NUAK2 Inhibitors, KHKI-01128 and KHKI-01215, Exhibit Potent Anticancer Activity Against SW480 Colorectal Cancer Cells.

BACKGROUND/AIM: NUAK family kinase 2 (NUAK2) is a promising target for cancer therapeutics due to its reported role in protein phosphorylation, a critical process in cancer cell survival, proliferation, invasion, and senescence. This study aimed to identify novel inhibitors that disrupt NUAK2 activity. We have already identified two KRICT Hippo kinase inhibitor (KHKI) compounds, such as KHKI-01128 and KHKI-01215. Our aim was to evaluate the impact of KHKI-01128 and KHKI-01215 on NUAK2 activity and elucidate its mechanism in colorectal cancer cells. MATERIALS AND METHODS: To evaluate anticancer properties of these inhibitors, four in vitro assays in the SW480 cell line (time-resolved fluorescence resonance energy transfer assay, KINOMEscan kinase profiling, viability, and apoptosis assays) and two pharmacological mechanism analyses (Gene Set Enrichment Analysis and western blotting) were performed. RESULTS: KHKI-01128 and KHKI-01215 exhibited potent inhibitory activity against NUAK2 (half-maximal inhibitory concentration=0.024±0.015 µM and 0.052±0.011 µM, respectively). These inhibitors suppressed cell proliferation, with half-maximal inhibitory concentrations of 1.26±0.17 µM and 3.16±0.30 µM, respectively, and induced apoptosis of SW480 cells. Gene Set Enrichment Analysis revealed negative enrichment scores of -0.84 for KHKI-01128 (false-discovery rate=0.70) and 1.37 for KHKI-01215 (false-discovery rate=0.18), indicating that both effectively suppressed the expression of YES1-associated transcriptional regulator (YAP) target genes. CONCLUSION: These results suggest that KHKI-01128 and KHKI-01215 are potent NUAK2 inhibitors with promising potential for pharmaceutical applications.

Reliability and Agreement Assessment of Sarcopenia Diagnosis through Comparison of Bioelectrical Impedance Analysis and Dual-Energy X-ray Absorptiometry.

A unified diagnostic criterion has yet to be established for sarcopenia. Therefore, we analyzed the reliability and validity of sarcopenia diagnosis using bioelectrical impedance analysis (BIA) compared with the gold standard, dual-energy X-ray absorptiometry (DEXA), and evaluated the predictive accuracy of BIA for diagnosis. The clinical trial, involving a total of 239 participants, was conducted between December 2018 and September 2019 on healthy volunteers without significant medical histories. The participants underwent health assessments, followed by sequential DEXA and BIA measurements. In both the low and normal appendicular skeletal muscle (ASM) groups, there were significant differences in the right arm, left arm, right leg, left leg, ASM, and ASM index (ASMI) between DEXA and BIA across all age groups (p < 0.05). BIA tended to overestimate compared to DEXA, but ASMI values for males and females were consistent with the criteria for sarcopenia. Bland-Altman analysis showed that each segment in both the low and normal ASM groups fell within the limits of agreement (LOA). The diagnosis of sarcopenia using BIA was significantly different from that using DEXA. However, it exhibited a significantly high correlation, fell within the LOA, and demonstrated high predictive accuracy. BIA can be considered an effective tool for diagnosing sarcopenia.

Autoimmune adverse event following COVID-19 vaccination in Seoul, South Korea.

BACKGROUND: There is growing evidence that the coronavirus disease 2019 (COVID-19) vaccination can affect the regulation of the immune system, leading to the development of autoimmune diseases. However, the autoimmune adverse events (AEs) after COVID-19 vaccination remain largely unclear. OBJECTIVE: We sought to investigate the autoimmune AEs after COVID-19 vaccination from a population-based cohort in South Korea. METHODS: A total of 4,203,887 participants, representing 50% of the population residing in Seoul, were recruited from the National Health Insurance Service database and then divided into 2 groups on the basis of COVID-19 vaccination. The cumulative incidence, hazard ratios (HRs), and 95% CIs of autoimmune AEs were assessed following COVID-19 vaccination. RESULTS: The incidence of vitiligo has been observed to be significantly higher in the vaccination group compared with the no vaccination group. The cumulative incidence of vitiligo began to show a significant difference starting 2 weeks after vaccination, and it reached 2.2% in the vaccination group and 0.6% in the no vaccination group by 3 months after COVID-19 vaccination. Vitiligo (HR, 2.714; 95% CI, 1.777-4.146) was an increased risk among autoimmune AEs. Furthermore, the risk of vitiligo was the highest for heterologous vaccination (HR, 3.890; 95% CI, 2.303-6.573) compared with using cDNA vaccine (HR, 2.861; 95% CI, 1.838-4.453) or mRNA vaccine (HR, 2.475; 95% CI, 1.607-3.813). CONCLUSIONS: Vitiligo as an autoimmune AE was noted to be substantially higher in the COVID-19-vaccinated group compared with the controls. Therefore, the occurrence of vitiligo could be considered as one of the significant AEs post-COVID-19 vaccination.

ACY-241, a histone deacetylase 6 inhibitor, suppresses the epithelial-mesenchymal transition in lung cancer cells by downregulating hypoxia-inducible factor-1 alpha.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1α activity is essential in normal tissues, its presence in the tumor microenvironment represents a significant risk factor as it can induce angiogenesis and confer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1α even under normoxia. In this study, we observed an inclination toward increased normoxic HIF-1α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF-1α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a significant reduction in HIF-1α expression upon HDAC6 inhibition. Moreover, the downregulation of HIF-1α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also demonstrated an inhibitory effect on cell invasion and migration by reducing HIF-1α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer.

Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA).

Due to the outbreak of the SARS-CoV-2 virus, drug repurposing and Emergency Use Authorization have been proposed to treat the coronavirus disease 2019 (COVID-19) during the pandemic. While the efficiency of the drugs has been discussed, it was identified that certain compounds, such as chloroquine and hydroxychloroquine, cause QT interval prolongation and potential cardiotoxic effects. Drug-induced cardiotoxicity and QT prolongation may lead to life-threatening arrhythmias such as torsades de pointes (TdP), a potentially fatal arrhythmic symptom. Here, we evaluated the risk of repurposed pyronaridine or artesunate-mediated cardiac arrhythmias alone and in combination for COVID-19 treatment through in vitro and in silico investigations using the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. The potential effects of each drug or in combinations on cardiac action potential (AP) and ion channels were explored using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Chinese hamster ovary (CHO) cells transiently expressing cardiac ion channels (Nav1.5, Cav1.2, and hERG). We also performed in silico computer simulation using the optimized O'Hara-Rudy human ventricular myocyte model (ORd model) to classify TdP risk. Artesunate and dihydroartemisinin (DHA), the active metabolite of artesunate, are classified as a low risk of inducing TdP based on the torsade metric score (TMS). Moreover, artesunate does not significantly affect the cardiac APs of hiPSC-CMs even at concentrations up to 100 times the maximum serum concentration (Cmax). DHA modestly prolonged at APD90 (10.16%) at 100 times the Cmax. When considering Cmax, pyronaridine, and the combination of both drugs (pyronaridine and artesunate) are classified as having an intermediate risk of inducing TdP. However, when considering the unbound concentration (the free fraction not bound to carrier proteins or other tissues inducing pharmacological activity), both drugs are classified as having a low risk of inducing TdP. In summary, pyronaridine, artesunate, and a combination of both drugs have been confirmed to pose a low proarrhythmogenic risk at therapeutic and supratherapeutic (up to 4 times) free Cmax. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.

Intramolecular cyclization of N-cyano sulfoximines by N-CN bond activation.

Metal-free halogenated anhydrides promote the intramolecular cyclization of N-cyano sulfoximines. Trifluoro- or trichloroacetic anhydride (TFAA or TCAA, respectively) activate the N-cyano groups of N-cyano sulfoximines, leading to the intramolecular cyclization of 2-benzamide-N-cyano sulfoximines 1. This method results in excellent yields of thiadiazinone 1-oxides 2. A full intramolecular cyclization pattern was suggested by (i) labeling experiments with 13C, (ii) isolating of N-trifluoroacetyl sulfoximine 1ac, and (iii) confirming the generation of the intermediate 1ad by LC/MS analysis.

PCR-like performance of rapid test with permselective tunable nanotrap.

Highly sensitive rapid testing for COVID-19 is essential for minimizing virus transmission, especially before the onset of symptoms and in asymptomatic cases. Here, we report bioengineered enrichment tools for lateral flow assays (LFAs) with enhanced sensitivity and specificity (BEETLES2), achieving enrichment of SARS-CoV-2 viruses, nucleocapsid (N) proteins and immunoglobulin G (IgG) with 3-minute operation. The limit of detection is improved up to 20-fold. We apply this method to clinical samples, including 83% with either intermediate (35%) or low viral loads (48%), collected from 62 individuals (n = 42 for positive and n = 20 for healthy controls). We observe diagnostic sensitivity, specificity, and accuracy of 88.1%, 100%, and 91.9%, respectively, compared with commercial LFAs alone achieving 14.29%, 100%, and 41.94%, respectively. BEETLES2, with permselectivity and tunability, can enrich the SARS-CoV-2 virus, N proteins, and IgG in the nasopharyngeal/oropharyngeal swab, saliva, and blood serum, enabling reliable and sensitive point-of-care testing, facilitating fast early diagnosis.

N-Cyano sulfilimine functional group as a nonclassical amide bond bioisostere in the design of a potent analogue to anthranilic diamide insecticide.

To explore the potential of the N-cyano sulfilimine group as an amide bond isostere, a derivative of the blockbuster anthranilic diamide, chlorantramiliprole, was synthesized and evaluated with regard to its physicochemical properties, permeability, and biological activity. Given the combination of N-cyano sulfilimine chlorantraniliprole 1 and its strong hydrogen bond acceptor character, high permeability, and excellent insecticidal activity, the N-cyano sulfilimine functional group could be considered as an amide bond isostere.

Microstructure, Tensile, and Fatigue Properties of Large-Scale Austenitic Lightweight Steel.

High-Mn lightweight steel, Fe-0.9C-29Mn-8Al, was manufactured using steelmaking, ingot-making, forging, and rolling processes. After the final rolling process, a typical austenite single phase was observed on all sides of the thick plate. The microstructural changes after annealing and aging heat-treatments were observed, using optical and transmission electron microscopy. The annealed coupon exhibited a typical austenite single phase, including annealing twins in several grains; the average grain size was 153 µm. After aging heat treatment, κ-carbide was observed within the grains and on the grain boundaries. Additionally, the effect of aging heat treatment on the mechanical properties was analyzed, using a tensile test. The fine κ-carbide that precipitated within the grains in the aged coupon improved the 0.2% offset yield and the tensile stresses, as compared to the as-annealed coupon. To estimate the applicability of high-Mn lightweight steel for low-pressure (LP) steam turbine blades, a low-cycle fatigue (LCF) test was carried out at room temperature. At a total strain amplitude of 0.5 to 1.2%, the LCF life of high-Mn lightweight steel was approximately three times that of 12% Cr steel, which is used in commercial LP steam turbine blades. The LCF behavior of high-Mn lightweight steel followed the Coffin-Manson equation. The LCF life enhancement in the high-Mn lightweight steel results from the planar dislocation gliding behavior.

Proteomic genotyping of SNP of Complement Factor H (CFH) Y402H and I62V using multiple reaction monitoring (MRM) assays.

The single nucleotide polymorphisms (SNPs) of complement factor H (CFH) gene are well-known genetic risk factors for age-related macular degeneration (AMD). To identify whether the measurement of plasma protein concentrations of CFH variants using the multiple reaction monitoring (MRM) assay can determine the genotypes of CFH SNP rs1061170 and rs800292, 120 patients with AMD and 26 controls were included in this study. The number of cases were TT:TC:CC = 121:24:1 in CFH SNP Y402H and GG:AG:AA = 72:57:17 in CFH SNP I62V. Plasma concentrations of tryptic peptides were measured using the MRM assay, and tyrosine/histidine (Y/H) and valine/isoleucine (V/I) CFH variant protein ratios were obtained. To discriminate the genotypes by the plasma protein ratios, cut-off values were set for Y/H ratios (TT: > 4.428; TC: 1.00-4.428; CC: < 1.00) and V/I ratios (GG: > 1.09; AG: 0.0089-1.08; AA: < 0.0089). Correlation analysis revealed that the plasma CFH variant protein ratios and genotypes of CFH were exactly matched (100%) without overlap in the total patients and controls. The measurement of plasma protein CFH variants using the MRM assay can accurately identify the genotypes of CFH SNPs of Y402H and I62V.

Fabric muscle with a cooling acceleration structure for upper limb assistance soft exosuits.

Soft exosuits used for supporting human muscle strength must be lightweight and wearable. Shape memory alloy (SMA) spring-based fabric muscles (SFM) are light and flexible, making them suitable for soft and shape-conformable exosuits. However, SFMs have a slow actuation speed owing to the slow cooling rate of the SMA spring. This paper proposes a forced air-cooling fan-integrated fabric muscle (FCFM) that improves the cooling rate by arranging a thin-diameter SMA spring bundle with a high surface-area-to-volume ratio inside a breathable fabric with integrated fans. The relaxation time of an FCFM weighing 30 g and containing a 2.6 g SMA spring bundle, which contains 200 thin springs, was reduced by over 70.2% via forced-air cooling using the integrated fans. A 4 kg weight, which is 1530 times the mass of the SMA spring bundle, was hung from the FCFM and was repeatedly actuated in ten-second cycles. An upper limb assistive soft exosuit with FCFMs was fabricated and worn on a mannequin holding a dumbbell, and the arm extension time after flexion was improved by 4.5 times. Additionally, the assistive performance of the exosuits for repetitive tasks in specific scenarios was evaluated, and the strong potential of the proposed FCFM for soft exosuits was verified.

Nanoelectrokinetic-assisted lateral flow assay for COVID-19 antibody test.

A lateral flow assay (LFA) platform is a powerful tool for point-of-care testing (POCT), especially for self-testing. Although the LFA platform provides a simple and disposable tool for Coronavirus disease of 2019 (COVID-19) antigen (Ag) and antibody (Ab) screening tests, the lower sensitivity for low virus titers has been a bottleneck for practical applications. Herein, we report the combination of a microfluidic paper-based nanoelectrokinetic (NEK) preconcentrator and an LFA platform for enhancing the sensitivity and limit of detection (LOD). Biomarkers were electrokinetically preconcentrated onto a specific layer using the NEK preconcentrator, which was then coupled with LFA diagnostic devices for enhanced performance. Using this nanoelectrokinetic-assisted LFA (NEK-LFA) platform for self-testing, the severe acute respiratory syndrome coronavirus 2 Immunoglobulin G (SARS-CoV-2 IgG) sample was preconcentrated from serum samples. After preconcentration, the LOD of the LFA was enhanced by 32-fold, with an increase in analytical sensitivity (16.4%), which may offer a new opportunity for POCT and self-testing, especially in the COVID-19 pandemic and endemic global context.

Acid-Catalyzed Hydrolysis and Intramolecular Cyclization of N-Cyano Sulfoximines for the Synthesis of Thiadiazine 1-Oxides.

Herein, we describe a novel approach for the practical synthesis of thiadiazine 1-oxides 10. The first example of an intramolecular cyclization with 2-N-cyano-sulfonimidoyl amides 9 to form the desired thiadiazine 1-oxides 10 was developed. One-pot acid-induced hydrolysis of the cyano group and the intramolecular cyclocondensation protocol readily provided various heterocyclic frameworks in good to moderate yields. Notably, the crystal structures of N-urea sulfoximine 11 and thiadiazine 1-oxide 10i have been determined using X-ray crystallography.

Performance evaluation of the Anysis-200 platelet function analyzer in cardiac patients.

BACKGROUND: Platelet function analysis is crucial in assessing the hemostatic status to evaluate congenital and acquired platelet function defects. The Anysis-200 analyzer is a new automated lab-on-a-chip-based platelet function analyzer. OBJECTIVE: We aimed to evaluate a new platelet function analyzing system, the Anysis-200 in comparison to the Platelet Function Analyzer (PFA)-200 in cardiac patients. METHODS: Citrated blood was collected from 174 patients who visited the Department of Cardiology. The Anysis-200 consists of two kits, the microchips with collagen and epinephrine-coated membrane (C/EPI) or adenosine diphosphate-coated membrane (C/ADP). Platelet clogging in the Anysis-200 is measured by the blood migration distance obtained by a camera, which is compatible with the closure time in the PFA-200. We performed Anysis-200 and PFA-200 analyzers simultaneously and compared the results. RESULTS: The sensitivity and specificity of the Anysis-200 C/EPI kit in comparison to the PFA-200 C/EPI kit were 63.41% and 91.43%, respectively. Regarding the C/ADP kit, the sensitivity and specificity of the Anysis-200 were 58.97% and 74.29%, respectively. The agreement rate between the Anysis-200 and PFA-200 for C/EPI was 83.35% and 70.14% for C/ADP. CONCLUSIONS: The Anysis-200, which applies a novel method to detect platelet clogging, has shown moderate to fair agreement with the PFA-200. This test is potentially useful for screening cardiac patients with an abnormal platelet function.

The Impact of Left Atrial Reduction During Surgical Ablation of Atrial Fibrillation.

Enlarged left atrium (LA) is a risk factor for ablation failure after atrial fibrillation (AF) surgery. It predisposes patients to thromboembolic events, even in successful ablation; therefore, concomitant resection of the LA wall during surgical ablation was introduced. This study examined the clinical impacts of LA reduction in patients undergoing concomitant ablation for AF. This study enrolled 1484 patients with enlarged LA (≥50 mm) who underwent surgical AF ablation during major cardiac surgery between January 2001 and August 2018. Among them, 876 (59%) patients underwent concomitant LA reduction (Reduction group), whereas in the remaining 608 (41%), the LA wall was unresected (Preservation group). The primary outcome of interest was overall stroke. The secondary outcomes were overall mortality, late recurrence of AF, early postoperative complications and postoperative echocardiographic parameters. Outcomes were compared after adjusting baseline characteristics with inverse probability of treatment weighting (IPTW) using propensity score. The median follow-up was 60.1 months. After IPTW adjustment, long-term mortality (P = 0.250) and AF-free rates (P = 0.196) did not significantly differ between groups. However, the Reduction group showed a decreased risk of stroke (hazard ratio 0.54; 95% confidence interval 0.32-0.90; P = 0.018). Early postoperative complications rate such as mortality or reoperation for bleeding, was not significantly different between the 2 groups. The Reduction group showed smaller LA diameter (50.6 ± 8.0 mm vs 53.6 ± 8.9 mm; P < 0.001) on follow-up echocardiography. LA reduction effectively decreased LA size and appeared to decrease the stroke risk in patients with enlarged LA undergoing ablation for AF.

A pretreatment-free electrical capacitance biosensor for exosome detection in undiluted serum.

The exosome is considered a useful biomarker for the early diagnosis of cancer. However, pretreatment of samples used in diagnosis is time-consuming. Herein, we fabricated a capacitance-based electrical biosensor that requires no pretreatment of the sample; it is composed of a DNA aptamer/molybdenum disulfide (MoS2) heterolayer on an interdigitated micro-gap electrode (IDMGE)/printed circuit board (PCB) system for detecting exosomes in an undiluted serum sample. The DNA aptamer detects the CD63 protein on the exosome as the biomarker, while the MoS2 nanoparticle enhances electrical sensitivity. In this study, for the first time, the IDMGE system was used to amplify the electrical signal efficiently for exosome detection. The IDMGE amplifies the capacitance signal as the gap between electrodes decreases, making it easy to detect the target by utilizing the heightened sensitivity. Moreover, it is possible to immobilize a bio-probe more efficiently than with an electrical sensitivity-enhancing electrode with the same area. The thiol-modified (SH-) CD63 DNA aptamer was introduced as the bio-probe that selectively binds to the CD63 protein on the exosome surface. The capacitance signal from the IDMGE electrical sensor increased linearly with the increase in the concentration of exosomes in human serum expressed on a logarithmic scale, the detection limit being 2192.6 exosomes/mL. The proposed biosensor can detect exosomes in undiluted human serum with high selectivity and sensitivity. A blind test was also carried out to test the reliability of the biosensor. The capacitance-based electrical biosensor thus offers a new platform for cancer diagnosis in the future.

Recent Advances in Aptasensor for Cytokine Detection: A Review.

Cytokines are proteins secreted by immune cells. They promote cell signal transduction and are involved in cell replication, death, and recovery. Cytokines are immune modulators, but their excessive secretion causes uncontrolled inflammation that attacks normal cells. Considering the properties of cytokines, monitoring the secretion of cytokines in vivo is of great value for medical and biological research. In this review, we offer a report on recent studies for cytokine detection, especially studies on aptasensors using aptamers. Aptamers are single strand nucleic acids that form a stable three-dimensional structure and have been receiving attention due to various characteristics such as simple production methods, low molecular weight, and ease of modification while performing a physiological role similar to antibodies.

ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy.

Histone deacetylase 6 (HDAC6) is a promising target for cancer treatment because it regulates cell mobility, protein trafficking, cell growth, apoptosis, and metastasis. However, the mechanism of HDAC6-induced anticancer drug resistance is unclear. In this study, we evaluated the anticancer effect of ACY-241, an HDAC6-selective inhibitor, on erlotinib-resistant pancreatic cancer cells that overexpress HDAC6. Our data revealed that ACY-241 hyperacetylated the HDAC6 substrate, α-tubulin, leading to a significant reduction in cell viability of erlotinib-resistant pancreatic cells, BxPC3-ER and HPAC-ER. Notably, a synergistic anticancer effect was observed in cells that received combined treatment with ACY-241 and erlotinib. Combined treatment effectively induced autophagy and inhibited autophagy through siLC3B, and siATG5 alleviated ACY-241-mediated cell death, as reflected by the recovery of PARP cleavage and apoptosis rates. In addition, combined ACY-241 and erlotinib treatment induced autophagy and subsequently, cell death by reducing AKT-mTOR activity and increasing phospho-AMPK signaling. Therefore, HDAC6 may be involved in the suppression of autophagy and acquisition of resistance to erlotinib in ER pancreatic cancer cells. ACY-241 to overcome erlotinib resistance could be an effective therapeutic strategy against pancreatic cancer.

Multi-layered proteogenomic analysis unravels cancer metastasis directed by MMP-2 and focal adhesion kinase signaling.

The role of matrix metalloproteinase-2 (MMP-2) in tumor cell migration has been widely studied, however, the characteristics and effects of MMP-2 in clinical sample of metastatic colorectal cancer (CRC) remain poorly understood. Here, in order to unveil the perturbed proteomic signal during MMP-2 induced cancer progression, we analyzed plasma proteome of CRC patients according to disease progression, HCT116 cancer secretome upon MMP-2 knockdown, and publicly available CRC tissue proteome data. Collectively, the integrative analysis of multi-layered proteomes revealed that a protein cluster containing EMT (Epithelial-to-Mesenchymal Transition)-associated proteins such as CD9-integrin as well as MMP-2. The proteins of the cluster were regulated by MMP-2 perturbation and exhibited significantly increased expressions in tissue and plasma as disease progressed from TNM (Tumor, Node, and Metastasis) stage I to II. Furthermore, we also identified a plausible association between MMP-2 up-regulation and activation of focal adhesion kinase signaling in the proteogenomic analysis of CRC patient tissues. Based on these comparative and integrative analyses, we suggest that the high invasiveness in the metastatic CRC resulted from increased secretion of MMP-2 and CD9-integrin complex mediated by FAK signaling activation.

Strain hardening recovery mediated by coherent precipitates in lightweight steel.

We investigated the effect of κ-carbide precipitates on the strain hardening behavior of aged Fe-Mn-Al-C alloys by microstructure analysis. The κ-carbides-strengthened Fe-Mn-Al-C alloys exhibited a superior strength-ductility balance enabled by the recovery of the strain hardening rate. To understand the relation between the κ-carbides and strain hardening recovery, dislocation gliding in the aged alloys during plastic deformation was analyzed through in situ tensile transmission electron microscopy (TEM). The in situ TEM results confirmed the particle shearing mechanism leads to planar dislocation gliding. During deformation of the 100 h-aged alloy, some gliding dislocations were strongly pinned by the large κ-carbide blocks and were prone to cross-slip, leading to the activation of multiple slip systems. The abrupt decline in the dislocation mean free path was attributed to the activation of multiple slip systems, resulting in the rapid saturation of the strain hardening recovery. It is concluded that the planar dislocation glide and sequential activation of slip systems are key to induce strain hardening recovery in polycrystalline metals. Thus, if a microstructure is designed such that dislocations glide in a planar manner, the strain hardening recovery could be utilized to obtain enhanced mechanical properties of the material.