Preparation and Properties of Reversible Emulsion Drilling Fluid Stabilized by Modified Nanocrystalline Cellulose.

Reversible emulsion drilling fluids can concentrate the advantages of water-based drilling fluids and oil-based drilling fluids. Most of the existing reversible emulsion drilling fluid systems are surfactant-based emulsifier systems, which have the disadvantage of poor stability. However, the use of modified nanoparticles as emulsifiers can significantly enhance the stability of reversible emulsion drilling fluids, but ordinary nanoparticles have the disadvantages of high cost and easily causing environmental pollution. In order to solve the shortcomings of the existing reversible emulsion drilling fluid system, the modified nanocrystalline cellulose was considered to be used as an emulsifier to prepare reversible emulsion drilling fluid. After research, the modified nanocrystalline cellulose NWX-3 can be used to prepare reversible emulsions, and on this basis, reversible emulsion drilling fluids can be constructed. Compared with the reversible emulsion drilling fluid stabilized by HRW-DMOB (1.3 vol.% emulsifier), the reversible emulsion drilling fluid stabilized by the emulsifier NWX-3 maintained a good reversible phase performance, filter cake removal, and oily drill cuttings treatment performance with less reuse of emulsifier (0.8 vol.%). In terms of temperature resistance (150 °C) and stability (1000 V < W/O emulsion demulsification voltage), it is significantly better than that of the surfactant system (temperature resistance 120 °C, 600 V < W/O emulsion demulsification voltage < 650 V). The damage of reservoir permeability of different types of drilling fluids was compared by physical simulation, and the damage order of core gas permeability was clarified: water-based drilling fluid > reversible emulsion drilling fluid > oil-based drilling fluid. Furthermore, the NMR states of different types of drilling fluids were compared as working fluids, and the main cause of core permeability damage was the retention of intrusive fluids in the core.

Enhanced Aquathermolysis of Water-Heavy Oil-Ethanol Catalyzed by B@Zn(II)L at Low Temperature.

In order to study the synergistic effects of exogenous catalysts and in situ minerals in the reservoir during heavy oil aquathermolysis, in this paper, a series of simple supported transition metal complexes were prepared using sodium citrate, chloride salts and bentonite, and their catalytic viscosity reduction performances for heavy oil were investigated. Bentonite complex catalyst marked as B@Zn(II)L appears to be the most effective complex. B@Zn(II)L was characterized by scanning electron microscopy (SEM), Fourier-Transform Infrared (FTIR) spectroscopy, thermo-gravimetric analysis (TGA) and N2 adsorption-desorption isotherms. Under optimized conditions, the viscosity of the heavy oil was decreased by 88.3%. The reaction temperature was reduced by about 70 °C compared with the traditional reaction. The results of the group composition analysis and the elemental content of the heavy oil indicate that the resin and asphaltene content decreases, and the saturated and aromatic HC content increases. The results of TGA and DSC of the heavy oil show that the macromolecular substances in the heavy oil were cracked into small molecules with low boiling points by the reaction. GC-MS examination of water-soluble polar compounds post-reaction indicates that B@Zn(II)L can diminish the quantity of polar substances in heavy oil and lower the aromatic nature of these compounds. Thiophene and quinoline were utilized as model compounds to investigate the reaction mechanism. GC-MS analysis revealed that C-C, C-N and C-S bonds were cleaved during the reaction, leading to a decrease in the viscosity of heavy oil.

The Phase Inversion Mechanism of the pH-Sensitive Reversible Invert Emulsion.

Reversible emulsification drilling fluids can achieve conversion between oil-based drilling fluids and water-based drilling fluids at different stages of drilling and completion, combining the advantages of both to achieve the desired drilling and completion effects. The foundation of reversible emulsion drilling fluids lies in reversible emulsions, and the core of a reversible emulsion is the reversible emulsifier. In this study, we prepared a reversible emulsifier, DMOB(N,N-dimethyl-N'-oleic acid-1,4-butanediamine), and investigated the reversible phase inversion process of reversible emulsions, including the changes in the reversible emulsifier (HLB) and its distribution at the oil-water interface (zeta potential). From the perspective of the acid-alkali response mechanism of reversible emulsifiers, we explored the reversible phase inversion mechanism of reversible emulsions and reversible emulsification drilling fluids. It was revealed that the reversible phase inversion of emulsions could be achieved by adjusting the pH of the emulsion system. Then the proportion of ionic surfactants changed in the oil-water interface and subsequently raised/lowered the HLB value of the composite emulsifier at the oil-water interface, leading to reversible phase inversion of the emulsion. The introduction of organic clays into reversible emulsification drilling fluid can affect the reversible conversion performance of the drilling fluids at the oil-water interface. Thus, we also investigated the influence of organic clays on reversible emulsions. It was demonstrated that a dosage of organic clay of ≤2.50 g/100 mL could maintain the reversible phase inversion performance of reversible emulsions. By analyzing the microstructure of the emulsion and the complex oil-water interface, we revealed the mechanism of the influence of organic clay on the reversible emulsion. Organic clay distributed at the oil-water interface not only formed a complex emulsifier with surfactants, but also affected the microstructure of the emulsion, resulting in a difficult acid-induced phase transition, an easy alkali-induced phase transition, and improved overall stability.

Study on the Properties Changes of Reversible Invert Emulsion during the Process from O/W to W/O with Alkali.

The reversible emulsion drilling fluid system combines the advantages of both oil-based and water-based drilling fluids, which can achieve ideal results in different stages of drilling and completion, and the system can be reused to effectively reduce costs. However, the research on reversible emulsions mainly focuses on the development of new reversible emulsifiers, while the specific phase transformation mechanism of reversible emulsion systems is still unclear. In this paper, a stable reversible emulsion was prepared using the reversible emulsifier DMOB as a raw material, and the reversible emulsion performance of the alkali response from the O/W emulsion phase to the W/O emulsion was studied. The microstructure of reversible emulsions was studied by a microscope, a cryogenic transmission electron microscopy, and a laser particle size analyzer. The changes in macroscopic properties of reversible emulsions in the process of alkali conversion were studied by pH, conductivity, demulsification voltage, static stability, viscosity, rheology, and other indicators, and the conversion mechanism of reversible emulsions from O/W emulsion ⟶ bicontinuous structure ⟶ O/W/O emulsion ⟶ W/O emulsion was clarified. The details are as follows: in the first stage, when the amount of NaOH ≤ 0.43 vol.%, the overall particle size of the emulsion decreases first and then increases with the increase in NaOH dosage. In the second stage, when the amount of NaOH was 0.45 vol.%, a double continuous structure was formed inside the emulsion. In the third stage, when the amount of NaOH is 0.48 vol.%, the O/W/O emulsion is formed, and with the increase in stirring time, the internal oil droplets gradually accumulate and are discharged from the water droplets, and finally, the W/O emulsion is formed. In the fourth stage, when the dosage of 0.50 vol.% ≤ NaOH ≤ 5.00 vol.%, the W/O emulsion was formed, and with the increase of NaOH dosage, the structure and compactness between water droplets increased first and then decreased. In the whole process, with the increase in the amount of NaOH solution, the total particle size of the emulsion first decreased and then increased.

The Effect of Sodium Bentonite in the Thermo-Catalytic Reduction of Viscosity of Heavy Oils.

To study the synergistic catalysis of an ex situ catalyst and in situ clay in the aquathermolysis of heavy oil, in this paper, a series of bentonite-supported catechol-metal complexes were prepared, and the catalytic viscosity reduction performance in the aquathermolysis of heavy oil was investigated. Under the optimized conditions, the viscosity can be reduced by 73%, and the pour point can be lowered by 15.0 °C at most, showing the synergistic catalysis of the ex situ catalyst and in situ clay in this aquathermolytic reaction. Thermogravimetry, physical adsorption-desorption, and scanning electron microscopy were conducted to characterize the thermal stability and microstructure of the ex situ catalyst. The components of the heavy oil before and after the reaction were fully characterized. Six model compounds were used to simulate the aquathermolysis reaction process. In order to study the mechanism of viscosity reduction after the catalytic aquathermolysis reaction, the compounds were analyzed by GC-MS. It is believed that these results will be beneficial in the future for related research in this field.

Oil-Soluble Exogenous Catalysts and Reservoir Minerals Synergistically Catalyze the Aquathermolysis of Heavy Oil.

Oil is the "blood" and economic lifeblood of modern industry, but traditional light crude oil has been over-consumed, and it has been difficult to meet human demand for energy, so the exploitation of heavy oil is particularly important. In this paper, an oil-soluble catalyst was synthesized to catalyze the pyrolysis reaction of heavy oil in collaboration with reservoir minerals, so as to achieve efficient viscosity reduction of heavy oil and reduce production costs. The experimental results showed that Zn(II)O + K had the best synergistic viscosity reduction effect after the aquathermolysis of No. 1 oil sample under the reaction conditions of 180 °C, 4 h, 30% of water, and 0.2% of catalyst, respectively, and the viscosity reduction rate was 61.74%. Under the catalysis of the isopropanol system, the viscosity reduction rate was increased to 91.22%. A series of characterizations such as freezing point, thermogravimetric analysis, DSC analysis, component analysis, gas chromatography, wax crystal morphology analysis, and GC-MS analysis of aqueous organic matter were carried out on heavy oil after reaction by different reaction systems, and it could be verified that the viscosity of heavy oil was reduced. Finally, through the study of the reaction mechanism of the model compound, combined with the aqueous phase analysis, it can be clearly found that the depolymerization between macromolecules, the breaking of heteroatom chains, hydrogenation, ring opening, and other effects mainly occur during the reaction, thereby weakening the van der Waals force and hydrogen bond of the recombinant interval, inhibiting the formation of grid structure in heavy oil and effectively reducing the viscosity of heavy oil.

Recent Advances in g-C3N4-Based Materials and Their Application in Energy and Environmental Sustainability.

Graphitic carbon nitride (g-C3N4), with facile synthesis, unique structure, high stability, and low cost, has been the hotspot in the field of photocatalysis. However, the photocatalytic performance of g-C3N4 is still unsatisfactory due to insufficient capture of visible light, low surface area, poor electronic conductivity, and fast recombination of photogenerated electron-hole pairs. Thus, different modification strategies have been developed to improve its performance. In this review, the properties and preparation methods of g-C3N4 are systematically introduced, and various modification approaches, including morphology control, elemental doping, heterojunction construction, and modification with nanomaterials, are discussed. Moreover, photocatalytic applications in energy and environmental sustainability are summarized, such as hydrogen generation, CO2 reduction, and degradation of contaminants in recent years. Finally, concluding remarks and perspectives on the challenges, and suggestions for exploiting g-C3N4-based photocatalysts are presented. This review will deepen the understanding of the state of the art of g-C3N4, including the fabrication, modification, and application in energy and environmental sustainability.

Preparation of Multifunctional Surfactants Derived from Sodium Dodecylbenzene Sulfonate and Their Use in Oil-Field Chemistry.

Four products were obtained from sodium dodecylbenzene sulfonate (SDBS) and formaldehyde (40% solution) using a simple reaction. The products were characterized by TGA, IR, UV and MS to confirm the major chemicals in each sample. The new products could reduce the interfacial tension between oil and water in the experimental temperature range further compared to SDBS. The emulsion ability was also enhanced by SDBS-1 to SDBS-4. The oil-displacement efficiencies of SDBS-1 to SDBS-4 were obviously higher than that of SDBS, and the oil-displacement efficiency of SDBS-2 was the best, with an efficiency of 25%. The experimental results all indicate that these products have an excellent ability to reduce oil-water interfacial tension and that they can be used in the oil and petrochemical industry for oil production and have certain practical uses.

Robust sparse reconstruction of attenuated acoustic field with unknown range of source.

In this paper, we present a gridless algorithm to recover an attenuated acoustic field without knowing the range information of the source. This algorithm provides the joint estimation of horizontal wavenumbers, mode amplitudes, and acoustic attenuation. The key idea is to approximate the acoustic field in range as a finite sum of damped sinusoids, for which the sinusoidal parameters convey the ocean information of interest (e.g., wavenumber, attenuation, etc.). Using an efficient finite rate of innovation algorithm, an accurate recovery of the attenuated acoustic field can be achieved, even if the measurement noise is correlated and the range of the source is unknown. Moreover, the proposed method is able to perform joint recovery of multiple sensor data, which leads to a more robust field reconstruction. The data used here are acquired from a vertical line array at different depths measuring a moving source at several ranges. We demonstrate the performance of the proposed algorithm both in synthetic simulations and real shallow water evaluation cell experiment 1996 data.

Enhanced Crude Oil Sorption by Modified Plant Materials in Oilfield Wastewater Treatment.

The treatment of oilfield wastewater with high crude oil content and complex composition is a problem requiring considerable attention. In order to effectively remove crude oil contained in wastewater, in this work, rice straw, as an oil-absorbing material, was modified and used as a sorbent for crude oil. Rice straw was modified with alkali and cetyltrimethylammonium chloride (CTAC) by simple substitution reaction. The adsorption capacity of modified rice straw for oil was evaluated. The results illustrate that the adsorption rate of rice straw for crude oil was increased from 0.83 to 8.49 g/g, with the optimal conditions of 18% NaOH reacted for 90 min at 50 °C and 2% CTAC reacted for 60 min at 20 °C. The proposed modification method could be used for different materials to enhance the adsorption rate. The results of the contact angle test show that the modified straw changed from hydrophilic to hydrophobic, which may be the main reason for the improvement in the oil absorption rate. Finally, the surface structure of rice straw was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and N2 adsorption-desorption isotherms, which further confirmed the hydrophobicity of the modified rice straw.

Resource utilization of medical waste under COVID-19: Waste mask used as crude oil fluidity improver.

The disposal of medical waste has become an increasing environmental issue since the COVID-19 epidemic outbreaks. Conventional disposal methods have produced waste of fossil resources and environmental problems. In this study, the waste medical mask-derived materials were tested as viscosity reducer and pour point depressant to evaluate the possibility of being used as crude oil fluidity improver. The results show that the materials derived from the three parts of the waste medical mask can reduce the viscosity and pour point of each crude oil samples from different oilfields in China. The middle layer of the medical mask (PP-2) displays the highest efficiency, and the viscosity reduction rate and maximum pour point reduction reaches 81% and 8.3 °C at 500 ppm, respectively. A probable mechanism of improving rheological properties of the crude oil samples by the medical mask-derived materials was further proposed after the differential scanning calorimetry (DSC) analysis and the wax crystal morphology analysis. We hope this work could provide a way to solve the current environmental issues under COVID-19.

Construction of NIR and Ratiometric Fluorescent Probe for Monitoring Carbon Monoxide under Oxidative Stress in Zebrafish.

Carbon monoxide (CO), as a crucial gasotransmitter, is endogenously produced by the degradation of heme and plays a critical role in regulating various physiological and pathophysiological processes such as oxidative stress. Thus, an effective fluorescent probe for investigating the relationships between CO and oxidative stress in vivo is necessary. In this paper, a ratiometric near-infrared (NIR) fluorescent probe (CP-CO) based on a coumarin-benzopyran fluorophore for imaging CO is developed. CP-CO itself displays strong coumarin emission due to its spironolactone structure. After the probe is reacted with CO and PdCl2, a notable enhancement of emission intensity at 690 nm can be found, which results in an obvious red shift of emission (200 nm). Moreover, CP-CO exhibits high sensitivity toward CO and produces a high enhancement ratio (203-fold). In addition, the probe is applied for ratiometric monitoring of exogenous and endogenous CO levels in HepG2 cells. Furthermore, the fluorescence imaging of CP-CO in zebrafish is performed by two-photon excitation along with excellent penetration ability. Most importantly, CP-CO can visualize the upregulation of CO under lipopolysaccharide (LPS)-induced oxidative stress in a zebrafish model, which vividly reveals its excellent ability in the elucidation of CO function in related biological events.

Accurate Fluorescence Diagnosis of Cancer Based on Sequential Detection of Hydrogen Sulfide and pH.

Cancer ranks as a leading cause of death in every country of the world. However, if they are discovered early, a lot of cancers can be prevented or cured. Discovering and monitoring cancer markers are the main methods for early diagnosis of cancer. To date, many fluorescent probes designed and used for early cancer diagnosis can only react with a single marker, which always causes insufficient accuracy in complex systems. Herein, a novel near-infrared (NIR) fluorescent probe (CyO-DNP) for the sequential detection of H2S and H+ is synthesized. In this probe, a heptamethine dye is selected as the fluorophore and a 2,4-dinitrophenyl (DNP) ether is chosen as recognition group. In the presence of H2S, CyO-DNP is transformed into CyO, which exhibits an intense fluorescence at 663 nm. Then, H+ induces the protonation of CyO to obtain CyOH, and the final fluorescence emission at 793 nm significantly enhances. Owing to the low cytotoxicity and the NIR fluorescence emission, CyO-DNP can sequentially monitor endogenous H2S and H+ in cancer cells and image exogenous and endogenous H2S and H+ in mice. It is worth mentioning that CyO-DNP can effectively avoid the false positive signal caused by the liver and kidney and discriminate normal mice and tumor mice accurately. For all we know, CyO-DNP is the first fluorescent probe for early accurate diagnosis of cancer by sequentially detecting H2S and H+.

Monitoring the Fluctuation of Hydrogen Peroxide in Diabetes and Its Complications with a Novel Near-Infrared Fluorescent Probe.

Diabetes is one of the metabolic diseases marked by hyperglycemia and is often accompanied by the occurrence of some complications. As a biomarker of oxidative stress, hydrogen peroxide (H2O2) has close association with the occurrence and development of diabetes and its complications. Unfortunately, there is no fluorescent probe reported for imaging H2O2 in diabetic mice. Here, a novel near-infrared (NIR) fluorescent probe named QX-B was designed and synthesized to detect H2O2. For the probe, the quinolinium-xanthene dye is used as the fluorophore and borate ester is chosen as the response group. After the addition of H2O2, a strong NIR fluorescence signal at 772 nm is observed. The probe not only shows high sensitivity with 10-fold enhancement but also displays excellent selectivity to H2O2 over other possible interfering species. In the meantime, the possible response mechanism of QX-B toward H2O2 was proposed and verified by the high-performance liquid chromatography (HPLC) experiment, mass spectra (MS) experiment, and density functional theory (DFT) calculation. Furthermore, based on the low cell cytotoxicity of QX-B, it has been applied in imaging exogenous and endogenous H2O2 in HeLa cells, HCT116 cells, 4T1 cells, and zebrafish successfully. More importantly, inspired by the performance of NIR fluorescence, QX-B has been used in monitoring H2O2 in diabetic mice for the first time. This provides very important information for the diagnosis and treatment of diabetes and its complications.

The construction of a near-infrared fluorescent probe with dual advantages for imaging carbon monoxide in cells and in vivo.

As a kind of toxic gas, carbon monoxide (CO) can hinder uptake of oxygen in humans. However, more and more studies have shown that CO is an important gaseous messenger in the body and playing an indispensable role in intracellular signaling pathways. So, it is necessary to develop an analytical method to study CO in living organisms. Although there are many CO-responsive probes, most of them have the disadvantages of a small Stokes shift or short emission wavelength. In order to address the above issue, a novel probe (FDX-CO) with a large Stokes shift (190 nm) and long emission wavelength (770 nm) was firstly synthesized to detect CO. The probe shows high sensitivity and superior selectivity toward CO. Moreover, the probe was successfully used for visualizing exogenous and endogenous CO in cells by fluorescence imaging, 3D quantification analysis and flow cytometric analysis. More importantly, FDX-CO could excellently detect CO in mice, which suggests that this probe has the potential ability to image CO in vivo. This probe can be viewed as a useful tool in the research of CO.

ATP-responsive near-infrared fluorescence MOF nanoprobe for the controlled release of anticancer drug.

A near-infrared (NIR) fluorescence nanoprobe named RhI-DOX@ZIF-90 has been synthesized by wrapping the guest molecule (RhI and DOX) into ZIF-90 framework. The nanoprobe itself is non-fluorescent and the drug (DOX) is inactive. Upon the addition of ATP, the structure of RhI-DOX@ZIF-90 is degraded. The fluorescence of RhI is recovered and DOX is released. The nanoprobe can detect ATP with high sensitivity and selectivity. There is good linear relationship between the nanoprobe and ATP concentration from 0.25 to 10 mM and the detection limit is 0.10 mM. The nanoprobe has the ability to monitor the change of ATP level in living cells and DOX is released inducing apoptosis of cancer cells. RhI-DOX@ZIF-90 is capable of targeting mitochondria, which provides a basis for improving the efficiency of drug delivery by mitochondrial administration. In particular, the nanoprobe is preferentially accumulated in the tumor sites and detect ATP in tumor mice by fluorescence imaging using near-infrared fluorescence. At the same time, DOX can be released accurately in tumor sites and have good anti-tumor efficiency. So, this nanoprobe is a reliable tool to realize early diagnosis of cancer and improve effect of anticancer drug.

Novel Strategy for Validating the Existence and Mechanism of the "Gut-Liver Axis" in Vivo by a Hypoxia-Sensitive NIR Fluorescent Probe.

Liver fibrosis is a major stage in the development of liver disease, and it is important to investigate its pathogenesis for early intervention or even reversal. Recent studies have found that intestinal disease can aggravate liver fibrosis through the role of the "gut-liver axis". Hypoxia is considered to be a typical characteristic of many diseases including ulcerative colitis and liver fibrosis. However, there is no fluorescent probe for hypoxia detection to investigate the "gut-liver axis". Herein we design and synthesize a turn-on fluorescent probe termed Cy-AP, which displays high sensitivity and selectivity to hypoxia given by sodium dithionite (Na2S2O4) in vitro with near-infrared (NIR) emission (725 nm). The possible response mechanism of Cy-AP toward hypoxia is given and proved though HPLC, MS, and theory calculation. Moreover, on the basis of low cell cytotoxicity, the probe is used in visualizing hypoxia in four cell lines (HepG2, HCT116, HeLa, and MCF-7 cells) by fluorescence imaging, flow cytometry, and 3D imaging. Furthermore, due to its NIR emission, Cy-AP can monitor the hypoxia condition in vivo such as in liver fibrosis mice and ulcerative colitis mice models. In particular, the probe can validate the existence and mechanism of the "gut-liver axis" in vivo by monitoring hypoxia. To the best of our knowledge, this is the first work to give a strategy for studying the "gut-liver axis" by a NIR hypoxia-sensitive fluorescent probe, which will provide some powerful support for delaying the progression of liver fibrosis and thus promoting the treatment of liver disease.

Dual pH/ROS-Responsive Nanoplatform with Deep Tumor Penetration and Self-Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy.

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA-NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active-targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self-amplified drug release for effective drug delivery. The RLPA-NPs are constructed by encapsulation of a pH-sensitive polymer octadecylamine-poly(aspartate-1-(3-aminopropyl) imidazole) (OA-P(Asp-API)) and a ROS-generation agent, ß-Lapachone (Lap), in micelles assembled by the tumor-penetration peptide internalizing RGD (iRGD)-modified ROS-responsive paclitaxel (PTX)-prodrug. iRGD could promote RLPA-NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, OA-P(Asp-API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA-NPs escape from the endosome through the "proton sponge effect". At the same time, the RLPA-NPs micelle disassembles, releasing Lap and PTX-prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA-NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA-NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.

Lapatinib in combination with capecitabine versus continued use of trastuzumab in breast cancer patients with trastuzumab-resistance: a retrospective study of a Chinese population.

BACKGROUND: The efficacy and safety of lapatinib plus capecitabine (LC or LX) versus trastuzumab plus chemotherapy in patients with HER-positive metastatic breast cancer who are resistant to trastuzumab is unknown. METHODS: We retrospectively analyzed data from breast cancer patients who began treatment with regimens of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) at eight hospitals between May 2010 and October 2017. RESULTS: Among 554 patients who had developed resistance to trastuzumab, the median PFS (progression free survival) was 6.77 months in the LX group compared with 5.6 months in the TBP group (hazard ratio 0.804; 95% CI, 0.67 to 0.96; P = 0.019). The central nervous system progression rate during treatment was 5.9% in the LX group and 12.5% in the TBP group (P = 0.018). CONCLUSION: The combination of lapatinib and capecitabine showed a prolonged PFS relative to TBP in patients who had progressed on trastuzumab.

EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties.

Trastuzumab is a successful, rationally designed therapy that provides significant clinical benefit for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients. However, about half of individuals with HER2-positive breast cancer do not respond to trastuzumab treatment because of various resistance mechanisms, including but not limited to: 1) shedding of the HER2 extracellular domain, 2) steric hindrance ( e.g., MUC4 and MUC1), 3) parallel pathway activation (this is the general mechanism cited in the quote above), 4) perturbation of downstream signaling events ( e.g., PTEN loss or PIK3CA mutation), and 5) immunologic mechanisms (such as FcR polymorphisms). EPHA5, a receptor tyrosine kinase, has been demonstrated to act as an anticancer agent in several cancer cell types. In this study, deletion of EPHA5 can significantly increase the resistance of HER2-positive breast cancer patients to trastuzumab. To investigate how EPHA5 deficiency induces trastuzumab resistance, clustered regularly interspaced short palindromic repeat technology was used to create EPHA5-deficient variants of breast cancer cells. EPHA5 deficiency effectively increases breast cancer stem cell (BCSC)-like properties, including NANOG, CD133+, E-cadherin expression, and the CD44+/CD24-/low phenotype, concomitantly enhancing mammosphere-forming ability. EPHA5 deficiency also caused significant aggrandized tumor malignancy in trastuzumab-sensitive xenografts, coinciding with the up-regulation of BCSC-related markers and intracellular Notch1 and PTEN/AKT signaling pathway activation. These findings highlight that EPHA5 is a potential prognostic marker for the activity of Notch1 and better sensitivity to trastuzumab in HER2-positive breast cancer. Moreover, patients with HER2-positive breast cancers expressing high Notch1 activation and low EPHA5 expression could be the best candidates for anti-Notch1 therapy.-Li, Y., Chu, J., Feng, W., Yang, M., Zhang, Y., Zhang, Y., Qin, Y., Xu, J., Li, J., Vasilatos, S. N., Fu, Z., Huang, Y., Yin, Y. EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties.