Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivo.

Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clinical use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepared by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new preparation were found to remain nearly constant over 1 year. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concentration at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg(-1) along with yellow laser irradiation; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.

[Time-related expression of IL-6, IL-8 and TNF-alpha following explosive injury to rabbit's chest].

OBJECTIVE: To explore the relationship between the expression changes of cytokines, interleukin-6 (IL-6), interleukin-8(IL-8), and tumor necrosis factor-alpha (TNF-alpha), and the wound time following explosive injury to rabbit's chest. METHODS: The rabbit's model of explosive injury was established. The expression levels of IL-6, IL-8 and TNF-alpha in the plasma were detected by ELISA method at different wound time (0.5-12h). RESULTS: The level of IL-6 increased at 3h after wounding and reached peak at 6 h. The level of IL-8 increased at 1 h and reached peak at 6 h. The level of TNF-alpha increased at 0.5 h and reached peak at 3 h. CONCLUSION: IL-6, IL-8 and TNF-alpha have a time-related expression after explosive injury.

Covalent organic framework isomers with divergent photocatalytic properties.

A pair of isomeric Py-BT-COFs with the same composition, but slightly different atomic arrangements, were designed and synthesized. The minute structural variations of the Py-BT-COF isomers generated significantly different redox and photophysical properties and correspondingly led to different photocatalytic manifestations in H2 evolution and rhodamine B degradation.

Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) presents significant clinical and therapeutic challenges due to its aggressive nature and generally poor prognosis. We initiated a Phase II clinical trial (ChiCTR1900027160) to assess the efficacy of a pioneering neoadjuvant chemo-immunotherapy regimen comprising programmed death-1 (PD-1) blockade (Toripalimab), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the oral fluoropyrimidine derivative S-1, in patients with locally advanced ESCC. This study uniquely integrates clinical outcomes with advanced spatial proteomic profiling using Imaging Mass Cytometry (IMC) to elucidate the dynamics within the tumor microenvironment (TME), focusing on the mechanistic interplay of resistance and response. Sixty patients participated, receiving the combination therapy prior to surgical resection. Our findings demonstrated a major pathological response (MPR) in 62% of patients and a pathological complete response (pCR) in 29%. The IMC analysis provided a detailed regional assessment, revealing that the spatial arrangement of immune cells, particularly CD8+ T cells and B cells within tertiary lymphoid structures (TLS), and S100A9+ inflammatory macrophages in fibrotic regions are predictive of therapeutic outcomes. Employing machine learning approaches, such as support vector machine (SVM) and random forest (RF) analysis, we identified critical spatial features linked to drug resistance and developed predictive models for drug response, achieving an area under the curve (AUC) of 97%. These insights underscore the vital role of integrating spatial proteomics into clinical trials to dissect TME dynamics thoroughly, paving the way for personalized and precise cancer treatment strategies in ESCC. This holistic approach not only enhances our understanding of the mechanistic basis behind drug resistance but also sets a robust foundation for optimizing therapeutic interventions in ESCC.

Unsupervised machine learning effectively clusters pediatric spastic cerebral palsy patients for determination of optimal responders to selective dorsal rhizotomy.

Selective dorsal rhizotomy (SDR) can reduce the spasticity in patients with spastic cerebral palsy (SCP) and thus improve the motor function in these patients, but different levels of improvement in motor function were observed among patients after SDR. The aim of the present study was to subgroup patients and to predict the possible outcome of SDR based on the pre-operational parameters. A hundred and thirty-five pediatric patients diagnosed with SCP who underwent SDR from January 2015 to January 2021 were retrospectively reviewed. Spasticity of lower limbs, the number of target muscles, motor functions, and other clinical parameters were used as input variables for unsupervised machine learning to cluster all included patients. The postoperative motor function change is used to assess the clinical significance of clustering. After the SDR procedure, the spasticity of muscles in all patients was reduced significantly, and the motor function was promoted significantly at the follow-up duration. All patients were categorized into three subgroups by both hierarchical and K-means clustering methods. The three subgroups showed significantly different clinical characteristics except for the age at surgery, and the post-operational motor function change at the last follow-up in these three clusters was different. Three subgroups clustered by two methods could be identified as "best responders", "good responders" and "moderate responders" based on the increasement of motor function after SDR. Clustering results achieved by hierarchical and K-means algorithms showed high consistency in subgrouping the whole group of patients. These results indicated that SDR could relieve the spasticity and promote the motor function of patients with SCP. Unsupervised machine learning methods can effectively and accurately cluster patients into different subgroups suffering from SCP based on pre-operative characteristics. Machine learning can be used for the determination of optimal responders for SDR surgery.

A New Parameter of Hip Instability in Developmental Dysplasia of the Hip (DDH): Teardrop Distance.

Background: Hip instability is one of the etiologies of accelerated onset of osteoarthritis in developmental dysplasia of the hip (DDH). There are some radiological parameters for hip instability in hip dysplasia like broken shenton's line, elevated acetabular index, reduced lateral center edge angle (LCEA), upsloping lateral sourcil. We have discovered a new index of teardrop distance (TD) for assessing instability. Herein, we hypothesized that increased TD could be used as evidence of hip instability in DDH patients, which we verified using TD as an auxiliary diagnostic parameter for DDH, from supine to standing position. Methods: Female DDH patients undergoing Bernese periacetabular osteotomy (PAO) were enrolled in the DDH group, and normal female volunteers were in the control group. Anteroposterior radiographs of the pelvis in the supine and standing positions were taken, and LCEA, Tönnis angle (TA), sharp angle (SA), and TD were tested using Stata software to analyze the changes between supine and standing anteroposterior pelvic radiographs. Results: There were 26 female volunteers with 52 hips in the control group: supine TD 6.80 ± 0.98 mm, standing TD 6.65 ± 1.3 mm (P > 0.05). A total of 78 patients with 135 hips were included in the DDH group: supine TD 10.51 ± 3.50 mm, standing TD 10.93 ± 4.23 mm (P < 0.05). In either supine or standing position, TD in the DDH group was significantly wider than that in the control group (P < 0.05). In the DDH group, TD was correlated with TA and LCEA (rp 0.494-0.588, P < 0.05); TD was not correlated with SA, weight, or BMI (P > 0.05). There was a weak correlation between TD difference and standing LCEA (rp -0.276, P < 0.05). Conclusion: TD > 10 mm was a common imaging feature of DDH. It increased from supine to standing position, thus indicating hip instability in DDH patients. The hip parameters of both positions should be compared, fully considering the factors of hip stability.

Aptamer-siRNA chimera and gold nanoparticle modified collagen membrane for the treatment of malignant pleural effusion.

Malignant pleural effusion is one of the most common complications of advanced lung cancer and there is no effective clinical treatment at present. Here, we constructed an aptamer-siRNA chimeras/PEI/PEG/gold nanoparticle (AuNP)/collagen membrane that can progressively activate T cells by layer by layer assembly. Electron microscope showed this collagen membrane could be divided into 10 layers with a total thickness of 50-80µm, and AuNPs could be observed. Aptamer-siRNA chimeras could bind specifically to OX40+ cells and silencing programmed death receptor-1 (PD-1) gene. In vitro experiments demonstrated that chimeras/PEI/PEG/AuNPs gradually activated T cells to continuously kill lung adenocarcinoma cells in malignant pleural effusion. Animal experiments showed that chimeras/PEI/PEG/AuNP/collagen membrane effectively treated malignant pleural effusion. Compared with PD-1 inhibitor group, the number of cancer cells, ki-67 proliferation index and CD44 expression in the pleural effusion was significantly decreased and the lymphocyte/cancer cell ratio was significantly increased in the chimeras/AuNP-CM group. Flow cytometry showed that compared with PD-1 inhibitor group, T cell number in the chimeras/AuNP-CM group was significantly increased, while the proportion of PD-1+ T cells was markedly decreased. In conclusion, we constructed an chimeras/PEI/PEG/AuNP/collagen membrane, which was more effective in the treatment of malignant pleural effusion, and had less side effects than PD-1 inhibitors.

The Inhibitory Effect of Regulatory T Cells on the Intimal Hyperplasia of Tissue-Engineered Blood Vessels in Diabetic Pigs.

Severe inflammatory response and functional impairment of endothelial progenitor cells (EPCs) often lead to the implantation failure of EPC-captured tissue-engineered blood vessels (TEBVs) in diabetes. Regulatory T cells (Treg cells) are the most important inhibitory immune cells, but their effects in angiogenesis remain undefined, and the differences in the microenvironment may be an important reason. Here, we constructed a TEBV coated with an anti-CD34 antibody-functionalized heparin-collagen multilayer (anti-CD34 antibody-modified TEBV) using layer-by-layer self-assembly. Then, TEBVs were implanted into diabetic pigs. All TEBVs remained unobstructed 60 days after implantation, although varying degrees of intimal hyperplasia were detectable. Severe intimal hyperplasia was observed in the control group and peripheral injection of Treg cells group. Intravenous injection of Treg cells significantly inhibited intimal hyperplasia, inflammation, and cell apoptosis. Moreover, intravenous injection increased the proportion of circulating EPCs, while peripheral injection did not have these effects and reduced microvessel density around the TEBV. Interestingly, many Nestin+ cells could be detected in TEBVs, most of which were fusiform, showing the characteristics of smooth-muscle cells. Treg cell intravenous transplantation markedly reduced the number of Nestin+ cells in the TEBV. In conclusion, Treg cells inhibited the intimal hyperplasia of TEBVs in diabetic pigs by promoting EPC mobilization, anti-inflammatory action, and cellular protection.

Efficacy and safety of combined treatment with pembrolizumab in patients with locally advanced or metastatic esophageal squamous cell carcinoma in the real world.

Background: Treatments for patients with advanced esophageal cancer are still limited. Pembrolizumab has demonstrated antitumor activity in patients with advanced esophageal cancer in previous studies. Few studies have assessed safety and efficacy in routine clinical practice. We investigated the real-world outcomes of pembrolizumab for patients with advanced esophageal cancer. Methods: This retrospective, observational study collected 57 advanced esophageal squamous cell carcinoma (ESCC) patients from October 1, 2019 to October 1, 2021, 57 who received different patterns of treatments according to the staging were collected. Briefly, patients diagnosed with locally advanced and surgically resectable ESCC received neoadjuvant therapy followed by surgery. For patients with locally advanced, unresectable ESCC, the treatment regimen including chemoradiotherapy combined with pembrolizumab was performed. Patients with metastatic ESCC or those not suitable for radiotherapy received pembrolizumab plus chemotherapy. Safety was assessed in all treated patients. The objective response rate (ORR) was used to evaluate the efficacy. Results: The ORR was 74.1% (40/54) among all patients. The most common adverse events (AEs) were leukopenia (36.8%, 21/57), nausea (28.1%, 16/57), and thrombocytopenia (14%, 8/57). Grade III and higher AEs were observed in 9 of the 57 patients (15.8%). Conclusions: For patients with advanced ESCC, combined treatment with pembrolizumab was effective and safe. Multicenter studies should be carried out for further confirmation.

Meta-analysis on the association between knee extensor strength and structural changes of knee osteoarthritis.

This study aimed to perform a meta-analysis to evaluate whether knee extensor (KE) strength weakness was associated with increased structural worsening in knee osteoarthritis (KOA) including joint space narrowing (JSN) and cartilage loss. PubMed, Embase, Scopus, ScienceDirect, Web of Science, and Cochrane library were searched from their inception to May 2020, to identify eligible studies. Odds ratios (ORs) accompanied by 95% confidence intervals (CIs) were calculated for the relationship between KE strength and outcomes. Totally eleven longitudinal studies were included. The pooled crude OR indicated no significant association between KE strength weakness and KOA progression of JSN (OR: 1.13, 95% CI: 0.90, 1.42), and this result duplicated after confounders were adjusted (OR: 1.10, 95% CI: 0.87, 1.39). Subgroup analysis showed the association remained non-significant in sex-specific outcomes and subsets of neutral and malaligned knees, but there was a trend toward increased risk of JSN progression in female knees with low strength (OR: 1.24, 95% CI: 0.87, 1.76, I2 = 82%). The pooled crude OR showed that KE strength weakness was associated with increased risk of cartilage loss (OR:1.43, 95% CI: 1.05, 1.95). After adjustment, we found a non-significant trend that low KE strength could increase the risk of cartilage loss (OR: 1.25, 95% CI: 0.95, 1.64), and this trend was separately observed in tibiofemoral or patellofemoral compartments. This meta-analysis suggested that KE strength weakness was not significantly associated with an increased risk of radiographic structural KOA progression in patients with KOA or known risk factors for KOA. However, there was a trend that women with weaker KE strength displayed a higher risk of JSN worsening and that KE strength weakness had an association with an increased risk of cartilage damage. Key points • Knee extensor strength weakness is not significantly associated with an increased risk of radiographic structural KOA progression in patients with or at risk of knee osteoarthritis. • There is a non-significant trend toward an increased risk of JSN progression in female knees with low knee extensor strength. • There is a trend that low KE strength can increase the risk of cartilage loss no matter in tibiofemoral or patellofemoral compartments, but it's not significant.

The relationship between the number of circulating tumor cells and the prognosis in patients with esophageal squamous cell carcinoma.

BACKGROUND: Esophageal cancer (EC) is one of the most common malignancies worldwide, with high morbidity and mortality rates. Circulating tumor cell (CTC) detection has become a novel approach in clinical study of EC. In this study, the relationship between CTCs/c-Kit expression of CTCs and the prognosis of EC patients was analyzed in EC. METHODS: A total of 43 EC patients with R0 resection were recruited for this study. The CanPatrol method was used to detect the CTC number in the peripheral blood of patients before and after operations, and the epithelial/interstitial type was classified. Multiple RNA in situ hybridization (RNA-ISH) was used to observethe c-Kit expression of CTCs. Post-operation follow-up occurred over 3 years. Logistic regression or the Cox proportional risk regression model was applied to analyze the relationship between CTC number, CTCs and disease characteristics, pathological stages and prognosis of patients with EC, and changes in CTCs before and after operations. c-Kit expression in different CTCs and the relationship between c-Kit expression and prognosis were also studied. RESULTS: The detection rate of CTCswas 81% (35/43). The detection rates of epithelial-, mixed- and stromal-type CTCs were 53%, 63%, and 33%, respectively. The 3-year overall survival rate was 67%. A CTC level of >2 indicated an increased risk of recurrence, metastasis, and death (P=0.018, 0.002, respectively). Following the operations, the total number of CTCs decreased in 29 cases. Of these, 6 cases were unchanged, and 8 cases demonstrated elevated CTCs. There was a significant difference in the positive rate of mixed-type CTCs before and after the operations. The rate of c-Kit expression in CTCs of EC patients was 46% pre-operation. No statistically significant correlations were found between c-Kit expression and postoperative recurrence/metastasis/survival of EC patients. CONCLUSIONS: Preoperative CTC numbers, especially interstitial CTCs, were used as an auxiliary index in the prognosis of EC patients. The mRNA expression of c-Kit was detected in CTCs preoperatively in patients with EC, but no significant correlation between the c-Kit expression and the prognosis of EC patients was found.

[Primary report of lobectomy with single utility port complete video-assisted thoracoscopic surgery].

BACKGROUND AND OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) has been widely used in the diagnosis and treatment of chest diseases. The aim of this study was to explore the feasibility and clinical value of lobectomy with single utility port complete VATS. METHODS: From September 2009 to December 2009, 21 cases underwent lobectomy with single utility port complete VATS. Of 21 patients, right upper lobectomy was 12 cases, left lower lobectomy 5 cases, right lower lobectomy 2 cases, left upper lobectomy 1 case, right middle lobectomy 1 case. RESULTS: The operation process were smooth in all patients and without conversion to thoracotomy. The mean operative time was (132.7 +/- 16.2) min and the mean intraoperative blood loss was (110.5 +/- 24.6) mL. The average chest tube drainage time was (3.1 +/- 1.3) d, and the mean hospitalization day was (5.2 +/- 3.2) d. All patients recovered smoothly and without severe complications. There were no post-operative deaths. CONCLUSION: Lobectomy with single utility port VATS is technically feasible and has the advantages of minimal invasive and rapid recovery.

Effectiveness and safety of minimally invasive Ivor Lewis and McKeown oesophagectomy in Chinese patients with stage IA-IIIB oesophageal squamous cell cancer: a multicentre, non-interventional and observational study.

OBJECTIVES: To compare the long-term overall survival and outcomes of patients with oesophageal squamous cell cancer treated with minimally invasive McKeown or Ivor Lewis oesophagectomy. METHODS: A multicentre, non-interventional, retrospective, observational study was performed in oesophageal squamous cell cancer patients pathologically confirmed with stage IA-IIIB middle or lower thoracic tumours who underwent minimally invasive oesophagectomy between 1 January 2010 and 30 June 2017 in 7 hospitals in China. Cox proportional hazards models assessed factors associated with overall survival and disease recurrence. The primary outcome was overall survival and cancer recurrence; the secondary outcomes included number of lymph nodes resected, 30-day mortality and postoperative complications. RESULTS: A total of 1540 patients were included (950 McKeown, 590 Ivor Lewis). The mean age was 61.6 years, and 1204 were male. The mean number of lymph nodes removed during the McKeown procedure was 21.2 ± 11.4 compared with 14.8 ± 8.9 in Ivor Lewis patients (P < 0.001). The 5-year overall survival rates were 67.9% (McKeown) and 55.0% (Ivor Lewis). McKeown oesophagectomy was associated with improved overall survival (Ivor Lewis versus McKeown hazard ratio 1.36, 95% confidence interval 1.11-1.66; P = 0.003), particularly in patients with stage T3 tumours (middle thoracic oesophagus). However, postoperative complications occurred more frequently following McKeown oesophagectomy (42.2% vs 17.6% Ivor Lewis; P < 0.001). CONCLUSIONS: Minimally invasive McKeown oesophagectomy was associated with improved overall survival and a decreased risk of disease recurrence, while Ivor Lewis patients had fewer postoperative complications. McKeown oesophagectomy may represent the optimal technique for patients with stage T3 tumours. CLINICAL TRIAL REGISTRATION: CLINICALTRIAL.GOV: NCT03428074.

Neoadjuvant chemoradiotherapy plus surgery in the treatment of potentially resectable thoracic esophageal squamous cell carcinoma.

BACKGROUND: In recent years, neoadjuvant chemoradiotherapy (NCRT) combined with surgery has been gradually applied in patients with locally advanced thoracic esophageal cancer, but its effectiveness and safety remains unclear. In this clinical trial, we prospectively investigated the efficacy and safety of NCRT plus surgery in the treatment of thoracic esophageal squamous cell carcinoma (TESCC). AIM: To investigate the efficacy and safety of NCRT combined with surgery in the treatment of potentially resectable TESCC. METHODS: Thirty patients with advanced TESCC hospitalized in our hospital from July 2016 to June 2019 were prospectively studied. All patients received NCRT, which included intensity modulated conformal radiotherapy (40-44 Gy/20-22f, 2 Gy/f) and chemotherapy (paclitaxel 150-175 mg/m2d1, 22 + lobaplatin 25-30 mg/m2d2, 23 for two cycles). Surgery was performed after radiotherapy and chemotherapy. The effectiveness and safety of these treatments were observed. RESULTS: Among these 30 patients, complete response was achieved in two cases (6.7%) and partial response in 26 cases (86.7%), yielding an objective response rate of 100%. All patients underwent radical surgery successfully. The R0 resection rate was 100%, and the pathologic complete response rate was 33.3%. The incidence of grade III- IV granulocytopenia was 10% during the NCRT, and anastomotic leakage occurred in one patient after surgery. CONCLUSION: For patients with potentially resectable TESCC, NCRT can effectively reduce the tumor size, increase R0 resection rate, and achieve obvious pathological degradation, with mild adverse reactions. Thus, it is worthy of wider clinical application.

Clinical and imaging features in 16 infants exposed to food contaminated with melamine and cyanuric acid.

OBJECTIVE: The objective of our study was to describe the clinical and imaging features of infants exposed to milk formula contaminated with melamine and cyanuric acid. CONCLUSION: The imaging feature of patients exposed to food contaminated with melamine and cyanuric acid was multiple calculi of the urinary tract that varied greatly in size and shape. Most patients presented with symptoms of urinary obstruction.

Identification of nine microRNAs as potential biomarkers for lung adenocarcinoma.

Lung cancer is a leading global cause of cancer-related death, and lung adenocarcinoma (LUAD) accounts for ~ 50% of lung cancer. Here, we screened for novel and specific biomarkers of LUAD by searching for differentially expressed mRNAs (DEmRNAs) and microRNAs (DEmiRNAs) in LUAD patient expression data within The Cancer Genome Atlas (TCGA). The identified optimal diagnostic miRNA biomarkers were used to establish classification models (including support vector machine, decision tree, and random forest) to distinguish between LUAD and adjacent tissues. We then predicted the targets of identified optimal diagnostic miRNA biomarkers, functionally annotated these target genes, and performed receiver operating characteristic curve analysis of the respective DEmiRNA biomarkers, their target DEmRNAs, and combinations of DEmiRNA biomarkers. We validated the expression of selected DEmiRNA biomarkers by quantitative real-time PCR (qRT-PCR). In all, we identified a total of 13 DEmiRNAs, 2301 DEmRNAs and 232 DEmiRNA-target DEmRNA pairs between LUAD and adjacent tissues and selected nine DEmiRNAs (hsa-mir-486-1, hsa-mir-486-2, hsa-mir-153, hsa-mir-210, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-577, and hsa-mir-4732) as optimal LUAD-specific biomarkers with great diagnostic value. The predicted targets of these nine DEmiRNAs were significantly enriched in transcriptional misregulation in cancer and central carbon metabolism. Our qRT-PCR results were generally consistent with our integrated analysis. In summary, our study identified nine DEmiRNAs that may serve as potential diagnostic biomarkers of LUAD. Functional annotation of their target DEmRNAs may provide information on their roles in LUAD.

Construction of a nomogram predicting the overall survival of patients with distantly metastatic non-small-cell lung cancer.

PURPOSE: This study aimed to establish a nomogram to predict the overall survival (OS) of the general non-small-cell lung cancer (NSCLC) patients with distant metastasis. PATIENTS AND METHODS: We investigated Surveillance, Epidemiology, and End Results database for NSCLC patients with distant metastasis diagnosed between 2010 and 2014. Statistically significant prognostic factors were identified using uni- and multivariable Cox regression analyses. A nomogram incorporating these prognostic factors was developed and evaluated by the Harrell's concordance index (C-index), calibration plots, and risk group stratifications. RESULTS: We finally included 18,209 patients for analysis. These patients were divided into two groups, 14,567 cases for the training cohort and 3,642 for the validation cohort. Marital status, sex, race, age, histology, T stage, N stage, histological differentiation, bone metastasis, brain metastasis, liver metastasis, with M1a disease, surgery of primary cancer, and chemotherapy were identified as the prognostic factors of the OS and integrated to construct the nomogram. The nomogram had a C-index of 0.704 (95% CI: 0.699-0.709) in the training set and 0.699 (95% CI: 0.689-0.709) in the validation set. The calibration curves for 1- and 2-year OS in the training and validation sets showed acceptable agreement between the predicted and observed survival. Also, the nomogram was capable of stratifying patients into different risk groups within the patients who presented with bone, liver, or brain metastasis, as well as in each T, N stage, respectively. CONCLUSION: A nomogram was established and validated to predict individual prognosis for the general patients with distantly metastatic NSCLC. Global prospective data with the latest TNM classification and more comprehensive prognostic factors are needed to improve this model.

Non-coding RNAs: new biomarkers and therapeutic targets for esophageal cancer.

Esophageal cancer is one of the most common gastrointestinal malignant diseases and there is still no effective treatment. The incidence of esophageal cancer in the world is relatively high and on the increase year by year. Thus, the elaboration on the carcinogenesis of esophageal cancer and the identification of new biomarkers and therapeutic targets is quite beneficial to optimizing the current therapeutic regimen for treating such deadly disease. More and more evidence has shown that non-coding RNAs play an important role in the development and progression of multiple human cancers, including esophageal cancer. microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two functional kinds of non-coding RNAs that have been well investigated. They exert tumor suppressive or promoting effect by specifically regulating the expression of certain downstream target genes, which is tumor specific. It is also proved that miRNAs and lncRNAs level in tissue and plasma from esophageal cancer patients are closely correlated with the survival and disease progression, which could be used as a prognostic factor and therapeutic target for esophageal cancer.

Novel BRCA2-Interacting Protein, LIMD1, Is Essential for the Centrosome Localization of BRCA2 in Esophageal Cancer Cell.

Mutation of breast cancer 2, early onset (BRCA2) has been identified as a vital risk factor for esophageal cancer (EC). To date, several proteins have been reported as BRCA2-interacting proteins and are associated with multiple biological processes. This study's aim was to identify a novel interactive protein of BRCA2 and to explore its functional roles in EC. A yeast two-hybrid screening was performed to identify a novel BRCA2-interacting protein. Glutathione-S-transferase (GST) pull-down analysis was performed to find out how the binding domain of BRCA2 interacts with LIM domains containing 1 (LIMD1). The interaction between LIMD1 and BRCA2 at the endogenous level was confirmed by using coimmunoprecipitation and immunobloting. Furthermore, two different sequences of short hairpin RNAs (shRNAs) against LIMD1 were transfected into the human EC cell line ECA109. Afterward, the effects of LIMD1 suppression on the centrosome localization of BRCA2 and cell division were analyzed using an immunofluorescence microscope. Results showed that LIMD1 was a novel BRCA2-interacting protein, and LIMD1 interacted with the conserved region of BRCA2 (amino acids 2,750-3,094) in vitro. Importantly, after interfering with the protein expression of LIMD1 in ECA109 cells, the centrosome localization of BRCA2 was significantly abolished and abnormal cell division was significantly increased. These results suggested that LIMD1 is a novel BRCA2-interacting protein and is involved in the centrosome localization of BRCA2 and suppression of LIMD1, causing abnormal cell division in EC cells.

Combination of 2-deoxy d-glucose and metformin for synergistic inhibition of non-small cell lung cancer: A reactive oxygen species and P-p38 mediated mechanism.

Targeting metabolism of lung cancer cells is a promising methodology for the treatment of lung cancer. In this regard, 2-Deoxy d-glucose (2-dDG) has been reported to inhibit cell proliferation by intervening the glycolytic pathway. However, phase I clinical trial of 2-dDG demonstrated cardiac side effects at higher dosage. Metformin (Met), on the other hand, has been reported to improve pathological response to chemotherapy in non-small cell lung cancer (NSCLC) patients. In this study, we propose that combination therapy of 2-dDG with Met will demonstrate enhanced cytotoxicity than either compound alone. Our results indicated that inhibition concentration 25 (IC25) for combined treatment of Met and 2-dDG showed more toxicity as compared to individual agents on a NSCLC cell line, A549. This augmented toxicity is associated with increased lipid peroxidation and decreased glutathione level as well as decreased super oxide dismutase and catalase activities. Combination of Met and 2-dDG also demonstrated enhanced DNA damage, DNA adduct formation, intracellular reactive oxygen species (ROS) level, and mitochondrial membrane potential alteration, as well as increased apoptosis, caspase-3 activity, P-p38 and P-AMP-activated protein kinase (AMPK) level. It was also shown that inhibition of caspase-3 and p38 kinase partially (75%-87%) reversed Met and 2-dDG induced cell death, without affecting the ROS levels. On the other hand, pre-treatment of cells with N-acetyl cysteine (NAC) reversed Met and 2-dDG induced cell death to >90%. Taken together, the results of this study demonstrated that combination of Met and 2-dDG showed better toxicity than individual compounds and cell death is ROS, P-p38 and caspase-3 mediated, thereby providing a proof of concept for the combination of Met and 2-dDG as a potential treatment protocol for NSCLC.