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Introduction: The purpose of this study was to assess clinical characteristics and risk factors for tigecycline-associated prothrombin time (PT) and activated partial thromboplastin time (aPTT) prolongation. Methods: We performed a retrospective analysis on coagulation parameters before and during tigecycline treatment in 55 patients in our hospital with severe infections, mainly pneumonia caused by Acinetobacter baumannii. Patients were divided into different groups according to prolongation of PT and aPTT, and clinical features involved were explored. Univariate and multivariable binary logistic regression analyses were used to identify risk factors for tigecycline-associated PT and aPTT increase. Results: We found that PT values increased from 12.73 ± 1.87 to 13.86 ± 2.06 during the treatment compared with premedication (p < 0.001), and the aPTT level prolonged significantly from 33.63 ± 11.24 to 38.15 ± 11.81 (p < 0.001). The multivariate analyses identified 2 variables that were associated with tigecycline-induced PT prolongation: albumin level (p = 0.018) and weight-adjusted tigecycline dosage (p = 0.005). In addition, treatment duration was the only risk factor for tigecycline-induced aPTT prolongation (p = 0.043). Conclusion: Albumin level, weight-adjusted tigecycline dosage, treatment duration may serve as risk indicators for tigecycline-associated coagulation dysfunction. Physicians should be careful with coagulation disorder when prescribing tigecycline in clinical practice, especially in patients with risk factors.

Anthocyanins extracted from flowers were prepared to trace carbonation in cementitious materials. For condition where a broad partial carbonated zone is presented, the new-developed indicator is more competitive over phenolphthalein.

Zinc oxide nanoparticles (nano-ZnO) were dispersed uniformly into cement paste by using ultrasonic treatment, and the effects of nano-ZnO on the setting time, strengths, hydration, and microstructure of the cement paste were investigated. The addition of nano-ZnO to cement paste showed a remarkable influence on the early hydration process of the cement paste, whose setting time increased drastically when the content of nano-ZnO was only 0.2 wt% (by weight of cement). The isothermal calorimetry and electrical resistance tests showed that the addition of nanoparticles can prolong the induction period of cement hydration and influence the hydration rate during the acceleration period. The mechanical test results indicated that long-age strengths of cement paste were improved with the increase of nano-ZnO concentrations. Furthermore, nano-ZnO refined the pore diameter distribution and formed a compact microstructure of the cement paste at 28 days.

CNTs and CNFs are drawing widespread attention due to the unique structure and excellent properties, such as the mechanical property and the electrical property. It will significantly improve the cement-based composites’ properties when adding CNTs/CNFs into composites. This paper briefly introduces the CNTs’/CNFs’ basic properties and dispersion methods, and elucidates the properties of cement-based composites recombining CNTs/CNFs, including the mechanical property, the deformation property, the durability property, the thermal conductivities and electrical conductivities. This paper also summarizes the problems existing in present research, and gives some proposes for future study.

In this study, the influences of ultrasonic and surfactants on the dispersion of graphene sheets in water were evaluated using UV–vis spectroscopy, and homogenous dispersions of graphene sheets in water were obtained by using sodium dodecyl benzene sulfonate (SDBS). Then, the highly dispersed graphene sheets were introduced to cement paste through high-speed mixing, and the mechanical and microstructural properties of graphene-modified cement material was evaluated. Experiment results indicated that the addition of 0.025 wt% graphene sheets increased the 7-day composite compressive strength by 14.9%, the flexural strength by 23.6% and direct tensile strength by 15.2%. X-ray diffraction (XRD) analysis showed that the addition of graphene sheets lowered the orientation index of calcium hydroxide (CH) crystals significantly. Moreover, mercury intrusion porosimetry (MIP) and microscope imaging (SEM) indicated that a high degree of dispersion of graphene sheets was achieved, and the two-dimensional graphene sheets promote hydration and suppress the extension process of cracks.

In the paper, the early age tensile creep behavior of high performance concrete (HPC) containing mineral admixtures was experimentally investigated. The results showed that, when the loading age was at 1 d and 2 d, the addition of fly ash (FA) increased the early age specific tensile creep of HPC, while blast furnace slag (BFS) showed an opposite effect. When the loading age was later than 3 d, the early age specific tensile creep of HPC was not obviously influenced by FA and BFS. Based on the experimental results, a rheology-based model (named as “ZC”, initials for the word “Self-developed” in Chinese) was proposed to predict the early age tensile creep of HPC with mineral admixtures. The ZC model was validated with other experimental results, and the prediction results agreed well with the experimental data. Moreover, the limitations and further improvements on the proposed model were also discussed in the paper.

The cracks in concrete are a fast transport path for chlorides and influence the service life of concrete structures in chloride environments. This study aimed to reveal the effect of crack geometry on chloride diffusion in cracked concrete. The chloride diffusion process in cracked concrete was simulated with the finite difference method by solving Fick’s law. The results showed that the apparent chloride diffusivity was lower in more tortuous cracks, and the cracks with more narrow points also showed lower apparent chloride diffusivity. For tortuous cracks, a higher crack width meant relatively more straight cracks, and consequently, higher apparent chloride diffusivity, while a lower crack width resulted in more tortuous cracks and lower apparent chloride diffusivity. The crack depth showed a more significant influence on the chloride penetration depth in cracked concrete than crack geometry did. Compared with rectangular and V-shaped cracks, the chloride diffusion process in cracked concrete with a tortuous crack was slower at the early immersion age. At the same crack depth, the crack geometry showed a marginal influence on the chloride penetration depth in cracked concrete during long-term immersion.

To enhance the understanding about the utilization of steel slags as a cementitious material, we comparatively studied the chemical, mineralogical and morphological properties of two types of steel slag; basic-oxygen-furnace carbon slag (BOF C) and electric-arc-furnace stainless steel slag (EAF S). Moreover, we studied the standard consistency, setting time and the effect of the slag replacement ratios on the fluidity and compressive strength of blended cement mortar. The experimental results showed that BOF C had higher alkalinity, higher pH value and more hydraulic phases than EAF S. Both types of slag showed water reduction effect due to its high fineness. Neat BOF C paste showed flash set and acceleration in the initial setting time of blended cement especially at high slag proportions. However, EAF S prolonged the setting time of blended cement even at low slag proportions. The pH values for blended cement contained 50% BOF C or EAF S were lower than those of pure cement paste. Despite of slag type, compressive strength gradually decreased with increasing slags content. The strength of BOF C mortar was higher than that of EAF S mortar with the same replacement ratio for the same age. Slag activity index demonstrated that BOF C and EAF S conformed to the Chinese National Standard (GB/T 20491-2006) requirements for steel slag as grade one and grade two, respectively.

The influence of the curing temperature (150 °C, 200 °C, 250 °C, and 300 °C) and curing time (4 h, 8 h, and 12 h) on the mechanical properties and shrinkage development of reactive powder concrete (RPC) was studied, and a curing regime for improving its mechanical properties is proposed. Test results show that the compressive and flexural strengths of specimens increase at curing temperatures of 200 °C to 250 °C, but decrease at curing temperature of 300 °C. Meanwhile, shrinkage measurement results indicate that the ultimate shrinkage of high-temperature cured RPC at 50% relative humidity (RH) is lower than in the control group. Scanning electron microscope results reveal that high-temperature curing improves the microscopic pore structure of RPC and makes the interfacial transition zone denser. Furthermore, the dry-heat curing regime can accelerate the cement hydration process, and tobermorite or xonotlite was found to be one of the major crystalline hydrates at high temperature.

The representative volume element (RVE) plays an important role in the mechanics and physics of random heterogeneous materials with a view to predicting their effective properties. Estimating the RVE size, therefore, is of high importance. In this paper, potassium iodide (KI) was applied first time as the staining agent, and local sand fraction of mortar was calculated combining staining technique and computed tomography (CT). Besides, an extended attenuation method was refined in this study, and spatial distribution of local porosity for mortars was obtained. The RVE size was estimated depending on gray-scale value, local sand fraction and local porosity, respectively, and the results reveal that, the RVE size depending on gray-scale value is smaller than that depending on local porosity or depending on local sand volume fraction; besides, both the RVE sizes depending on local sand fraction and depending on local porosity comply with that obtained from numerical modelling, where a RVE size is suggested to be 3–5 times greater than the maximum sand size. Keywords: Staining, Computed tomography(CT), Porosity, Mortar, Representative volume element(RVE), Cement-based material

Objective In the post-HAART era, the incidence of some AIDS-defining cancers declined markedly likely reflecting HAART-related improvements in immunity, whereas incidence of some cancers such as cervical cancer has not been affected. Therefore, it is valuable to find whether antiretroviral drugs or prophylactic microbicides could treat or prevent these cancers, especially the cervical cancer. Design We screened the anti-HIV drugs, approved or in phase III clinical trials, to identify a potential anticancer drug candidate. Methods We chose cervical HeLa and SiHa cancer cells and focused on studying the antitumor effects in vitro and in vivo. Cell proliferation was measured by MTT assay, the cytotoxic effect was obtained through apoptosis as evidenced by Annexin V flow cytometry assay because of the arresting of cancer cells in G2/M phase of cell cycle. Nude mice xenograft model was performed to detect the antitumor effect in vivo. Results TMC120 was identified as a potential anticancer drug candidate. TMC120 displayed potent cytotoxic effect on various human cancer cells, including cervical carcinoma cell line HeLa and SiHa. Further mechanism study showed that TMC120 enhanced the polymerization of microtubules, which was followed by mitotic arrest, as well as abnormal mitotic spindles. TMC120 also substantially retarded the growth rate of the tumor in vivo. Conclusion TMC120 is a potential chemoprophylactic and therapeutic agent for cervical cancers in a manner similar to paclitaxel, and could be suitable for helping healthy women to prevent HIV infection and cervical cancer.

Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5–20 μmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.

The early age volume deformation is the main course for the cracking of high-performance concrete (HPC). Hence, the shrinkage behavior and the restrained stress development of HPC under different restraints and curing conditions were experimentally studied in this paper. The method to separate the stress components in the total restraint stress was proposed. The total restrained stress was separated into autogenous shrinkage stress, drying shrinkage stress and thermal stress. The results showed that the developments of the free shrinkage (autogenous shrinkage and drying shrinkage) and the restrained stress were accelerated when the drying began, but the age when the drying began did not significantly influence the long-term shrinkage and restrained stress of HPC, the autogenous shrinkage stress continuously contributed to the development of the total restrained stress in HPC, the drying shrinkage stress developed very rapidly soon after the drying began, and the thermal stress was generated when the temperature dropped. The thermal stress was predominant at the early age, but the contributions of the three stresses to the total restrained stress were almost the same at the age of 56 d in this study.

Permeability of concrete is regarded as a basic indicator of its durability. This paper proposed a simple model to predict the permeability of engineered cementitious composites (ECC), which are fiber reinforced cementitious composites with extremely high ductility and toughness. The permeability of cement paste in ECC was firstly determined based on the general effective media theory. The needed microstructure information of cement paste was obtained from a simulated microstructure. Porosity of the interfacial transition zone (ITZ) was obtained with an ITZ porosity model, and then used to calculate the permeability of ITZ. The permeability of the matrix was determined according to the general self-consistent scheme, and the influence of fiber was simplified with its volume fraction. The calculated permeability of ECC was verified with results from water permeability tests and the accuracy of the model was acceptable for cement-based materials.

Sewage sludge ash (SSA) is the waste obtained from the incineration of wastewater sludge. SSA could be recycled in cement-based materials, but normally SSA in China is sulfate rich, and how the sulfate-rich sewage sludge ash (SR-SSA) influence the properties and microstructure of cement-based materials is still unknown. This study aimed to investigate the possibility of recycling use SR-SSA in cement-based materials. The effect of SR-SSA on the basic properties, volume deformation and microstructure of the cement paste was experimentally studied. The findings of this study indicated that the addition of SR-SSA reduced the workability, compressive strength and flexural strength, retarded the setting times, reduced the autogenous shrinkage and caused greater long-term drying shrinkage and higher potential expansion of the cement paste. The formation of excessive ettringite and the coarse pore structure contributed to the properties reduction and volume instability of cement pastes with excessive SR-SSA. However, replacing 5% cement with SR-SSA didn’t induce much detrimental influence on the properties of cement paste. It is feasible to recycle SR-SSA in cement-based materials by replacing up to 5% cement. At the same time, replacing 5% cement with SR-SSA could result in 4.98% lower CO2 emission and 25.42% lower financial cost. In case of recycling all SR-SSA in China, it is possible to expect annual reduction in CO2 emission of 6.8 billion kg CO2-e and financial cost of 16.1 billion RMB yuan. This study could help to recycle SR-SSA and improve the sustainability of cement-based materials.

Pervious concrete (PC) is utilized in pavement engineering as a kind of environment-friendly material, but its application is limited to some extent since the contradiction between strength and permeability is not easy to be compromised. In this paper, interface transition zone (ITZ) of PC was enhanced using silica fume (SF), fly ash (FA) and dispersible latex powder (DLP). The interface reinforcement effect was characterized by micro hardness of ITZ. In order to correlate pore structure of PC to its permeability, a new method based on slice image (PSI) was proposed. The micro hardness tests results indicated that the compactness of ITZ in PC had been improved with SF and FA, and the bonding strength between matrix and aggregate could be elevated. The proposed method was proved to be feasible and accurate in terms of the observation that the porosity measured through the method coincided with that obtained from the frequently-used CT scanning method.

We experimentally investigated the effect of curing conditions on the durability of UHPC under flexural load. Moreover, the mechanisms of the effect of curing conditions were revealed from the microstructural point of view with environmental scanning electron microscopy (ESEM) and X-ray computerized tomography (X-ray CT). The experimental results show that the flexural load has negative influence on the durability of UHPC, but UHPC still exhibits excellent durability under flexural load. Besides, the curing conditions do show influences on the durability of UHPC. Compared with standard and steam curing, oven curing led to a lower chloride resistance and freeze-thaw performance of UHPC. The microstructure of UHPC paste was detected with ESEM. It is revealed that, compared with standard and steam cured UHPC, the lower reaction degree and internal microcracks are the causes for the lower chloride resistance of oven cured UHPC. The defects distribution in UHPC before and after freeze-thaw action was investigated with X-ray CT. The number of defects in oven cured UHPC increases the fastest during the freeze-thaw action due to its more defective microstructure

Obatoclax, a pan-inhibitor of anti-apoptotic Bcl-2 proteins, exhibits cytotoxic effect on cancer cells through both apoptosis-dependent and -independent pathways. Here we show that obatoclax caused cytotoxicity in both cisplatin-sensitive and -resistant esophageal cancer cells. Although obatoclax showed differential apoptogenic effects in these cells, it consistently blocked autophagic flux, which was evidenced by concomitant accumulation of LC3-II and p62. Obatoclax was trapped in lysosomes and induced lysosome clustering. Obatoclax also substantially reduced the expression of lysosomal cathepsins B, D and L. Moreover, cathepsin knockdown was sufficient to induce cytotoxicity, connecting lysosomal function to cell viability. Consistent with the known function of autophagy, obatoclax caused the accumulation of polyubiquitinated proteins and showed synergy with proteasome inhibition. Taken together, our studies unveiled impaired lysosomal function as a novel mechanism whereby obatoclax mediates its cytotoxic effect in esophageal cancer cells.

It has been demonstrated that COX-2-selective inhibitor celecoxib shows synergy with oxaliplatin for suppressing tumor growth. However, the benefit of adding celecoxib to oxaliplatin-based regimen in human esophageal cancer is largely unknown. In the present study, we demonstrated that celecoxib antagonized oxaliplatin-induced cytotoxicity and apoptosis independent of COX-2 inhibition in human esophageal cancer cells. Celecoxib decreased cellular oxaliplatin accumulation and Pt-DNA adduction formation due to reduced drug influx. Celecoxib alone or combined with oxaliplatin substantially reduced the expression of organic cation transporter 2 (OCT2). To this end, OCT2 knockdown was sufficient to reduce oxaliplatin uptake, connecting OCT2 expression to oxaliplatin accumulation. Moreover, oxaliplatin combined with celecoxib also showed no beneficial effect when compared with monotherapy in esophageal cancer cell-xenografted nude mice. To conclude, our data provide evidence that the addition of celecoxib to oxaliplatin-containing regimens for patients with OCT2-expressing cancers should be cautious.

Permeability of concrete is one of its most important characteristics determining the durability. In this study, water permeability of a new class of fiber reinforced concrete materials called Eco-Friendly Ductile Cementitious Composites (EDCC) was studied, with and without an applied compressive stress. Hollow-core specimens were used and permeability tests were performed under full flow-equilibrium conditions. Four applied stress levels of 0.3fu, 0.4fu, 0.5fu and 0.6fu were investigated, where fu is the compressive strength of the EDCC in question. Permeability tests under identical conditions were carried out on plain control specimens without fiber reinforcement (termed Plain Cementitious Composites, PCC). The results indicated that the permeability of unstressed specimens declined over time due to the continuous hydration. A ‘critical’ compressive stress level (fcc) was identified and defined, which when exceeded, a dramatic increase in the coefficient of permeability occurred. The ‘critical’ compressive stress level (fcc) was noted to be between 0.5fu ~ 0.6fu for EDCC and 0.4fu ~ 0.5fu for PCC. In other words, EDCC was more damage tolerant than PCC, and even when fcc was exceeded, the impact of stress on the permeability of EDCC was far less pronounced compared to PCC.

Detection and analysis of concrete cracks feature are important aspects of concrete crack research, and non-contact measurement of concrete cracks is an important research direction. In this paper, measurement and analysis of concrete crack feature based on smartphone APP of digital image processing techniques (SADIPT) in android system was investigated. The results showed that the size of single pixel point (SSPP, η ) has a good linear relationship with the shooting distance in basic lens under no amplification. The relations between all kinds zoom lens of smartphone and the shooting distance followed the exponential function law. The SSPP of zoom lens ( η ' ) can be calculated with an exponential function, and it was determined by smartphone’s camera’s CMOS (complementary metal oxide semiconductor) performance, and the magnification of zoom lens can effectively improve the measurement accuracy. The η ' function curves of the same maximum magnification ratio with same basic pixel were slightly different for different smartphone camera’s CMOS while the influence of basic pixel of smartphone zoom lens on η ' was significant. The SSPP η ' under non-amplification mode decreased as the base pixel increased, but it’s not linear. The results showed that the relations between SSPP η ' of all zoom lens and amplification ratio followed the exponential function law at same shooting distance. The accuracy of measuring concrete cracks with smartphone zoom lens or shortening the shooting distance can meet the requirements of engineering detection.

The flexural response of ultrahigh performance fiber-reinforced concrete (UHPFRC) was simulated based on the lattice fracture model. Fiber was modelled as separated beam that was connected to the matrix with interface beams. The simulated results were compared with the experimental results. Deviations occurred at the late stage of the strain-softening period. But both the strain-hardening behavior and multicracking phenomenon were observed in the simulation. The effects of fiber orientation and fiber content were studied with the lattice fracture model. The flexural strength and toughness of UHPFRC improved as the fibers were aligned distributed or the fiber content increased. The proposed model has the potential to help with the materials design of UHPFRC, and the limitations of the model were also discussed in the paper.

The chloride diffusion coefficient is the most important parameter when predicting chloride ingress in concrete. This paper proposed a model for calculating the chloride diffusion coefficient of steel fiber reinforced concrete (SFRC). Considering the concrete structures in service are usually subjected to external loads, the effect of bending load was discussed and expressed with a stress factor ks in the model. The chloride diffusion coefficient of cement paste was calculated with capillary porosity and then used to predict the chloride diffusion coefficient of SFRC. Some factors in the model were determined with experimental results. Chloride bulk diffusion tests were performed on SFRC and plain concrete (without fiber) specimens under bending load. SFRC showed slightly better chloride resistance for unstressed specimens. The compressive stress decreased the chloride diffusion coefficient of SFRC, while it caused no change in plain concrete. For the tensile zone, the chloride resistance of concrete was improved significantly by adding steel fibers. Overall, SFRC performed better chloride resistance, especially under bending load. The proposed model provides a simple approach for calculating the chloride diffusion coefficient of SFRC under bending load.

This work aims to investigate the damage in ultrahigh-performance concrete (UHPC) caused by freezing-thawing action. Freezing-thawing tests were carried out on UHPCs with and without steel fibers. Mercury intrusion porosimetry (MIP), scanning electron microscopy (SEM), and X-ray computed tomography (X-ray CT) were applied to detect the microstructure of the UHPC matrix before and after the freezing-thawing tests. The results showed that UHPC possessed very excellent freezing-thawing resistance due to its dense microstructure. After the freezing-thawing action, cracks occurred and were prone to initiate at the sand-paste interface in the UHPC matrix. MIP results also indicated that cracks appeared in the UHPC matrix after the freezing-thawing action. The number of defects that can be seen by X-ray CT increased in UHPC after the freezing-thawing action as well. The mismatch of the thermal expansion coefficients of the aggregate and the paste is considered to be the reason for the cracking at the sand-paste interface. The steel fibers in UHPC inhibited the propagation of cracks in the matrix and improved the freezing-thawing performance of UHPC.

Chloride transport property is very important for the durability and service life of reinforced concrete structures subjected to marine environments and de-icing salt. In reality, for different reasons, concrete structures are frequently cracked, and cracks can alter the chloride transport properties of concrete. Recently, several studies have been conducted by both experiment and simulation on the influence of cracks on the chloride transport properties of concrete. The aim of this paper is to review these research efforts. The experimental methods and simulation approaches on the chloride transport properties of cracked concrete are introduced. Detailed discussions on the findings from these experimental and simulation studies are given. The chloride transport properties of cracked concrete are influenced by various factors, such as crack geometry, concrete composition, and load condition. Research in this area is still on-going, and many problems need to be settled before proposing reliable models for predicting the service life of real cracked concrete structures in chloride environments. Hence, some further research topics are recommended. The influences of other factors, such as carbonation, freeze-thaw, fatigue, and saturation degree, on the transport properties of cracked concrete should be revealed.

Over the last twenty years, remarkable advances have taken place in the research and application of ultra-high performance concrete (UHPC), which exhibits outstanding mechanical properties and excellent durability. It has shown great potential for the next generation infrastructure construction from the sustainability point of view. This paper will give an overview on UHPC, with particular focus on the properties, applications and perspectives. After several decades of development, several types of commercial UHPC materials are available in the market, and the properties of UHPC have been characterized by numerous experimental and field tests. Generally speaking, the performance (e.g. mechanical properties and durability) of UHPC is much better than normal concrete (NC) and high performance concrete (HPC). Therefore, the uses of UHPC are growing all over the world, in both fields of new construction and retrofitting. Nevertheless, it is still a special material and technology, which is not worldwide accepted. So some application prospects of UHPC are briefly introduced in the paper, and the efforts, which have to be made to turn UHPC into a widespread ‘regular’ technology, are discussed. This paper aims to help designers, engineers, architects and infrastructure owners to know the capacities of UHPC and thus to increase the applications of this material.

Cisplatin-based chemotherapy frequently resulted in acquired resistance. The underpinning mechanism of such resistance remains obscure especially in relation to autophagic response. This study thus investigated the role of autophagy in the anticancer activity of cisplatin in human esophageal cancer cells with acquired cisplatin resistance. In response to cisplatin treatment, EC109 cells exhibited substantial apoptosis and senescence whereas cisplatin-resistant EC109/CDDP cells exhibited resistance. In this respect, cisplatin increased ERK phosphorylation whose inhibition by MEK inhibitor significantly attenuated the cytotoxic and cytostatic effect of cisplatin. Notably, cisplatin preferentially induces autophagy in EC109/CDDP cells but not in EC109 cells. Moreover, the induction of autophagy was accompanied by the suppression of mTORC1 activity. Abolition of autophagy by pharmacological inhibitors or knockdown of ATG5/7 re-sensitized EC109/CDDP cells. Co-administration of an autophagy inhibitor chloroquine and cisplatin significantly suppressed tumor growth whereas cisplatin monotherapy failed to elicit anticancer activity in nude mice xenografted with EC109/CDDP cells. To conclude, our data implicate autophagic response as a key mechanism of acquired resistance to cisplatin, suggesting that autophagy is a novel target to improve therapy efficiency of cisplatin toward human esophageal cancers with acquired resistance.

Pan-Bcl-2 family inhibitor obatoclax has been demonstrated to be effective against various cancers, of which the mechanism of action is not fully understood. In this study, we demonstrate that obatoclax suppressed esophageal cancer cell viability with concomitant G1/G0-phase cell cycle arrest. At the tested concentrations (1/2 IC50 and IC50), obatoclax neither induced PARP cleavage nor increased the Annexin V-positive population, suggesting G1/G0-phase arrest rather than apoptosis accounts for most of the reduction of cell viability produced by obatoclax. Double knockdown of Bak and Bax by small interference RNA failed to block obatoclax-induced G1/G0-phase arrest, implying its role in cell cycle progression is Bak/Bax-independent. The cell cycle arresting effect of obatoclax was associated with up-regulation of p21(waf1/Cip1). Knockdown of p21(waf1/Cip1) significantly attenuated obatoclax-induced G1/G0-phase arrest. Although obatoclax stimulated phosphorylation of Erk, p38, and JNK, pharmacological inhibition of p38 but not Erk or JNK blocked obatoclax-induced G1/G0-phase arrest. Moreover, knockdown of p38 abolished the cell cycle arresting effect of obatoclax. In consistent with this finding, inhibition of p38 blocked obatoclax-induced p21(waf1/Cip1) expression while inhibition of Erk or JNK failed to exert similar effect. To conclude, these findings suggest that obatoclax induced cell cycle arrest via p38/p21(waf1/Cip1) signaling pathway. This study may shed a new light on the anti-cancer activity of obatoclax in relation to cell cycle arrest.