Negative prognostic impact of Co-mutations in TGFß and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. METHODS: The comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. RESULTS: The top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-ß and TP53 pathways were significantly associated with worse DFS. CONCLUSIONS: Resected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-ß and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

[Distribution, Sources, and Ecological Risk Evaluation of Heavy Metals in Surface Sediments of Taihu Lake].

For the surface sediment samples of Taihu Lake in 2010, the eight physicochemical indices of pH, temperature, Eh, water content, porosity, grain size, total phosphorus, and Loss-on-ignition were measured and analyzed, along with the contents of nine heavy metals:Cu, Zn, Ni, Cr, Pb, Ba, Mn, Co, and V. The order of magnitudes of heavy metal content of surface sediments in Taihu Lake was:Mn>Ba>Zn>Cr>V>Ni>Pb>Cu>Co. This suggested that the contents of the nine heavy metals were beyond the background value, which had a close connection to the geology of the Taihu Lake Basin and were influenced by human activity to varying degrees. The clustering analysis and the spatial distribution of the heavy metals revealed that the concentrations of heavy metals in the North and South Taihu Lake sections decreased from the lake shore to the lake center, the concentrations of heavy metals in the West Taihu Lake section increased from the lake shore to the lake center, and the distribution of heavy metals in the center of the lake remained relatively uniform. According to the correlation study, the metal elements were positively correlated with one another to varying degrees, indicating that they originate from the same source of pollution. According to the PCA and PMF analyses, there were some different sources of heavy metals in Taihu Lake, in which the transportation and industrial complex source were the most important sources, the diagenesis was the second major source, and agriculture was the third major source. Furthermore, the heavy metal pollution was evaluated using the geoaccumulation and the potential ecological risk indices. This offers a solid theoretical backing for the future management of heavy metal pollution in Taihu Lake.

Circulating tumor DNA analysis detects micrometastatic disease and predicts recurrence in a patient with colon cancer: A case report.

RATIONALE: Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide, and approximately 50% of patients with early-stage disease develop metastases. A critical limitation for successful management of CRC is early disease detection and identification of progression. Next-generation sequencing-based circulating tumor DNA (ctDNA) profiling has emerged as a promising biomarker for the assessment of minimal or molecular residual disease in CRC. PATIENT CONCERNS: The patient was initially diagnosed with resectable CRC with uncertain small lung nodules. DIAGNOSES: The patient was diagnosed with sigmoid colon adenocarcinoma placed at 15 to 20 cm above the anal verge (ypT4N1R0). Lung nodules were found in the apical part of the upper lobe of the right lung and the dorsal segment of the lower lobe of the left lung. INTERVENTIONS: The patient received systemic therapy and local treatment and plasma ctDNA-MRD detection was performed for monitoring the molecular disease status after surgery. OUTCOMES: The patient achieved a complete response after treatment. However, he presented with disease recurrence in liver lesions. The postoperative ctDNA detection suggested the possibility of micrometastatic pulmonary disease, and that was confirmed by follow-up examination. Serial ctDNA detection revealed disease relapse ahead of radiologic imaging by a lead time of 9 months. This case demonstrated the potential of ctDNA analysis to be a sensitive and specific tool for the detection of micrometastatic disease and prediction of recurrence.

A Liquid Metal Temperature Detection System Based on Multi-Node Sapphire Fiber Sensor.

In order to accurately detect the temperature of molten aluminum and overcome the adverse influence of high temperature and corrosiveness on the sensing results, a temperature detection system based on a multi-node sapphire fiber sensor was proposed and developed. Through the structural parameter design of the fiber sensor, the scheme of utilizing the 0.7 mm diameter fiber and 0.5 mm groove was formulated. Simulation and analysis were carried out to determine the ultrasonic response distribution of the signal passing through the whole fiber sensor. The results indicate that the system is capable of distinguishing test signals from various positions and temperatures. Following the completion of the static calibration, the temperature of the molten aluminum was observed in real-time, and the data of the temperature measurements conducted at the two groove locations were compared. According to the obtained results, the test accuracy was greater than 1 degree Celsius and the temperature test stability was good, laying a solid foundation for the potential development of temperature measurement devices.

Next generation sequencing targeted detection of somatic mutations in patients with mucinous adenocarcinoma of the appendix.

The aim of this study was to investigate the mutations in mucinous adenocarcinoma of the appendix (MAA). SNV was detected in 15 patients with MAA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and reactome pathway analyses were performed. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), microsatellite instability (MSI) was analysis. Finally, the human leukocyte antigen (HLA) typing of the samples was detected. The results showed that TP53 (27 %) and KRAS (20 %) were the highest mutation frequency in the sample, mainly occur in p53 pathway and RTK-RAS pathway. GO analysis reveals mutated genes are closely related to the regulation of GTPase activity, regulation of small GTPase mediated signal transduction and other BP, related to the CC and MF. Analysis of KEGG pathways indicated that the top canonical pathways associated with SNV was Wnt signaling pathway. Reactome pathway analysis further revealed that the mutant genes were closely related to muscle contraction. Only one patient had moderate TMB level and one patient with high MSI. In conclusion, the most common mutated genes and the signaling pathways closely related to MAA development were detected in this study, which will contribute to the development of immunotherapy for patients with MAA.

Conversion therapy with tislelizumab for high microsatellite instability, unresectable stage III gastric cancer: a case report.

Gastric cancer (GC) is the fifth-highest ranked cancer for incidence and second for mortality from cancer worldwide. Conversion therapy has recently emerged as an alternative therapy for advanced/metastatic GC patients who are unable to undergo surgical resection at the time of diagnosis. Herein, we present the case of a patient with unresectable stage III GC of high microsatellite instability (MSI), high tumor mutation burden (TMB), and Epstein-Barr virus (EBV) positive. The patient received conversion therapy involving a combination of chemotherapy and immunotherapy regimens. After 3 courses of chemotherapy combined with tislelizumab, the patient underwent laparoscopic radical total gastrectomy. The pathological examination demonstrated that there was no cancerous tissue at the proximal or distal end of the tumor and no lymph node metastases in the lesser or greater curvature, indicating a pathologic complete response. Thereafter, the patient continued tislelizumab treatment to prevent postoperative carcinoma recurrence and metastasis, and to improve prognosis. In conclusion, our study confirmed that chemotherapy combined with immunotherapy is a promising conversion therapy for GC patients with locally unresectable lesions or distant lymph node metastasis, and these findings warrant large-scale clinical studies. This report highlights the clinical importance of next-generation sequencing technology in investigating therapeutic strategy to provide the maximal clinical benefit for patients with GC.

Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT.

BACKGROUND: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. METHODS: We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. RESULTS: Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. CONCLUSION: Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

ctDNA facilitated the diagnosis of a patient with synchronous urothelial carcinoma and non-small cell lung cancer: case report.

The diagnosis and treatment for multiple primary cancers have been a great challenge in clinical practice. Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA that circulates in the blood. Herein we report a case that ctDNA facilitated the diagnosis of synchronous urothelial carcinoma (UC) and lung adenocarcinoma. A 58-year-old male patient was diagnosed with UC initially. Computed tomography (CT) revealed multiple metastases without the brain after surgery and adjuvant chemotherapy. However, the patient had a progressively worsened headache symbol during system therapy. We explored the genome variations using next-generation sequencing (NGS). HRAS and TP53 mutations were detected from UC surgical tissue and postoperative ctDNA. Unexpectedly, the epidermal growth factor receptor (EGFR) exon 19 deletion (19del) mutation, which is common in non-small cell lung cancer (NSCLC), was also identified in ctDNA. Pathological analysis of a neck lymph node confirmed adenocarcinoma derived from the lung. Meanwhile, EGFR 19del was detected in neck lymph node biopsy. The ctDNA contained both UC and lung adenocarcinoma-derived mutations. Thus, the diagnosis was modified into synchronous UC and lung adenocarcinoma. Interestingly, the lung adenocarcinoma-derived lesions responded well to osimertinib (80mg, once daily), while the UC did not. His headache rapidly subsided and disappeared. This case demonstrates that ctDNA analysis may better capture the molecular heterogeneity harbored by multiple primary tumors in a patient and can facilitate the diagnosis and therapy of patients with simultaneous cancers.

Multifunctional nano-enabled delivery systems in Alzheimer's disease management.

Alzheimer's disease (AD) is the most common neurodegenerative disorder that leads to cognitive and behavioral impairment. Unfortunately, both effective diagnosis and treatment for AD remain elusive, probably owing to the complicated and uncertain etiology of the disease. To date, a number of hypotheses have been proposed that may explain AD pathogenesis, including the amyloid cascade hypothesis, the tau hypothesis, the cholinergic hypothesis, the metal ion hypothesis, the oxidative stress hypothesis and so on. Thus, the development of multifunctional compounds capable of concurrently targeting multiple pathogenic factors of AD has been suggested as an effective solution to combat this disease. Nano-enabled delivery systems (NDS) have promising potential to achieve multifunctional diagnostics/therapeutics against various targets of AD simultaneously due to the unique advantages of nanocarriers, such as easy multifunctionalization on surfaces, high surface-to-volume ratio with large payloads, and potential ability to cross the blood-brain barrier (BBB), making them capable of overcoming the limitations of traditional drug candidates. This review focuses on the recent developments of multifunctional NDS in AD management, including multitherapeutics, multimodal imaging-guided diagnostics, and theranostics. The multifunctionalization strategies, working mechanisms, and in vivo activities of the representative examples are highlighted. Finally, the opportunities and challenges of multifunctional NDS for future research are also discussed.

Clinical characteristics and risk of second primary lung cancer after cervical cancer: A population-based study.

BACKGROUND: Lung cancer is increasingly common as a second primary malignancy. However, the clinical characteristics of second primary non-small cell lung cancer after cervical cancer (CC-NSCLC) compared with first primary non-small cell lung cancer (NSCLC1) is unknown. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry between 1998 and 2010 was used to conduct a large population-based cohort analysis. The demographic and clinical characteristics, as well as prognostic data, were systematically analyzed. The overall survival (OS) in the two cohorts was further compared. The risk factors of second primary lung cancer in patients with cervical cancer were also analyzed. RESULTS: A total of 557 patients (3.52%) developed second primary lung cancer after cervical cancer, and 451 were eligible for inclusion in the final analyses. Compared with NSCLC1, patients with CC-NSCLC had a higher rate of squamous cell carcinoma (SCC) (36.59% vs 19.07%, P < 0.01). The median OS was longer for CC-NSCLC than for NSCLC1 before propensity score matching (PSM) (16 months vs. 13 months) but with no significant difference after PSM (16 months vs. 17 months). The high-risk factors for the development of cervical cancer to CC-NSCLC include age 50-79 years, black race [odds ratio (OR) 1.417; 95% confidence interval (CI) 1.095-1.834; P < 0.05], and history of radiotherapy (OR 1.392; 95% CI 1.053-1.841; P < 0.05). CONCLUSION: Age 50-79 years, black race, and history of radiotherapy were independent risk factors for second primary lung cancer in patients with cervical cancer. Patients with CC-NSCLC had distinctive clinical characteristics and better prognosis compared with patients with NSCLC1.

A randomized, double-blind, placebo-controlled study of B-cell lymphoma 2 homology 3 mimetic gossypol combined with docetaxel and cisplatin for advanced non-small cell lung cancer with high expression of apurinic/apyrimidinic endonuclease 1.

Background Overexpression of apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC) patients. Gossypol, a new inhibitor of APE1, in combination with docetaxel and cisplatin is believed to improve the efficacy of chemotherapy for advanced NSCLC with high APE1 expression. Methods Sixty-two patients were randomly assigned to two groups. Thirty-one patients in the experimental group received 75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 with gossypol administered at 20 mg once daily on days 1 to 14 every 21 days. The control group received placebo with the same docetaxel and cisplatin regimen. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and toxicity. Results There were no significant differences in PFS and OS between the experimental group and the control group. The median PFS (mPFS) in the experimental and control groups was 7.43 and 4.9 months, respectively (HR = 0.54; p = 0.06), and the median OS (mOS) was 18.37 and 14.7 months, respectively (HR = 0.68; p = 0.27). No significant differences in response rate and serious adverse events were found between the groups. Conclusion The experimental group had a better mPFS and mOS than did the control group, though no significant difference was observed. Because the regimen of gossypol combined with docetaxel and cisplatin was well tolerated, future studies with larger sample sizes should be performed.

Microarray analysis of the expression profile of immune-related gene in rapid recurrence early-stage lung adenocarcinoma.

BACKGROUND: Although much progress has been made in the diagnosis of early-stage lung adenocarcinoma (ES-LUAD), the prognosis for ES-LUAD patients with rapid recurrence is still poor. Importantly, there is currently no effective and precise method to screen patients who may develop rapid recurrence. Therefore, it is necessary to identify potential differentially expressed genes (DEGs) in ES-LUAD patients with rapid recurrence and non-rapid recurrence. METHODS: Affymetrix GeneChip Human Transcriptome Array was used to identify DEGs between ES-LUAD patients with rapid recurrence and non-rapid recurrence. Rapid recurrence was defined as recurrence-free survival (RFS) â‰¦ 1 year and non-rapid recurrence was defined as RFS â‰§ 3 years. The biological functions of the DEGs were analyzed by GO and KEGG pathway enrichment analyses. The protein-protein interaction (PPI) network of identified DEGs was conducted by STRING and Cytoscape software. The expression level of crucial hub genes and tumor-infiltrating lymphocytes (TILs) was verified by immunohistochemistry (IHC). RESULTS: A total of 416 DEGs were identified between ES-LUAD patients with and without rapid recurrence. The results of GO analysis revealed that 2 of the top 10 categories in the domain of cellular component, 2 of the top 10 in the domain of molecular function, and 9 of the top 10 in the domain of biological process were functionally related to immunity. The results of KEGG analysis showed that 6 of the top 8 pathways were functionally involved in immune regulation and inflammatory response. The PPI network analysis identified ten crucial nodal protein, including EGFR, MMP9, IL-1ß, PTGS2, MMP1, and 5 histone proteins, which constituted 25 key interactions. IL-1ß and PTGS2 expression were closely related to immunity and IHC analysis further revealed that low expression of IL-1ß and PTGS2 is associated with rapid recurrence. Kaplan-Meier analysis further revealed that LUAD patients with lower IL-1ß or PTGS2 expression had a worse RFS. When the TIL density of CD3+, CD4+, CD8+ and CD20+ subsets was less than 20%, ES-LUAD patients have a higher probability of rapid recurrence. CONCLUSION: There were significant differences in the expression of immune-related genes between patients with rapid recurrence and patient with non-rapid recurrence. Immune-related genes such as IL-1ß and PTGS2 and TIL density (20%) play important roles in rapid recurrence of ES-LUAD. This study provided a theoretical basis for distinguishing the two types of patients from an immunological perspective.

Small molecule-mediated co-assembly of amyloid-ß oligomers reduces neurotoxicity through promoting non-fibrillar aggregation.

Amyloid-ß (Aß) oligomers, particularly low molecular weight (LMW) oligomers, rather than fibrils, contribute very significantly to the onset and progression of Alzheimer's Disease (AD). However, due to the inherent heterogeneity and metastability of oligomers, most of the conventional anti-oligomer therapies have indirectly modulated oligomers' toxicity through manipulating Aß self-assembly to reduce oligomer levels, which are prone to suffering from the risk of regenerating toxic oligomers from the products of modulation. To circumvent this disadvantage, we demonstrate, for the first time, rational design of rigid pincer-like scaffold-based small molecules with blood-brain barrier permeability that specifically co-assemble with LMW Aß oligomers through directly binding to the exposed hydrophobic regions of oligomers to form non-fibrillar, degradable, non-toxic co-aggregates. As a proof of concept, treatment with a europium complex (EC) in such a structural mode can rescue Aß-mediated dysfunction in C. elegans models of AD in vivo. This small molecule-mediated oligomer co-assembly strategy offers an efficient approach for AD treatment.

A randomized phase 2 trial of apatinib vs observation as maintenance treatment following first-line induction chemotherapy in extensive- stage small cell lung cancer.

Background The 5-year survival rate for extensive-disease small-cell lung carcinoma (ED-SCLC) is only 1%. Recently, apatinib exerted promising effects on cancer patients after failure of first-line chemotherapy. Methods This study enrolled 24 ED-SCLC patients to study the efficacy and toxicity of apatinib in combination with chemotherapy and maintenance therapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints included toxicity and safety. Apatinib was given 250 mg/day during the chemotherapy interval, and as maintenance therapy after 4-6 cycles until the patient progressed, died, or was intolerant to drug toxicity. The study further evaluated the cytotoxicity, cell-cycle arrest and apoptotic induction of apatinib in A549 and H446 cells. Results There was no difference in short-term efficacy between combined and chemotherapy groups. Long-term efficacy showed that the median PFS was 7.8 months and 4.9 months in combination and chemotherapy groups, respectively [p = 0.002, HR(95%CI): 0.18(0.06-0.60)]. The median OS was 12.1 months and 8.2 months in combination and chemotherapy groups, respectively [p = 0.023, HR(95%CI): 0.38 (0.16-0.90)]. Multivariate Cox regression analysis showed that apatinib combined with chemotherapy was an independent prognostic factor for OS and PFS. The ECOG score was an independent prognostic factor affecting OS. In vitro analysis showed that apatinib inhibited cell proliferation and caused cell-cycle arrest and apoptosis. Conclusion Apatinib combination/maintenance therapy showed promising efficacy and safety to extend OS/PFS in ED-SCLC and will be a potent therapeutic option in future practice. Although the scale of this study is small, further research on large sample sizes is needed.

Guanine-guided time-resolved luminescence recognition of DNA modification and i-motif formation by a terbium(III)-platinum(II) complex.

Site-specific recognition of DNA modification or the formation of noncanonical structures has important applications in molecular biology, disease diagnosis, and gene expression analysis. In this study, we introduce a guanine-guided sensing tool using a terbium(III)-platinum(II) complex (TPC) as a time-resolved luminescence probe to site-specifically recognize DNA modification and i-motif formation in aqueous solution. The probe is composed of a TbIII center as the luminescent reporter and two PtII units as the receptor for guanine (G) nucleobase. TPC exhibits remarkable reaction selectivity for guanine nucleotides over other nucleotides, giving rise to a significant increase in luminescence. The luminescence enhancement of TPC is mainly attributed to an energy transfer from G base to the TbIII center after the specific coordination of PtII with N7 of guanine (N7-G), which would be facilitated by the phosphates through promoting the departure of coordinated water and bringing G closer to TbIIIvia noncovalent interactions. Based on such sensing feature, the enhanced luminescence of TPC sensitized by G nucleotides can correspondingly decrease upon N7-G modifications of DNA or i-motif formation through constructing simple guanine-guided sensing tools. This probe would provide a useful strategy for site-specific recognition of DNA for extensive purposes.

Tunable Magnetocaloric Properties of Gd-Based Alloys by Adding Tb and Doping Fe Elements.

In this paper, the magnetocaloric properties of Gd1-xTbx alloys were studied and the optimum composition was determined to be Gd0.73Tb0.27. On the basis of Gd0.73Tb0.27, the influence of different Fe-doping content was discussed and the effect of heat treatment was also investigated. The adiabatic temperature change (ΔTad) obtained by the direct measurement method (under a low magnetic field of 1.2 T) and specific heat capacity calculation method (indirect measurement) was used to characterize the magnetocaloric properties of Gd1-xTbx (x = 0~0.4) and (Gd0.73Tb0.27)1-yFey (y = 0~0.15), and the isothermal magnetic entropy (ΔSM) was also used as a reference parameter for evaluating the magnetocaloric properties of samples together with ΔTad. In Gd1-xTbx alloys, the Curie temperature (Tc) decreased from 293 K (x = 0) to 257 K (x = 0.4) with increasing Tb content, and the Gd0.73Tb0.27 alloy obtained the best adiabatic temperature change, which was ~3.5 K in a magnetic field up to 1.2 T (Tc = 276 K). When the doping content of Fe increased from y = 0 to y = 0.15, the Tc of (Gd0.73Tb0.27)1-yFey (y = 0~0.15) alloys increased significantly from 276 K (y = 0) to 281 K (y = 0.15), and a good magnetocaloric effect was maintained. The annealing of alloys (Gd0.73Tb0.27)1-yFey (y = 0~0.15) at 1073 K for 10 h resulted in an average increase of 0.3 K in the maximum adiabatic temperature change and a slight increase in Tc. This study is of great significance for the study of magnetic refrigeration materials with adjustable Curie temperature in a low magnetic field.

Tunable Mechanical Properties of Ti-Zr-Ni-Cr-V Amorphous Ribbons via Different Melt Spinning Speeds during Rapid Solidification Process.

In this paper, the effects of different melt spinning speeds on the mechanical properties of (TiZr)0.5(Ni0.6Cr0.1V0.1)2.1 amorphous ribbons were studied. Tensile tests of the specimens were used to investigate mechanical behavior and mechanical properties of amorphous ribbons. The effects of cooling rate on the glass transition temperature of amorphous ribbons was discussed. The correlation between the microstructure of serrated flow behavior in stress-strain curves and melt spinning speeds of ribbons was also evaluated. In addition, when the spinning speed was 45 m/s, a large number of dense and uniform dimples appeared on the fractured surface of the specimens. Furthermore, characteristics of serrated flow behavior were obvious, which meant that Ti-Zr-Ni-Cr-V amorphous ribbons showed minor plastic behavior. It is assumed that the influence of free volume led to a serrated flow behavior of the amorphous materials, and made the amorphous material exhibit partially plastic properties. Increasing the strain rate sensitivity meant the free volume increased with the increasing spinning speed. Tensile strength (σb) and elongation (δ) of samples exhibited a dramatic increasing trend with an increase in the spinning speed. In particular, Ti-Zr-Ni-Cr-V amorphous ribbons showed better mechanical properties, namely the tensile strength of the amorphous ribbon samples significantly increased from 321 MPa at a spinning speed of 30 m/s to 675 MPa at a speed of 45 m/s. The elongation increased from 0.53% at a speed of 30 m/s to 1.29% at a speed of 45 m/s.

Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer.

AT-101 is a BH3 mimetic and pan-Bcl-2 inhibitor that has shown potent anticancer activity in non-small-cell lung cancer (NSCLC) in murine models, but failed to show clinical efficacy when used in combination with docetaxel in NSCLC patients. Our recent study has demonstrated that AT-101 enhanced the antitumor effect of cisplatin (CDDP) in a murine model of NSCLC via inhibition of the interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway. This study explored the underlying mechanisms for the enhanced anticancer activity of CDDP by AT-101. Our results show that, when compared with monotherapy, AT-101 significantly enhanced the inhibitory effects of CDDP on proliferation and migration of A549 cells and on tube formation and migration in human umbilical vein endothelial cells. AT-101 promoted the proapoptotic activity of CDDP in A549 cells. AT-101 also enhanced the inhibitory effect of CDDP on DNA repair and redox activities of apurinic/apyrimidinic endonuclease 1 (APE1) in A549 cells. In tumor tissues from nude mice treated with AT-101 plus CDDP or monotherapy, the combination therapy resulted in greater inhibition of angiogenesis and tumor cell proliferation than the monotherapy. These results suggest that AT-101 can enhance the antitumor activity of CDDP in NSCLC via inhibition of APE1 DNA repair and redox activities and by angiogenesis and induction of apoptosis, but other mechanisms cannot be excluded. We are now conducting a Phase II trial to examine the clinical efficacy and safety profile of combined use of AT-101 plus CDDP in advanced NSCLC patients.

Sequential treatment with AT-101 enhances cisplatin chemosensitivity in human non-small cell lung cancer cells through inhibition of apurinic/apyrimidinic endonuclease 1-activated IL-6/STAT3 signaling pathway.

AT-101, known as R-(-)-gossypol, is a potent anticancer agent, but its chemosensitizing effects remain elusive. The present study aimed to examine whether AT-101 could increase the sensitivity of non-small cell lung cancer A549 cells to cisplatin (CDDP) and the underlying mechanisms. We evaluated the efficacy of the sequential treatment with AT-101 and CDDP using both in vitro and in vivo models. Our results showed that as compared to AT-101 or CDDP monotherapy, or AT-101 plus CDDP concurrent treatment, the sequential treatment significantly inhibited cell proliferation and migration and induced tumor cell death. Moreover, the efficacy of the sequential treatment was also confirmed in a mouse A549 xenograft model. Our study revealed that AT-101 inhibited the reduced status of apurinic/apyrimidinic endonuclease 1 (APE1) and attenuated APE1-mediated IL-6/STAT3 signaling activation by decreasing IL-6 protein expression; suppressing the STAT3-DNA binding; and reducing the expression of the downstream antiapoptotic proteins Bcl-2 and Bcl-xL. In conclusion, AT-101 enhances the sensitivity of A549 cells to CDDP in vitro and in vivo through the inhibition of APE1-mediated IL-6/STAT3 signaling activation, providing a rationale for the combined use of AT-101 and CDDP in non-small cell lung cancer chemotherapy.

Functional analysis of tanshinone IIA that blocks the redox function of human apurinic/apyrimidinic endonuclease 1/redox factor-1.

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein possessing both DNA repair and redox regulatory activities. It has been shown that blocking redox function leads to genotoxic, antiangiogenic, cytostatic, and proapoptotic effects in cells. Therefore, the selective inhibitors against APE1's redox function can be served as potential pharmaceutical candidates in cancer therapeutics. In the present study, we identified the biological specificity of the Chinese herbal compound tanshinone IIA (T2A) in blocking the redox function of APE1. Using dual polarization interferometry, the direct interaction between APE1 and T2A was observed with a KD value at subnanomolar level. In addition, we showed that T2A significantly compromised the growth of human cervical cancer and colon cancer cells. Furthermore, the growth-inhibitory or proapoptotic effect of T2A was diminished in APE1 knockdown or redox-deficient cells, suggesting that the cytostatic effect of T2A might be specifically through inhibiting the redox function of APE1. Finally, T2A pretreatment enhanced the cytotoxicity of ionizing radiation or other chemotherapeutic agents in human cervical cancer and colon cancer cell lines. The data presented herein suggest T2A as a promising bioactive inhibitor of APE1 redox activity.