Data-Driven Based Characterization of Anisotropic Mechanical Properties for Cancellous Bone From Low-Resolution CT Images.

OBJECTIVES: Exploring the anisotropic mechanical behavior of cancellous bone is crucial for in-vivo bone biomechanical analysis. However, it is challenging to characterize anisotropic mechanical behaviors under low-resolution (LR) clinical CT images due to a lack of microstructural information. The data-driven method proposed in this article accurately characterizes the anisotropic mechanical properties of cancellous bone from LR clinical CT images. METHODS: The trabecular bone cubes of sheep are used to obtain a high-resolution (HR) micro-CT and an LR clinical CT image dataset. First, an auto-encoder model is trained using HR image data. Microstructural features are extracted by the encoder. A fast super-resolution (FSR) model is trained to map LR bone cubes to the features extracted from corresponding HR samples. The pretrained FSR model is used to convert LR clinical CT images to encoded microstructural features. The features are later used to predict target histomorphological parameters, anisotropic elastic tensors, and fabric tensors based on a fully connected neural network. RESULTS: The data-driven model accurately predicts the elastic tensor and fabric tensor of trabecular bones with LR CT images with 0.6 mm/pixel spatial resolution. It was verified that LR clinical CT images could generate microstructural information using a generative deep-learning model and an up-sampling operation. SIGNIFICANCE: This study proves that clinical medical images of cancellous bone can be used for analysis of complex mechanical properties using a data-driven method, which is useful for real-time bone defect diagnosis and personalized bone prosthesis design in clinical application.

A Bayesian method with nonlinear noise model to calibrate constitutive parameters of soft tissue.

The measured mechanical responses of soft tissue exhibit large variability and errors, especially for the softest brain tissue, while calibrating its constitutive parameters in a deterministic way remains a common practice. Here we implement a Bayesian method considering the nonlinear noise model to calibrate constitutive parameters of brain tissue. A probability model is first developed based on the measured experimental data, likelihood function, and prior function, from which the posterior distributions of model parameters are formulated. The likelihood function considers the nonlinear behaviors of the constitutive response and noise distribution of the experimentally measured data. Meanwhile, the prior predictive distribution is computed to check the probability model preliminarily. Secondly, the Markov Chain Monte Carlo (MCMC) method is used to compute the posterior distributions of model parameters, enabling assessment of parameter uncertainty, correlation, and model calibration error. Finally, the posterior predictive distributions of the overall response, constitutive response, and noise response are computed to validate the probabilistic model, all of which are consistent with the corresponding data. Furthermore, the effect of the prior distribution, experimental data, and noise model on posterior distribution is studied. Our study provides a general approach to calibrating constitutive parameters of soft tissue despite errors and large variability in experimental data.

Mechanical mechanism and indicator of diffuse axonal injury under blast-type acceleration.

Diffuse axonal injury (DAI) caused by acceleration is one of the most prominent forms of blast-induced Traumatic Brain Injury. However, the mechanical mechanism and indicator of axonal deformation-induced injury under blast-type acceleration with high peak and short duration are unclear. This study constructed a multilayer head model that can reflect the response characteristics of translational and rotational acceleration (the peak time of which is within 0.5 ms). Based on von Mises stress, axonal strain and axonal strain rate indicators, the physical process of axonal injury is studied, and the vulnerable area under blast-type acceleration load is given. In the short term (within 1.75 ms), dominated by sagittal rotational acceleration peaks, the constraint of falx and tentorium rapidly imposes the inertial load on the brain tissue, resulting in a high-rate deformation of axons (axonal strain rate of which exceed 100 s-1). For a long term (after 1.75 ms), fixed-point rotation of the brain following the head causes excessive distortion of brain tissue (von Mises stress of which exceeds 15 kPa), resulting in a large axonal stretch strain where the main axonal orientation coincides with the principal strain direction. It is found that the axonal strain rate can better indicate the pathological axonal injury area and coincides with external inertial loading in the risk areas, which suggests that DAI under blast-type acceleration overload is mainly caused by the rapid axonal deformation instead of by the excessive axonal strain. The research in this paper helps understand and diagnose blast-induced DAI.

Origins of brain tissue elasticity under multiple loading modes by analyzing the microstructure-based models.

Constitutive behaviors and material properties of brain tissue play an essential role in accurately modeling its mechanical responses. However, the measured mechanical behaviors of brain tissue exhibit a large variability, and the reported elastic modulus can differ by orders of magnitude. Here we develop the micromechanical models based on the actual microstructure of the longitudinally anisotropic plane of brain tissue to investigate the microstructural origins of the large variability. Specifically, axonal fiber bundles with the specified configurations are distributed in an equivalent matrix. All micromechanical models are subjected to multiple loading modes, such as tensile, compressive, and shear loading, under periodic boundary conditions. The predicted results agree well with the experimental results. Furthermore, we investigate how brain tissue elasticity varies with its microstructural features. It is revealed that the large variability in brain tissue elasticity stems from the volume fraction of axonal fiber, the aspect ratio of axonal fiber, and the distribution of axonal fiber orientation. The volume fraction has the greatest impact on the mechanical behaviors of brain tissue, followed by the distribution of axonal fiber orientation, then the aspect ratio. This study provides critical insights for understanding the microstructural origins of the large variability in brain tissue elasticity.

Experimentally characterizing the spatially varying anisotropic mechanical property of cancellous bone via a Bayesian calibration method.

Traditional experimental tests for characterizing bone's mechanical properties usually hypothesize a uniaxial stress condition without quantitatively evaluating the influence of spatially varying principal material orientations, which cannot accurately predict the mechanical properties distribution of bones in vivo environment. In this study, a Bayesian calibrating procedure was developed using quantified multiaxial stress to investigate cancellous bone's local anisotropic elastic performance around joints as the spatial variation of main bearing orientations. First, the bone cube specimens from the distal femur of sheep are prepared using traditional anatomical axes. The multiaxial stress state of each bone specimen is calibrated using the actual principal material orientations derived from fabric tensor at different anatomical locations. Based on the calibrated multiaxial stress state, the process of identifying mechanical properties is described as an inverse problem. Then, a Bayesian calibration procedure based on a surrogate constitutive model was developed via multiaxial stress correction to identify the anisotropic material parameters. Finally, a comparison between the experiment and simulation results is discussed by applying the optimal model parameters obtained from the Bayesian probability distribution. Compared to traditional uniaxial methods, our results prove that the calibration based on the spatial variation of the main bearing orientations can significantly improve the accuracy of characterizing regional anisotropic mechanical responses. Moreover, we determine that the actual mechanical property distribution is influenced by complicated mechanical stimulation. This study provides a novel method to evaluate the spatially varying mechanical properties of bone tissues enduring complex mechanical loading accurately and effectively. It is expected to provide more realistic mechanical design targets in vivo for a personalized artificial bone prosthesis in clinical treatment.

Revealing the Effect of Skull Deformation on Intracranial Pressure Variation During the Direct Interaction Between Blast Wave and Surrogate Head.

Intracranial pressure (ICP) during the interaction between blast wave and the head is a crucial evaluation criterion for blast-induced traumatic brain injury (bTBI). ICP variation is mainly induced by the blast wave transmission and skull deformation. However, how the skull deformation influences the ICP remains unclear, which is meaningful for mitigating bTBI. In this study, both experimental and numerical models are developed to elucidate the effect of skull deformation on ICP variation. Firstly, we performed the shock tube experiment of the high-fidelity surrogate head to measure the ICP, the blast overpressure, and the skull surface strain of specific positions. The results show that the ICP profiles of all measured points show oscillations with positive and negative change, and the variation is consistent with the skull surface strain. Further numerical analysis reveals that when the blast wave reaches the measured point, the peak overpressure transmits directly through the skull to the brain, forming the local positive ICP peak, and the impulse induces the local inward deformation of the skull. As the peak overpressure passes through, the blast impulse impacts the nearby skull supported by the soft and incompressible brain tissue and extrudes the skull outward in the initial position. The inward and outward skull deformation leads to the oscillation of ICP. These numerical analyses agree with experimental results, which explain the appearance of negative and positive ICP peaks and the synchronization of negative ICP with surface strain. The study has implications for medical injury diagnosis and protective equipment design.

Screening the hub genes and analyzing the mechanisms in discharged COVID-19 patients retesting positive through bioinformatics analysis.

BACKGROUND: After encountering COVID-19 patients who test positive again after discharge, our study analyzed the pathogenesis to further assess the risk and possibility of virus reactivation. METHODS: A separate microarray was acquired from the Gene Expression Omnibus (GEO), and its samples were divided into two groups: a "convalescent-RTP" group consisting of convalescent and "retesting positive" (RTP) patients (group CR) and a "healthy-RTP" group consisting of healthy control and RTP patients (group HR). The enrichment analysis was performed with R software, obtaining the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, the protein-protein interaction (PPI) networks of each group were established, and the hub genes were discovered using the cytoHubba plugin. RESULTS: In this study, 6622 differentially expressed genes were identified in the group CR, among which RAB11B-AS1, DISP1, MICAL3, PSMG1, and DOCK4 were up-regulated genes, and ANAPC1, IGLV1-40, SORT1, PLPPR2, and ATP1A1-AS1 were down-regulated. 7335 genes were screened in the group HR, including the top 5 up-regulated genes ALKBH6, AMBRA1, MIR1249, TRAV18, and LRRC69, and the top 5 down-regulated genes FAM241B, AC018529.3, AL031963.3, AC006946.1, and FAM149B1. The GO and KEGG analysis of the two groups revealed a significant enrichment in immune response and apoptosis. In the PPI network constructed, group CR and group HR identified 10 genes, respectively, and TP53BP1, SNRPD1, and SNRPD2 were selected as hub genes. CONCLUSIONS: Using the messenger ribonucleic acid (mRNA) expression data from GSE166253, we found TP53BP1, SNRPD1, and SNRPD2 as hub genes in RTP patients, which is vital to the management and prognostic prediction of RTP patients.

Clinical significance of SQSTM1/P62 and nuclear factor-κB expression in pancreatic carcinoma.

BACKGROUND: Overexpression of SQSTM1 (sequestosome 1, P62) and nuclear factor-κB (NF-κB) plays an important role in the invasion and metastasis of a variety of malignant tumors. AIM: To explore the expression of P62 and NF-κB in pancreatic cancer and their relationship with clinicopathological features. METHODS: The expression levels of P62 and NF-κB were analyzed by immunohistochemistry with a tissue chip containing 40 cases of human pancreatic carcinoma. Then we analyzed the correlation among P62 expression, phospho-P65 expression, and clinicopathological features of pancreatic carcinoma samples. RESULTS: P62 expression was mainly observed in the cytoplasm of pancreatic carcinoma cells. Phosphorylated P65 (phospho-P65) was mainly expressed in the nucleus and cytoplasm of pancreatic carcinoma cells. There was a significant difference in P62 expression among T stages. And a significant difference in phosphor-P65 expression among pathology types was noted. In the cases with strongly positive P62 expression, significant differences were found in age. And there were significant differences in T stage and tumor-node-metastasis stage in the cases with strongly positive phosphor-P65 expression. CONCLUSION: In pancreatic carcinoma, P62 expression is significantly correlated with T stage. It may be a valuable malignant indicator for human pancreatic carcinoma.

Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer.

BACKGROUND: Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway. AIM: To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells. METHODS: Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth. RESULTS: IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1ß and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line. CONCLUSION: Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

Incidence, casualties and risk characteristics of civilian explosion blast injury in China: 2000-2017 data from the state Administration of Work Safety.

BACKGROUND: Civilian explosion blast injury is more frequent in developing countries, including China. However, the incidence, casualties, and characteristics of such incidents in China are unknown. METHODS: This is a retrospective analysis of the State Administration of Work Safety database. Incidents during a period from January 1, 2000 to April 30, 2017 were included in the analysis. The explosions were classified based on the number of deaths into extraordinarily major, major, serious and ordinary type. Descriptive statistics was used to analyze the incidence and characteristics of the explosions. Correlation analysis was performed to examine the potential correlations among various variables. RESULTS: Data base search identified a total of 2098 explosions from 2000 to 2017, with 29,579 casualties: 15,788 deaths (53.4%), 12,637 injured (42.7%) and 1154 missing (3.9%). Majority of the explosions were serious type (65.4%). The number of deaths (39.5%) was also highest with the serious type (P = 0.006). The highest incidence was observed in the fourth quarter of the year (October to December), and at 9:00-11:00 am and 4:00-6:00 pm of the day. The explosions were most frequent in coal-producing provinces (Guizhou and Shanxi Province). Coal mine gas explosions resulted majority of the deaths (9620, 60.9%). The number of explosion accidents closely correlated with economic output (regional economy and national GDP growth rate) (r = - 0.372, P = 0.040; r = 0.629, P = 0.028). CONCLUSIONS: The incidence and civilian casualties due to explosions remain unacceptabe in developing China. Measures that mitigate the risk factors are of urgently required.

Effects of Diisocyanate Structure and Disulfide Chain Extender on Hard Segmental Packing and Self-Healing Property of Polyurea Elastomers.

Four linear polyurea elastomers synthesized from two different diisocyanates, two different chain extenders and a common aliphatic amine-terminated polyether were used as models to investigate the effects of both diisocyanate structure and aromatic disulfide chain extender on hard segmental packing and self-healing ability. Both direct investigation on hard segments and indirect investigation on chain mobility and soft segmental dynamics were carried out to compare the levels of hard segmental packing, leading to agreed conclusions that correlated well with the self-healing abilities of the polyureas. Both diisocyanate structure and disulfide bonds had significant effects on hard segmental packing and self-healing property. Diisocyanate structure had more pronounced effect than disulfide bonds. Bulky alicyclic isophorone diisocyanate (IPDI) resulted in looser hard segmental packing than linear aliphatic hexamethylene diisocyanate (HDI), whereas a disulfide chain extender also promoted self-healing ability through loosening of hard segmental packing compared to its C-C counterpart. The polyurea synthesized from IPDI and the disulfide chain extender exhibited the best self-healing ability among the four polyureas because it had the highest chain mobility ascribed to the loosest hard segmental packing. Therefore, a combination of bulky alicyclic diisocyanate and disulfide chain extender is recommended for the design of self-healing polyurea elastomers.

Predicting the flow stress and dominant yielding mechanisms: analytical models based on discrete dislocation plasticity.

Dislocations are the carriers of plasticity in crystalline materials. Their collective interaction behavior is dependent on the strain rate and sample size. In small specimens, details of the nucleation process are of particular importance. In the present work, discrete dislocation dynamics (DDD) simulations are performed to investigate the dominant yielding mechanisms in single crystalline copper pillars with diameters ranging from 100 to 800 nm. Based on our simulations with different strain rates and sample size, we observe a transition of the relevant nucleation mechanism from "dislocation multiplication" to "surface nucleation". Two physics-based analytical models are established to quantitatively predict this transition, showing a good agreement for different strain rates with our DDD simulation data and with available experimental data. Therefore, the proposed analytical models help to understand the interplay between different physical parameters and nucleation mechanisms and are well suitable to estimate the material strength for different material properties and under given loading conditions.

Hypoxia preconditioning protects Ca2+-ATPase activation of intestinal mucosal cells against R/I injury in a rat liver transplantation model.

AIM: To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1α to protect rat intestinal tissue against I/R injury. METHODS: Rats received non-lethal hypoxic preconditioning therapy to induce HIF-1α expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively. RESULTS: HIF-1α expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-α was significantly lower in the HP group than in the AT group. CONCLUSION: Hypoxia-induced HIF-1α could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure.

Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment.

Integrin αvß6 and matrix metalloproteinase 9 correlate with survival in gastric cancer.

AIM: To investigate the expression of integrin αvß6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients. METHODS: Immunohistochemistry was used to determine the expressions of integrin αvß6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ(2) test and Fisher's exact test. Expression correlation of αvß6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvß6 and MMP-9 levels (that is, both markers positive, both markers negative, αvß6 positive with MMP-9 negative, and αvß6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis. RESULTS: The expressions of integrin αvß6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvß6 expression, and 42.06% for MMP-9 expression. The expression of αvß6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvß6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvß6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvß6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvß6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvß6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvß6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007). CONCLUSION: The expression of αvß6 and MMP-9 are closely correlated, and the combinational pattern of αvß6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

Cyclic deformation leads to defect healing and strengthening of small-volume metal crystals.

When microscopic and macroscopic specimens of metals are subjected to cyclic loading, the creation, interaction, and accumulation of defects lead to damage, cracking, and failure. Here we demonstrate that when aluminum single crystals of submicrometer dimensions are subjected to low-amplitude cyclic deformation at room temperature, the density of preexisting dislocation lines and loops can be dramatically reduced with virtually no change of the overall sample geometry and essentially no permanent plastic strain. This "cyclic healing" of the metal crystal leads to significant strengthening through dramatic reductions in dislocation density, in distinct contrast to conventional cyclic strain hardening mechanisms arising from increases in dislocation density and interactions among defects in microcrystalline and macrocrystalline metals and alloys. Our real-time, in situ transmission electron microscopy observations of tensile tests reveal that pinned dislocation lines undergo shakedown during cyclic straining, with the extent of dislocation unpinning dependent on the amplitude, sequence, and number of strain cycles. Those unpinned mobile dislocations moving close enough to the free surface of the thin specimens as a result of such repeated straining are then further attracted to the surface by image forces that facilitate their egress from the crystal. These results point to a versatile pathway for controlled mechanical annealing and defect engineering in submicrometer-sized metal crystals, thereby obviating the need for thermal annealing or significant plastic deformation that could cause change in shape and/or dimensions of the specimen.

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation.

Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22(-phox) expression via NF-κB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of ß-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redox-mediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment.

Clinical significance of integrin ß6 as a tumor recurrence factor in follicular thyroid carcinoma.

BACKGROUND: Overexpression of integrin ß6 plays an important role in a variety of malignant tumor invasion and metastasis. METHODS: The expression levels of integrin ß6, matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by immunohistochemistry with human follicular thyroid carcinomas. Then we investigated their correlation with clinical outcomes parameters, relationship, and the survival time. RESULTS: The integrin ß6 staining was expressed in cellular membrane and cytoplasm of follicular thyroid carcinoma cells. The MMP-2 and MMP-9 expressions were mainly found in cellular cytoplasm. In correlation with the clinical outcome parameters of 60 patients, there were significant statistical differences of integrin ß6, MMP-2, and MMP-9 expression levels in different size of tumor. Integrin ß6 and MMP-9 expressions have significant statistical differences in T classifications. MMP-2 and MMP-9 expressions have significant statistical differences in different M classification. Other clinical outcome parameters had no significant statistical differences. CONCLUSION: Integrin ß6 expression correlated significantly with MMP-9 expression, and may be a valuable recurrence indicator for follicular thyroid carcinomas.

A noninvasive approach to determine viscoelastic properties of an individual adherent cell under fluid flow.

Mechanical properties of cells play an important role in their interaction with the extracellular matrix as well as the mechanotransduction process. Several in vitro techniques have been developed to determine the mechanical properties of cells, but none of them can measure the viscoelastic properties of an individual adherent cell in fluid flow non-invasively. In this study, techniques of fluid-structure interaction (FSI) finite element method and quasi-3-dimensional (quasi-3D) cell microscopy were innovatively applied to the frequently used flow chamber experiment, where an adherent cell was subjected to fluid flow. A new non-invasive approach, with cells at close to physiological conditions, was established to determine the viscoelastic properties of individual cells. The results showed an instantaneous modulus of osteocytes of 0.49 ± 0.11 kPa, an equilibrium modulus of 0.31 ± 0.044 kPa, and an apparent viscosity coefficient of 4.07 ± 1.23 kPas. This new quantitative approach not only provides an excellent means to measure cell mechanical properties, but also may help to elucidate the mechanotransduction mechanisms for a variety of cells under fluid flow stimulation.

Theoretical Analysis of Novel Quasi-3D Microscopy of Cell Deformation.

A novel quasi-three-dimensional (quasi-3D) microscopy technique has been developed to enable visualization of a cell under dynamic loading in two orthogonal planes simultaneously. The three-dimensional (3D) dynamics of the mechanical behavior of a cell under fluid flow can be examined at a high temporal resolution. In this study, a numerical model of a fluorescently dyed cell was created in 3D space, and the cell was subjected to uniaxial deformation or unidirectional fluid shear flow via finite element analysis (FEA). Therefore, the intracellular deformation in the simulated cells was exactly prescribed. Two-dimensional fluorescent images simulating the quasi-3D technique were created from the cell and its deformed states in 3D space using a point-spread function (PSF) and a convolution operation. These simulated original and deformed images were processed by a digital image correlation technique to calculate quasi-3D-based intracellular strains. The calculated strains were compared to the prescribed strains, thus providing a theoretical basis for the measurement of the accuracy of quasi-3D and wide-field microscopy-based intracellular strain measurements against the true 3D strains. The signal-to-noise ratio (SNR) of the simulated quasi-3D images was also modulated using additive Gaussian noise, and a minimum SNR of 12 was needed to recover the prescribed strains using digital image correlation. Our computational study demonstrated that quasi-3D strain measurements closely recovered the true 3D strains in uniform and fluid flow cellular strain states to within 5% strain error.