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In cryogenic fracturing, a rock surface exposed to cryogenic fluids undergoes a large thermal gradient, and the resultant local tensile stress overcomes rock strength and initiates fractures. This study investigates the development of cracks generated from the cryogenic treatment of a borehole under no external confining stress on specimens. The experiments were performed on transparent PMMA specimens to observe fracture proliferation around boreholes. Liquid nitrogen was flowed through the boreholes to cool the borehole surface. The results show that initial fracture growth is characterized by abrupt starts and stops, and as the fracture propagates outward, the growth appears more continuous. In an early stage, horizontal/radial fractures and vertical fractures are the defining patterns. Horizontal fractures tend to be separated by a specific exclusion distance (i.e., spacing between cracks). While distinct horizontal/vertical fractures and exclusion distance manifest themselves at an early stage, fractures resulting from fracture interactions and curvatures can develop into complex shapes at later stages. Cryogenic thermal loading induces distinctively curved fractures. The tendency of curvature may prevent greater penetration. An increase in the borehole pressure during liquid nitrogen flow, however, can lessen fracture tortu-osity and facilitate radial propagation. A high flow pressure and rate are also advantageous in that they accelerate cooling and fracture propagation.

The development of advanced dielectric materials with high breakdown strength, high dischargeable energy densities, and great efficiencies is imperative to meet the ever-increasing demand of modern power systems and electronic devices. Herein, we present the layer-by-layer solution prepared bilayer-structured nanocomposite films with much enhanced capacitive performance via resolving the typical paradox between dielectric constant and breakdown strength in dielectric materials. The bilayered nanocomposite films are composed of Al2O3 dispersed in polystyrene as the interfacial barrier layer to inhibit electrical conduction and the polystyrene layer with TiO2 to enhance dielectric constant. The resulting layered film exhibits a discharged energy density of 4.43 J/cm3 along with ultrahigh charge−discharge efficiencies of >90%, which is among the highest energy densities ever achieved in the polystyrene-based dielectric polymer nanocomposites. In addition, the composite films show outstanding cyclic stability under high electric fields, which would enable the long-term efficient operation of film capacitors. This contribution represents an efficient route to high-energy-density dielectric composite materials by using interfacial barrier architectures.

Oriented microstructures are widely found in various biological systems for multiple functions. Such anisotropic structures provide low tortuosity and sufficient surface area, desirable for the design of high-performance energy storage devices. Despite significant efforts to develop supercapacitors with aligned morphology, challenges remain due to the predefined pore sizes, limited mechanical flexibility, and low mass loading. Herein, a wood-inspired flexible all-solid-state hydrogel supercapacitor is demonstrated by morphologically tuning the aligned hydrogel matrix toward high electrode-materials loading and high areal capacitance. The highly aligned matrix exhibits broad morphological tunability (47–12 µm), mechanical flexibility (0°–180° bending), and uniform polypyrrole loading up to 7 mm thick matrix. After being assembled into a solid-state supercapacitor, the areal capacitance reaches 831 mF cm−2 for the 12 µm matrix, which is 259% times of the 47 µm matrix and 403% times of nonaligned matrix. The supercapacitor also exhibits a high energy density of 73.8 µWh cm−2, power density of 4960 µW cm−2, capacitance retention of 86.5% after 1000 cycles, and bending stability of 95% after 5000 cycles. The principle to structurally design the oriented matrices for high electrode material loading opens up the possibility for advanced energy storage applications.

Xiwu Hui,1,* Can Yuan,1,* Weirong Cao,1 Wenli Ge,1 Di Zhang,1 Mo Dan,2 Qian Zhao,2 Boning Liu,1,* Bing Yao1,* 1Institute of Quality Analysis, CSPC Megalith Biopharmaceutical Co., Ltd., Shijiazhuang, Hebei, People’s Republic of China; 2Pharmacology Center, CSPC Pharmaceutical Group Co., Ltd., Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Boning Liu; Bing Yao, Institute of Quality Analysis, CSPC Megalith Biopharmaceutical Co., Ltd., No. 226 Huanghe Street, Shijiazhuang, Hebei, People’s Republic of China, Tel +8613284452520 ; +8613930148328, Fax +86031169085667, Email liuboning@mail.ecspc.com; yaob@mail.ecspc.comPurpose: Antibody-drug conjugates (ADCs) have emerged as a potent cancer therapeutic option in recent years. DP303c is a HER2-targeting ADC with a cleavable linker-MMAE payload. The current study aimed to evaluate the therapeutic potentials of DP303c in vitro as well as in vivo.Materials and Methods: Size exclusion chromatography (SEC), reverse-phase high-performance liquid chromatography (RP-HPLC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to analyze the physicochemical characterization of DP303c. An enzyme-linked immunosorbent assay (ELISA), a cell-based assay, and bio-layer interferometry (BLI) were used to evaluate DP303c’s affinity with HER2 and Fc receptors. A confocal laser scanning microscopy was used to observe the internalization of DP303c. Antibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxicity assays were used to investigate the activity of DP303c in vitro. The antitumor activity of DP303c was assessed in vivo in the HER2-positive cell-derived xenograft model.Results: DP303c was a site-specific anti-HER2 antibody-drug conjugate with a monomethyl auristatin E (MMAE) with an average drug-to-antibody ratio (DAR) of 2.0. DP303c showed a high affinity with HER2 and could be effectively internalized. In vitro and in vivo, DP303c showed stronger antitumor activity as compared to trastuzumab-DM1 (T-DM1) in a series of HER2-positive cancer cells and cell-derived xenograft (CDX) models, especially in the lower HER2-expressing cells. DP303c also exhibited high serum stability and a good PK profile.Conclusion: DP303c was a steady and homogenous DAR 2 ADC that was predicted to deliver MMAE inhibitor to tumor cells. DP303c demonstrated remarkable anticancer efficacy against T-DM1 in xenograft models. DP303c was a strong candidate for the treatment of patients with HER2-positive cancer.Keywords: antibody-drug conjugates, ADCs, site-specific conjugation, engineered microbial transglutaminase, monomethyl auristatin E

A laboratory study of cryogenic fracturing was performed to test its ability to improve oil/gas recovery from low-permeability reservoirs. Our objective is to develop well-stimulation technologies using cryogenic fluids [e.g., liquid nitrogen (LN)] to increase permeability in a large reservoir volume surrounding wells. The new technology has the potential to reduce formation damage caused by current stimulation methods and minimize or eliminate water usage. The concept of cryogenic fracturing is that a sharp thermal gradient (thermal shock) created at the surfaces of formation rocks by applying cryogenic fluid can cause strong local tensile stress and start fractures. We developed a laboratory system for cryogenic fracturing under true-triaxial loading, with LN-delivery/control and -measurement systems. The loading system simulates confining stresses by independently loading each axis up to approximately 5,000 psi on 888-in. cubes. Temperature in boreholes and at block surfaces and fluid pressure in boreholes were continuously monitored. Acoustic and pressure-decay measurements were obtained before and at various stages of stimulations. Cubic blocks (8 88-in.) of Niobrara shale, concrete, and sandstones were tested, and stress levels and anisotropies varied. Three schemes were considered: Gas fracturing without cryo-stimulation, gas fracturing after low-pressure cryogen flow-through, and gas fracturing after high-pressure cryogen flow-through. Results from pressure-decay tests show that LN stimulation clearly increases permeability, and repeated stimulations further increase the permeability. Acoustic velocities and amplitudes decreased significantly after cryo-stimulation, indicating fracture creation. In the gas fracturing without the stimulation, breakdown (complete fracturing) occurs suddenly without any initial leaking, and major fracture planes form along the plane containing principal-stress and intermediate-stress directions, as expected theoretically. However, in the gas fracturing after cryogenic stimulations, breakdown occurred gradually and with massive leaking because of thermal fractures created during stimulation. In addition, the major fracture direction does not necessarily follow the plane containing the principal-stress direction, especially at low confining-stress levels. In tests, we observed that cryogenic stimulation seems to disrupt the internal stress field. The increase in borehole temperature after stimulation affects the permeability of the specimen. When a stimulated specimen is still cold, it maintains high permeability because fractures remain open and local thermal tension is maintained near the borehole. When the rock warms back, fractures close and permeability decreases. In these tests, we have not used proppants. Overall, fractures are clearly generated by low- and high-pressure thermal shocks. The added pressure of the high-pressure thermal shocks helps to further propagate cryogenic fractures generated by thermal shock. Breakdown pressure is significantly lowered by LN stimulation, with observed breakdown-pressure reductions up to approximately 40%.

Niobrara shale cubes of 20 cm from Colorado were employed to investigate gas and supercritical CO2 injection-induced fracturing in naturally fractured caprocks of deep aquifers/depleted reservoirs and fractured shale reservoirs. Under tri-axial stresses, gas or supercritical CO2 was injected into the center of the cubes to induce fracturing. Real-time pressure and temperature, acoustic wave, pressure decay, fracture coloring, and gas fracturing were used to characterize the fracturing process and fracture morphology. Without pore pressure, CO2 injection-induced fracturing occurred and completed instantly, accompanied by an evident temperature drop. Strongly bonded fractures barely affected transverse fracture propagation, whereas weakly bonded or open fractures arrested the injected fluid first and then allowed it to generate new fractures perpendicular to the minimum horizontal stress. Breakdown pressures for cubes with preexisting fractures using gas and supercritical CO2 are much lower than both poroelastic predictions and slick-water fracturing pressure, and some are even lower than the minimum horizontal stress. This is attributed to unconformable preexisting fractures and the low viscosity of CO2. Moreover, decreasing tri-axial stress levels and increasing stress differences tend to lower the breakdown pressure. This study is instructive for understanding and tackling geomechanical issues related to CO2 geological storage and fracturing of shale reservoirs.

Xiling Hu,1,* Yao Zhang,2,* Bin Yao,2 Beisi Lin,2 Dan Yang,3 Cong Ling,4,* Lingling Gao3,* 1Department of Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3School of Nursing, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cong LingDepartment of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong, 510630, People’s Republic of ChinaTel +86-13580465121Email doctor200@126.comLingling GaoSchool of Nursing, Sun Yat-sen University, No. 74, Zhongshan Er Road, Guangzhou, Guangdong, 510085, People’s Republic of ChinaTel +86 13539965693Email gaoll@mail.sysu.edu.cnPurpose: The purpose of this exploratory qualitative study was to identify the needs and barriers to diabetes dietary education issues in a Chinese context among people with type 2 diabetes and also their family members.Patients and Methods: Nineteen patients with type 2 diabetes and 15 family members were randomly selected from a larger study in Guangzhou. Descriptive phenomenological qualitative inquiry guided this study.Results: Both patients and their family members claimed a variety of needs regarding diabetes dietary information and that it should be patient-centered. In addition, both groups identified the effectiveness and helpfulness of diabetes diet-related health education, but family members reported a lack of professional education. Patients reported that the barriers to diabetes diet-related health education were: 1) patients’ different faculties of memory and acceptance, 2) educators’ methods of explaining the information, 3) lack of advertising and intensity of publicity both inside and outside of the hospital. Family members identified that diabetes diet-related health education assisted them with taking care of patients with diabetes and it was also beneficial for themselves to gain more dietary knowledge and develop healthy dietary habits.Conclusion: It is necessary to make some adjustment to traditional diabetes dietary education. It may be a good strategy to investigate the needs and faculties of memory and acceptance of people with diabetes before starting a diabetes education program. Hospitals should intensify their publicity of diabetes education and make it more attractive to patients with diabetes and their family members. Educators should add information specifically for family members while conducting diabetes education. Tertiary hospitals could provide standardized training regarding diabetes-related health education to community family physicians; in this way, diabetes education could gradually be transferred to them and both groups of clinicians could share in the education.Keywords: diabetes, family members, dietary education, needs, barriers, qualitative

Bin Yao,1 Xue Han,2 Linrong Pang,1 Caihong Xu,1 Sisi Liu,2 Xiaochun Cheng,1 Jun Chen1 1Department of Radiotherapy and Chemotherapy, The Affiliated People’s Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Research and Development, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Xiaochun Cheng; Jun ChenDepartment of Radiotherapy and Chemotherapy, The Affiliated People’s Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of ChinaTel +86-13736005125; +86-13777975439Email cxc5125@163.com junchen201211@163.comAbstract: Anaplastic lymphoma kinase (ALK) rearrangement is extremely rare in lung squamous cell carcinoma (LSCC), and it remains controversial as to whether LSCC patients with ALK rearrangement can benefit from ALK tyrosine kinase inhibitors (TKIs). Here, we report an LSCC patient with ALK rearrangement who was treated with sequential ALK TKI therapies and experienced a clinical benefit of 35 months. Although the use of ALK TKIs showed clinical benefits, targeted next-generation sequencing (NGS) for dynamic monitoring of circulating tumor DNA (ctDNA) from patient plasma revealed the accumulation of ALK resistance mutations, which could provide valuable information in designing the treatment strategy. Our study highlights the importance of dynamic monitoring of ctDNA using NGS to discover tumor evolution to guide treatment decision-making and provides meaningful insights into the potential treatment options for ALK-positive LSCC patients.Keywords: ALK rearrangement, dynamic monitoring, resistance mutation, next-generation sequencing

Leakage risk assessment is an inevitable procedure in permanent sequestration and storage of CO2 in deep saline aquifers and depleted oil and gas reservoirs, where the integrity of caprock is most critical. Low porosity and low permeability concrete cubes were employed as caprock analogs to investigate the supercritical CO2 injection-induced fracturing processes under true tri-axial stress conditions. A systematic experimental procedure, consisting of active acoustic emission measurement, pressure decay, injection pressure and temperature monitoring, fracture coloring, and gas fracturing, is formulated to qualitatively and quantitatively characterize the injection-induced fracturing processes and fracture morphology. Occurrence of injection-induced fracturing can be directly identified from peaks of borehole pressure profiles as well as sharp drops on temperature profiles due to CO2 expansion, but generally there was no fracture propagation plateau appearing for the 20 cm rock cubes with zero pore pressure. Acoustic wave signatures, including both waveform change and arrival time delay, can effectively capture the extension of induced fractures inside the opaque rock. Initiation and propagation of supercritical CO2 injection-induced fractures are highly dominated by the tri-axial stresses, following the general trend of continuum mechanics at high stress levels with large stress difference. As the stress difference decreases, induced fractures branch off in relatively arbitrary directions. For these supercritical CO2 injection-induced fracturing experiments, poroelastic mechanics model makes a decent fit with the measured breakdown pressure of the caprock analogs. Findings in this study are valuable for risk analysis and operation optimization of geological CO2 sequestration and storage as well as for CO2 fracturing design and implementation in shale and tight reservoirs.

The concept of cryogenic fracturing is that a sharp thermal gradient developed by applying a cryogenic fluid on a rock surface causes a strong local tensile stress that initiates fractures. Prior field tests suggest that field application with special equipment rated for cryogenic temperatures may deliver potential benefits. The tests did not, however, identify the fracture mechanisms at work in downhole conditions. In this study, we present our laboratory designs and procedures developed for studying cryogenic fracturing mechanisms in a well environment, and examine typical data indicative of the performance of the system. The experimental apparatus and procedures were specifically designed to conduct cryogenic fracturing tests in specimens under confining stress, with integrated cryogen transport, measurements, and fracture characterization. A true-triaxial loading system was built to simulate reservoir stress levels and anisotropic stress application, and was designed to avoid thermal stresses in tests involving cryogen by arranging discrete components in an open chamber. To maximize thermal shock on the wellbore surface, tubing and wellhead are configured so that liquid nitrogen enters the borehole and flow out after contributing to thermal shock. The temperature at boreholes and along flow lines, borehole pressure, and liquid nitrogen consumption are monitored throughout treatments. Acoustic transmission and pressure-decay measurements are used to characterize fractures before and after the experiments. Breakdown tests performed on un-stimulated specimens and stimulated specimens compare breakdown pressures of the two groups and thus evaluate the performance of thermal fracturing. The laboratory design was able to effectively apply cryogenic stimulations to laboratory rock specimens. The characterization methods were able to capture fracture creation and rock property changes due to cryogenic fracturing.

During the past two decades, hydraulic fracturing has significantly improved oil and gas production from shale and tight sandstone reservoirs in the United States and elsewhere. Considering formation damage, water consumption, and environmental impacts associated with water-based fracturing fluids, efforts have been devoted to developing waterless fracturing technologies because of their potential to alleviate these issues. Herein, key theories and features of waterless fracturing technologies, including Oil-based and CO2 energized oil fracturing, explosive and propellant fracturing, gelled LPG and alcohol fracturing, gas fracturing, CO2 fracturing, and cryogenic fracturing, are reviewed. We then experimentally elaborate on the efficacy of liquid nitrogen in enhancing fracture initiation and propagation in concrete samples, and shale and sandstone reservoir rocks. In our laboratory study, cryogenic fractures generated were qualitatively and quantitatively characterized by pressure decay tests, acoustic measurements, gas fracturing, and CT scans. The capacity and applicability of cryogenic fracturing using liquid nitrogen are demonstrated and examined. By properly formulating the technical procedures for field implementation, cryogenic fracturing using liquid nitrogen could be an advantageous option for fracturing unconventional reservoirs.