (ChiCTR1900027634, Registered 22 November 2019). Eligible patients received docetaxel 75 mg/m2 (day 1) plus sintilimab 200 mg (day 3) Q3W. Those did not progress after 4-6 cycles received sintilimab 200 mg Q3W as maintenance treatment. The primary endpoint was PFS. RESULTS: Forty patients were enrolled between October 2019 and October 2020. With a median follow-up of 12.2 months, the median PFS was 5.8 months, and the PFS rates at 6 and 12 months were 48% and 30%, respectively. The median overall survival (OS) was 12.6 months, with a 12-month OS rate of 62.0%. The overall response rate was 32.4%, and the disease control rate was 89.2%. The incidence of all and ≥ grade 3 treatment-related adverse events (TRAEs) were 65% (26/40) and 17.5% (7/40), respectively. No TRAEs-related permanent treatment discontinuation or death occurred. bTMB reduction at 6 weeks was associated with a longer PFS (NR vs 3.0 months, P < 0.0001). CONCLUSION: This prospective phase II study in China suggested that sintilimab plus docetaxel might improve PFS and tumor response with good tolerability for Chinese patients with previously treated advanced NSCLC. bTMB reduction at 6 weeks could serve as a potential predictive biomarker for this regimen.

Management of Primary Brainstem Hemorrhage: A Review of Outcome Prediction, Surgical Treatment, and Animal Model.

Primary brainstem hemorrhage (PBH) has the worst prognosis of all types of intracerebral hemorrhage. Currently, the management of PBH is controversial. Hematoma classification, scoring systems, and electrophysiological monitoring are critical for predicting the outcome of PBH. Surgery may be an effective treatment for PBH. Clinical studies have emphasized the importance of animal models for understanding the pathogenesis and pathological mechanisms of PBH. In this study, combined with recent studies, the outcome prediction, surgical treatment, and animal models of PBH were reviewed.

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial.

OBJECTIVE: Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m2, day 3, every 3 weeks) for 4-6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated. RESULTS: Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005). CONCLUSION: ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

Delayed specific IgM antibody responses observed among COVID-19 patients with severe progression.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

Application-aware deadline constraint job scheduling mechanism on large-scale computational grid.

Recently, computational Grids have proven to be a good solution for processing large-scale, computation intensive problems. However, the heterogeneity, dynamics of resources and diversity of applications requirements have always been important factors affecting their performance. In response to these challenges, this work first builds a Grid job scheduling architecture that can dynamically monitor Grid computing center resources and make corresponding scheduling decisions. Second, a Grid job model is proposed to describe the application requirements. Third, this paper studies the characteristics of commercial interconnection networks used in Grids and forecast job transmission time. Fourth, this paper proposes an application-aware job scheduling mechanism (AJSM) that includes periodic scheduling flow and a heuristic application-aware deadline constraint job scheduling algorithm. The rigorous performance evaluation results clearly demonstrate that the proposed application-aware job scheduling mechanism can successful schedule more Grid jobs than the existing algorithms. For successful scheduled jobs, our proposed AJSM method is the best algorithm for job average processing time and makespan.

Protective effect of Shouwu Yizhi decoction against vascular dementia by promoting angiogenesis.

Shouwu is a traditional Chinese medicine (TCM) with neuroprotective effect. Shouwu Yizhi decoction (SYD) was designed based on TCM theory. However, little is known about the roles of SYD in Vascular dementia (VaD). The present study aimed to evaluate the potential effects of SYD on the vascular cognitive impairment and explore the underlying mechanism by establishing focal cerebral ischemia/reperfusion (I/R) rat model to induce VaD. SYD administration (54 mg·kg-1) for 40 days obviously improved the vascular cognitive impairment in the middle cerebral artery occlusion (MCAO) rats as evidenced by the declined neurological deficit score and shortened escape latency via neurological deficit assessment and Morris water maze test. Moreover, SYD decreased neuron damage-induced cell death and ameliorated the ultrastructure of endothelial cells in the MCAO rats, thereby alleviating VaD. Mechanistically, SYD caused increases in the expression of vascular endothelial growth factor (VEGF), CD34 and CD31, compared with the MCAO rats in coronal hippocampus. Simultaneously, the expression level of miR-210 was elevated significantly after SYD administration, compared with the vehicle rats (P < 0.01). The expression of Notch 4 at both mRNA and protein levels was upregulated remarkably along with the notably downregulated DLL4 expression under SYD administration compared with the vehicle rats (P < 0.05). Overall, the above results indicated that SYD promoted angiogenesis by upregulating VEGF-induced miR210 expression to activate Notch pathway, and further alleviated neuron damage and ameliorated the ultrastructure of endothelial cells in the MCAO rats, ultimately enhancing the cognition and memory of MCAO rats. Therefore, our findings preliminarily identified the effect and the mechanism of action for SYD on VaD in rats. SYD could be a potential candidate in treatment of VaD.

[Effect of Peimine on ERCC1 mRNA and LRP Expressions of A549/DDP Multidrug Resistance Cell Line].

OBJECTIVE: To explore the effect of peimine on excision repair cross-complementation 1 (ERCC1) mRNA and lung resistant protein (LRP) expressions in A549/cisplatin (DDP) multidrug resistance (MDR) cell line. METHODS: Lung cancer A549/DDP cells were cultured in vitro.Cells at logarithmic growth phase were divided into 4 groups, i.e., the blank control group, the DDP group, the ligustrazine group (DDP+ligustrazine), the peimine group (DDP + peimine). After 48-h drug action, ERCC1 mRNA expression was detected by RT-PCR and LRP expression detected by cell immunofluorescence. RESULTS: There was no statistical difference in expression levels of ERCC1 mRNA and LRP between the DDP group and the blank control group (P > 0.05). Compared with the DDP group, expression levels of ERCC1 mRNA and LRP obviously decreased in the ligustrazine group and the peimine group (P < 0.05). They were obviously lower in the peimine group than in the ligustrazine group (P < 0.05). CONCLUSIONS: Peimine could reverse MDR of A549/DDP cell line. Its mechanism might be associated with down-regulating ERCC1 mRNA and LRP expression levels.

Cervical cancer gene therapy by gene loaded PEG-PLA nanomedicine.

BACKGROUND AND AIMS: Advances in the treatment of cervical cancer over the last decade have predominantly involved the development of genes directed at molecular targets. Gene therapy is recognized to be a novel method for the treatment of cervical cancer. Genes can be administered into target cells via nanocarriers. This study aimed to develop systemically administrable nano-vectors. Floate (Fa) containing gene loaded nanoparticles (NPs) could target HeLa human cervical cancer cells through combination with receptors on the cells to increase the nuclear uptake of genetic materials. METHODS: Fa was linked onto Poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PLA) to form Fa-PEG-PLA, and the resulting material was used to load plasmids of enhanced green fluorescence protein (pEGFP) to obtain gene loaded nanoparticles (Fa-NPs/DNA). Physical-chemical characteristics, in vitro release and cytotoxicity of Fa-NPs/DNA were evaluated. The in vitro transfection efficiency of Fa-NPs/ DNA was evaluated in HeLa cells and human umbilical vein endothelial cells (HUVEC). PEG-PLA without Fa was used to load pEGFP from NPs/DNA as a control. RESULTS: Fa-NPs/DNA has a particle size of 183 nm and a gene loading quantity of 92%. After 72h of transfection, Fa-NPs/DNA displayed over 20% higher transfection efficiency than NPs/DNA and 40% higher than naked DNA in HeLa cells. However, in HUVECs, no significant difference appeared between Fa-NPs/DNA and NPs/DNA. CONCLUSIONS: Fa-PEG-PLA NPs could function as excellent materials for gene loading. This nano-approach could be used as tumor cell targeted medicine for the treatment of cervical cancer.

Pemetrexed plus dendritic cells as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer who had treatment with TKI.

The aim of this study was to determine the efficacy and toxicity of pemetrexed plus dendritic cells (DCs) in patients suffering from stage IIIB or IV lung adenocarcinoma, who had undergone maintenance treatment with gefitinib or erlotinib. Patients who had failed gefitinib or erlotinib maintenance treatment had ECOG performance statuses ranging from 0 to 2.27 patients received pemetrexed plus DCs as second-line treatment. Dosage: 500 mg/m(2) pemetrexed was administered on day 1 of a 21-day cycle. DCs were given for one cycle of 21 days. Three patients (11.1 %) experienced a partial response and 14 patients (51.9 %) showed stable disease. Ten patients (37.0 %) had progressive disease. The median time to progression-free survival (PFS) was 4.8 months [95 % confidence interval (CI) 4.4-5.2], and the median overall survival was 10.7 months (95 % CI 10.3-11.2). In the subgroup analysis, PFS had a significant difference between the low ratio of CD4/CD8 and normal ratio of CD4/CD8, with 4.5 months (95 % CI 4.2-4.9) and 5.0 months (95 % CI 4.5-5.7), (Log Rank = 0.039), respectively. No one patient experienced grade 4 toxicity. A regimen of pemetrexed combined with DCs is marginally effective and well tolerated in patients with stage IIIB or IV lung adenocarcinoma who had received gefitinib or erlotinib first-line treatment.

Overexpressed FOXC2 in ovarian cancer enhances the epithelial-to-mesenchymal transition and invasion of ovarian cancer cells.

Ovarian cancer is a highly invasive and metastatic disease with poor prognosis, particularly if this disease is diagnosed at an advanced stage, which is often the case. Researchers have argued that ovarian cancer cells that have undergone epithelial­to­mesenchymal transition (EMT) acquire aggressive malignant properties; however, the relevant molecular mechanisms in this setting are poorly understood. In cancer cases, the transcription factor forkhead box protein C2 (FOXC2) has been detected, but the function of this factor in ovarian cancer tumorigenesis remains unclear. In the present study, FOXC2 was overexpressed in invasive ovarian cancer cell lines and tissues. The invasive potential of ovarian cancer cells was significantly increased by ectopic FOXC2 expression but it was significantly decreased by RNA interference targeting FOXC2. E­cadherin and vimentin expression levels were modulated by FOXC2. These results indicated that FOXC2 was required for the maintenance of the mesenchymal phenotype after TGF­ß1 induced EMT in human ovarian cancer cells. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies. These therapies can then be performed to treat invasive ovarian tumor.