Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.

Structural Integrity of Anterior Ceramic Resin-Bonded Fixed Partial Denture: A Finite Element Analysis Study.

This study was conducted as a means to evaluate the stress distribution patterns of anterior ceramic resin-bonded fixed partial dentures derived from different materials and numerous connector designs that had various loading conditions imposed onto them through the utilization of the finite element method. A finite element model was established on the basis of the cone beam computed tomography image of a cantilevered resin-bonded fixed partial denture with a central incisor as an abutment and a lateral incisor as a pontic. Sixteen finite element models representing different conditions were simulated with lithium disilicate and zirconia. Connector height, width, and shape were set as the geometric parameters. Static loads of 100 N, 150 N, and 200 N were applied at 45 degrees to the pontic. The maximum equivalent stress values obtained for all finite element models were compared with the ultimate strengths of their materials. Higher load exhibited greater maximum equivalent stress in both materials, regardless of the connector width and shape. Loadings of 200 N and 150 N that were correspondingly simulated on lithium disilicate prostheses of all shapes and dimensions resulted in connector fractures. On the contrary, loadings of 200 N, 150 N, and 100 N with rectangular-shaped connectors correspondingly simulated on zirconia were able to withstand the loads. However, two of the trapezoidal-shaped zirconia connectors were unable to withstand the loads and resulted in fractures. It can be deduced that material type, shape, and connector dimensions concurrently influenced the integrity of the bridge.

Biomechanical comparison of different screw-included angles in crossing screw fixation for transverse patellar fracture in level walking: a quasi-dynamic finite element study.

BACKGROUND: A minimally invasive technique with various screw configurations without open surgery is currently used for the fixation of transverse patellar fractures. Percutaneous crossing screw configuration has been reported to have a good bone union rate in patellar fractures. However, the difference in mechanical stability of the fractured patella between different screw-included angles has not been fully investigated. Hence, this study aims to compare the mechanical stability of parallel and crossing screw fixations with different screw-included angles for the fixation of transverse patellar fractures during level walking. METHODS: A finite element knee model containing a patella with a transverse fracture is created. Two headless compression screws with different angles (0°, 30°, 60°, and 90°) are used to fix the fracture. The loading conditions of the knee joint during level walking are used to compare the stability of the fractured patella with different fixation screw configurations. RESULTS: The results indicate that the maximum fracture gap opening distance increased with an increase in the included angle. Two parallel screws yield the smallest gap distance among all screw configurations. The maximum gap opening distances at the anterior leading edge of the fractured patella with two parallel screws and two screws having an included angle of 90° are 0.73 mm and 1.31 mm, respectively, at 15% walking cycle. CONCLUSIONS: Based on these results, the superior performance of two parallel screws over crossing screw fixations in the fixation of transverse patellar fractures is established. Furthermore, the smaller the angle between the crossing screws, the better is the stability of the fractured patella.

The Use of Customized Three-Dimensionally Printed Mandible Prostheses with a Pressure-Reducing Device: A Finite Element Analysis in Different Chewing Positions, Biomechanical Testing, and In Vivo Animal Study Using Lanyu Pigs.

Segmental bony defects of the mandible constitute a complete loss of the regional part of the mandible. Although several types of customized three-dimension-printed mandible prostheses (CMPs) have been developed, this technique has yet to be widely used. We used CMP with a pressure-reducing device (PRD) to investigate its clinical applicability. First, we used the finite element analysis (FEA). We designed four models of CMP (P1 to P4), and the result showed that CMP with posterior PRD deployment (P4 group) had the maximum total deformation in the protrusion and right excursion positions, and in clenching and left excursion positions, posterior screws had the minimum von Mises stress. Second, the P4 CMP-PRD was produced using LaserCUSING from titanium alloy (Ti-6Al-4V). The fracture test result revealed that the maximum static pressure that could be withstood was 189 N, and a fatigue test was conducted for 5,000,000 cycles. Third, animal study was conducted on five male 4-month-old Lanyu pigs. Four animals completed the experiment. Two animals had CMP exposure in the oral cavity, but there was no significant inflammation, and one animal had a rear wing fracture. According to a CT scan, the lingual cortex of the mandible crawled along the CMP surface, and a bony front-to-back connection was noted in one animal. A histological examination indicated that CMP was significantly less reactive than control materials (p = 0.0170). Adequate PRD deployment in CMP may solve a challenge associated with CMP, thus promoting its use in clinical practice.

Investigating the Effects of Different Sizes of Silicone Rubber Vacuum Extractors during the Course of Delivery on the Fetal Head: A Finite Element Analysis Study.

During certain clinical situations, some parturients require instruments for operative vaginal delivery, and various designs of vacuum extractors may affect the fetal head. To investigate the biomechanical effects of divergent sizes of silicone rubber vacuum extractors, we employed finite element analysis in this study. First, we constructed computer models for different vacuum extractor sizes (diameters: 40 mm, 50 mm, 60 mm, and 70 mm), flat surface, hemispherical ball, and fetal head shape. A hemispherical ball was the main design for the vacuum extractor model, and the material used for the vacuum extractor was silicone rubber. Next, the settings of 1 mm vacuum extractor displacement and vacuum cap pressure of 60 cmHg were applied. The main observation markers of this study were the respective von Mises stresses on the vacuum extractor and skull by the reaction force on the fixed end. The concluded results revealed that vacuum extractors with larger diameters lead to greater reaction force, stress, and strain on fetal heads. Therefore, this study's biomechanical analytic consequences suggest that clinicians avoid selecting larger vacuum extractors during operative instrumental delivery so that fetal heads will experience less external force, deformation, and resultant complications. It could also provide a practical reference for obstetricians for instrumental vaginal delivery with the vacuum extractor made of silicone rubber.

TRIM37 Promotes Pancreatic Cancer Progression through Modulation of Cell Growth, Migration, Invasion, and Tumor Immune Microenvironment.

TRIM37 dysregulation has been observed in several cancer types, implicating its possible role in tumorigenesis. However, the role of TRIM37 in pancreatic cancer progression remains unclear. In the present study, we observed that TRIM37 knockdown resulted in reduced proliferation, clonogenicity, migration, and invasion ability of pancreatic cancer cells. Furthermore, an in vivo study using an orthotopic syngeneic animal model further confirmed that reduced expression of TRIM37 in cancer cells suppressed tumor growth in vivo. Moreover, in mice bearing TRIM37 knockdown pancreatic cancer cells, the proportion of CD11b+F4/80+MHCIIlow immunosuppressive macrophages was significantly reduced in tumor milieu, which might be due to the regulatory role of TRIM37 in cytokine production by pancreatic cancer cells. Collectively, these findings suggest a key role of TRIM37 in promoting pancreatic cancer progression.

Triangular configuration with headless compression screws in the fixation of transverse patellar fracture.

A triangular configuration with three parallel cannulated screws is an established treatment for fixing transverse patellar fractures; however, the stability achieved with this approach is slightly lower than that attained with cannulated screws combined with anterior wiring. In the present study, triangular configurations were modified by partially or totally replacing the cannulated screws with headless compression screws (HCSs). Through finite element simulation involving a model of distal femoral, patellar, and proximal tibial fractures, the mechanical stability levels of the modified triangular configurations were compared with that of two cannulated screws combined with anterior wiring. Four triangular screw configurations were developed: three HCSs in a forward and backward triangular configuration, two deep cannulated screws along with one superficial HCS, and two superficial cannulated screws with one deep HCS. Also considered were two parallel cannulated screws (inserted superficially or deeply) combined with anterior wiring. The six approaches were all examined in full knee extension and 45° flexion under physiological loading. The highest stability was obtained with the three HCSs in a backward triangular configuration, as indicated by the least fragment displacement and the smallest fracture gap size. In extension and flexion, this size was smaller than that observed under the use of two deeply placed parallel cannulated screws with anterior wiring by 50.3% (1.53 vs. 0.76 mm) and 43.2% (1.48 vs. 0.84 mm), respectively. Thus, the use of three HCSs in a backward triangular configuration is recommended for the fixation of transverse patellar fractures, especially without the use of anterior wiring.

Biomechanical analysis of the press-fit effect in a conical Morse taper implant system by using an in vitro experimental test and finite element analysis.

STATEMENT OF PROBLEM: The press-fit (Morse taper) implant system is commonly used to restore edentulous areas. However, abutment screws in this system may be damaged because of the 2- or 3-piece design, consequently causing complications. How these damaging situations occur is unclear. PURPOSE: The purpose of this in vitro and finite element analysis (FEA) study was to elucidate the mechanisms of the press-fit implant system underlying abutment screw damage. MATERIAL AND METHODS: The ANKYLOS implant system was used as a simulation model and for experimental test specimens. The experimental test was performed by using a material test system, and the obtained data were used to validate the FEA outcome. In the FEA simulation, the bilinear material property and nonlinear contact conditions were applied to simulate the process of tightening the abutment screw between the abutment and implant. A force of 300 N was then applied to the abutment to investigate the stress distribution and deformation of the implant system. RESULTS: In the experimental test, the fracture site of all specimens was observed at the abutment-screw thread. All implants and abutments exhibited permanent bending deformation. The results of the FEA simulation generally concurred with the experimental outcomes. CONCLUSIONS: The abutment torque used to generate the press-fit contact interface between the abutment and implant induced stresses within the implant components, substantially increasing the failure probability of the conical implant system during function.

Evaluation of total bone and cortical bone thickness of the palate for temporary anchorage device insertion.

BACKGROUND/PURPOSE: The palate has become a popular site for the placement of temporary anchorage devices (TADs) owing to its bone quantity and quality. This study aimed to investigate total and cortical bone thicknesses in the whole palate as well as palatal width using a standard grid system and cone-bean computed tomography (CBCT) images. MATERIALS AND METHODS: The CBCT images of 43 samples were selected. The total bone and cortical bone thicknesses of the palate were surveyed on 64 points per patient. The palatal width was measured. The difference between the age and sex groups was analyzed. RESULTS: The total palatal bone thickness in the adult group ranged from 9.85 ±â€¯2.04 to 1.87 ±â€¯0.79 mm. In the adolescent group, we found one-third of the incisor roots in the area 3 mm distal to the incisive foramen and 8 mm lateral to the mid-palatal suture. The cortical bone thickness in adults was significantly thicker in the posterior paramedian area than that in adolescents. CONCLUSION: The thickest vertical bone is located in the zone 3 mm distal to the incisive foramen and 4-8 mm lateral to the midpalate. The zone 6 mm posterior to the incisive foramen and 2-8 mm lateral to the midpalate exhibited optimal thickness and was away from the incisor roots. This region could be a safe zone for adolescent patients to place TADs. When TADs are to be inserted at the posterior palate, the 2-mm paramedian area should be the first region of choice.

Automotive 3.0 µm Pixel High Dynamic Range Sensor with LED Flicker Mitigation.

We present and discuss parameters of a high dynamic range (HDR) image sensor with LED flicker mitigation (LFM) operating in automotive temperature range. The total SNR (SNR including dark fixed pattern noise), of the sensor is degraded by floating diffusion (FD) dark current (DC) and dark signal non-uniformity (DSNU). We present results of FD DC and DSNU reduction, to provide required SNR versus signal level at temperatures up to 120 °C. Additionally we discuss temperature dependencies of quantum efficiency (QE), sensitivity, color effects, and other pixel parameters for backside illuminated image sensors. Comparing +120 °C junction vs. room temperature, in visual range we measured a few relative percent increase, while in 940 nm band range we measured 1.46x increase in sensitivity. Measured change of sensitivity for visual bands-such as blue, green, and red colors-reflected some impact to captured image color accuracy that created slight image color tint at high temperature. The tint is, however, hard to detect visually and may be removed by auto white balancing and temperature adjusted color correction matrixes.

Mechanical analysis of a dental implant system under 3 contact conditions and with 2 mechanical factors.

STATEMENT OF PROBLEM: A unidiameter abutment attached to a large-diameter implant has been reported to result in an unexpectedly high failure rate, inconsistent with the general understanding of dental implant mechanics. PURPOSE: The purpose of this finite element analysis study was to investigate the mechanical mechanism underlying these unexpected failures with the hypothesis that the cold welding or interference fit interface between abutment and implant increases the failure probability of a large-diameter implant system with a unidiameter abutment. MATERIAL AND METHODS: A conical implant system with different abutment gingival heights and implant diameters was analyzed for 3 contact conditions of the abutment-implant interface (bond and frictional coefficients of 0.3 and 0.7). A computer model was created using computed tomography images, and an oblique load of 100 N was applied to the abutment to determine the mechanical effect of the implant diameter and gingival height under the 3 contact conditions. RESULTS: When the abutment-implant interface was bonded, the peak stress of the abutment increased and that of the bone decreased with increasing implant diameter. When friction was applied to the abutment-implant interface, the peak stress of the implant, screw, and bone decreased with increasing implant diameter. Furthermore, the peak stress of the implant system and bone increased when the abutment gingival height increased under all contact conditions. CONCLUSIONS: Cold wielding or interference fit at the abutment-implant interface can prevent a screw fracture; however, it puts high stress on the unidiameter abutment neck when the implant diameter is increased. Screw loosening may lead to a slide between the abutment and implant, considerably increasing the stress of the screw. A system with a narrow diameter implant may cause an implant fracture rather than an abutment fracture when friction is applied to the abutment-implant interface.

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation.

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4-mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen-activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE-12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE-12 did not affect CXCL12-mediated calcium influx, indicating that CXCR7 does not modulate CXCR4-mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signalling through ß-arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.

Si Hybrid Solar Cells with 13% Efficiency via Concurrent Improvement in Optical and Electrical Properties by Employing Graphene Quantum Dots.

By employing graphene quantum dots (GQDs) in PEDOT: PSS, we have achieved an efficiency of 13.22% in Si/ PEDOT: PSS hybrid solar cells. The efficiency enhancement is based on concurrent improvement in optical and electrical properties by the photon downconversion process and the improved conductivity of PEDOT: PSS via appropriate incorporation of GQDs. After introducing GQDs into PEDOT: PSS, the short circuit current and the fill factor of rear-contact optimized hybrid cells are increased from 32.11 to 36.26 mA/cm(2) and 62.85% to 63.87%, respectively. The organic-inorganic hybrid solar cell obtained herein holds the promise for developing photon-managing, low-cost, and highly efficient photovoltaic devices.

Efficient hydrogen evolution catalysis using ternary pyrite-type cobalt phosphosulphide.

The scalable and sustainable production of hydrogen fuel through water splitting demands efficient and robust Earth-abundant catalysts for the hydrogen evolution reaction (HER). Building on promising metal compounds with high HER catalytic activity, such as pyrite structure cobalt disulphide (CoS2), and substituting non-metal elements to tune the hydrogen adsorption free energy could lead to further improvements in catalytic activity. Here we present a combined theoretical and experimental study to establish ternary pyrite-type cobalt phosphosulphide (CoPS) as a high-performance Earth-abundant catalyst for electrochemical and photoelectrochemical hydrogen production. Nanostructured CoPS electrodes achieved a geometrical catalytic current density of 10 mA cm(-2) at overpotentials as low as 48 mV, with outstanding long-term operational stability. Integrated photocathodes of CoPS on n(+)-p-p(+) silicon micropyramids achieved photocurrents up to 35 mA cm(-2) at 0 V versus the reversible hydrogen electrode (RHE), onset photovoltages as high as 450 mV versus RHE, and the most efficient solar-driven hydrogen generation from Earth-abundant systems.

Designing Efficient Solar-Driven Hydrogen Evolution Photocathodes Using Semitransparent MoQxCly (Q = S, Se) Catalysts on Si Micropyramids.

Silicon micropyramids with n(+) pp(+) junctions are demonstrated to be efficient absorbers for integrated solar-driven hydrogen production systems enabling significant improvements in both photocurrent and onset potential. When conformally coated with MoSx Cly , a catalyst that has excellent catalytic activity and high optical transparency, the highest photocurrent density for Si-based photocathodes with earth-abundant catalysts is achieved.

Hierarchical structures consisting of SiO2 nanorods and p-GaN microdomes for efficiently harvesting solar energy for InGaN quantum well photovoltaic cells.

We experimentally and theoretically demonstrated the hierarchical structure of SiO(2) nanorod arrays/p-GaN microdomes as a light harvesting scheme for InGaN-based multiple quantum well solar cells. The combination of nano- and micro-structures leads to increased internal multiple reflection and provides an intermediate refractive index between air and GaN. Cells with the hierarchical structure exhibit improved short-circuit current densities and fill factors, rendering a 1.47 fold efficiency enhancement as compared to planar cells.

Photon management with core-shell nanowire structures.

Antireflective Si/oxide core-shell nanowire arrays (NWAs) were fabricated by galvanic etching and subsequent annealing process. The excellent light-harvesting characteristics of the core-shell NWAs, such as broadband working ranges, omnidirectionality, and polarization-insensitivity, ascribed to the smooth index transition from air to the substrates, have been demonstrated. By tuning core-shell volume ratios, we obtained enhanced light trapping regions implemented in either the planar Si underneath NWAs or the core regions of NWAs, greatly benefiting the geometry design of planar and radial p-n junction cell structures, respectively. This photon management scheme indicates the potential use in nanostructured photovoltaic applications.

Significant efficiency enhancement of hybrid solar cells using core-shell nanowire geometry for energy harvesting.

A novel strategy employing core-shell nanowire arrays (NWAs) consisting of Si/regioregular poly(3-hexylthiophene) (P3HT) was demonstrated to facilitate efficient light harvesting and exciton dissociation/charge collection for hybrid solar cells (HSCs). We experimentally demonstrate broadband and omnidirectional light-harvesting characteristics of core-shell NWA HSCs due to their subwavelength features, further supported by the simulation based on finite-difference time domain analysis. Meanwhile, core-shell geometry of NWA HSCs guarantees efficient charge separation since the thickness of the P3HT shells is comparable to the exciton diffusion length. Consequently, core-shell HSCs exhibit a 61% improvement of short-circuit current for a conversion efficiency (η) enhancement of 31.1% as compared to the P3HT-infiltrated Si NWA HSCs with layers forming a flat air/polymer cell interface. The improvement of crystal quality of P3HT shells due to the formation of ordering structure at Si interfaces after air mass 1.5 global (AM 1.5G) illumination was confirmed by transmission electron microscopy and Raman spectroscopy. The core-shell geometry with the interfacial improvement by AM 1.5G illumination promotes more efficient exciton dissociation and charge separation, leading to η improvement (∼140.6%) due to the considerable increase in V(oc) from 257 to 346 mV, J(sc) from 11.7 to 18.9 mA/cm(2), and FF from 32.2 to 35.2%, which is not observed in conventional P3HT-infiltrated Si NWA HSCs. The stability of the Si/P3HT core-shell NWA HSCs in air ambient was carefully examined. The core-shell geometry should be applicable to many other material systems of solar cells and thus holds high potential in third-generation solar cells.

Ultra-high-responsivity broadband detection of Si metal-semiconductor-metal Schottky photodetectors improved by ZnO nanorod arrays.

This study describes a strategy for developing ultra-high-responsivity broadband Si-based photodetectors (PDs) using ZnO nanorod arrays (NRAs). The ZnO NRAs grown by a low-temperature hydrothermal method with large growth area and high growth rate absorb the photons effectively in the UV region and provide refractive index matching between Si and air for the long-wavelength region, leading to 3 and 2 orders of magnitude increase in the responsivity of Si metal-semiconductor-metal PDs in the UV and visible/NIR regions, respectively. Significantly enhanced performances agree with the theoretical analysis based on the finite-difference time-domain method. These results clearly demonstrate that Si PDs combined with ZnO NRAs hold high potential in next-generation broadband PDs.

Binary fingerprints at fluctuation-enhanced sensing.

We have developed a simple way to generate binary patterns based on spectral slopes in different frequency ranges at fluctuation-enhanced sensing. Such patterns can be considered as binary "fingerprints" of odors. The method has experimentally been demonstrated with a commercial semiconducting metal oxide (Taguchi) sensor exposed to bacterial odors (Escherichia coli and Anthrax-surrogate Bacillus subtilis) and processing their stochastic signals. With a single Taguchi sensor, the situations of empty chamber, tryptic soy agar (TSA) medium, or TSA with bacteria could be distinguished with 100% reproducibility. The bacterium numbers were in the range of 2.5 × 10(4)-10(6). To illustrate the relevance for ultra-low power consumption, we show that this new type of signal processing and pattern recognition task can be implemented by a simple analog circuitry and a few logic gates with total power consumption in the microWatts range.