Problem Solving MRI to Reduce False-Positive Biopsy Related to Breast US: Conductivity vs. DWI vs. Abbreviated Contrast-Enhanced MRI.

BACKGROUND: While breast ultrasound (US) is a useful tool for diagnosing breast masses, it can entail false-positive biopsy results because of some overlapping features between benign and malignant breast masses and subjective interpretation. PURPOSE: To evaluate the performance of conductivity imaging for reducing false-positive biopsy results related to breast US, as compared to diffusion-weighted imaging (DWI) and abbreviated MRI consisting of one pre- and one post-contrast T1-weighted imaging. STUDY TYPE: Prospective. SUBJECTS: Seventy-nine women (median age, 44 years) with 86 Breast Imaging Reporting and Data System (BI-RADS) category 4 masses as detected by breast US. FIELD STRENGTH/SEQUENCE: 3-T, T2-weighted turbo spin echo sequence, DWI, and abbreviated contrast-enhanced MRI (T1-weighted gradient echo sequence). ASSESSMENT: US-guided biopsy (reference standard) was obtained on the same day as MRI. The maximum and mean conductivity parameters from whole and single regions of interest (ROIs) were measured. Apparent diffusion coefficient (ADC) values were obtained from an area with the lowest signal within a lesion on the ADC map. The performance of conductivity, ADC, and abbreviated MRI for reducing false-positive biopsies was evaluated using the following criteria: lowest conductivity and highest ADC values among malignant breast lesions and BI-RADS categories 2 or 3 on abbreviated MRI. STATISTICAL TESTS: One conductivity parameter with the maximum area under the curve (AUC) from receiver operating characteristics was selected. A P-value <0.05 was considered statistically significant. RESULTS: US-guided biopsy revealed 65 benign lesions and 21 malignant lesions. The mean conductivity parameter of the single ROI method was selected (AUC = 0.74). Considering conductivity (≤0.10 S/m), ADC (≥1.60 × 10-3 mm2 /sec), and BI-RADS categories 2 or 3 reduced false-positive biopsies by 23% (15 of 65), 38% (25 of 65), and 43% (28 of 65), respectively, without missing malignant lesions. DATA CONCLUSION: Conductivity imaging may show lower performance than DWI and abbreviated MRI in reducing unnecessary biopsies. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Data-driven electrical conductivity brain imaging using 3 T MRI.

Magnetic resonance electrical properties tomography (MR-EPT) is a non-invasive measurement technique that derives the electrical properties (EPs, e.g., conductivity or permittivity) of tissues in the radiofrequency range (64 MHz for 1.5 T and 128 MHz for 3 T MR systems). Clinical studies have shown the potential of tissue conductivity as a biomarker. To date, model-based conductivity reconstructions rely on numerical assumptions and approximations, leading to inaccuracies in the reconstructed maps. To address such limitations, we propose an artificial neural network (ANN)-based non-linear conductivity estimator trained on simulated data for conductivity brain imaging. Network training was performed on 201 synthesized T2-weighted spin-echo (SE) data obtained from the finite-difference time-domain (FDTD) electromagnetic (EM) simulation. The dataset was composed of an approximated T2-w SE magnitude and transceive phase information. The proposed method was tested three in-silico and in-vivo on two volunteers and three patients' data. For comparison purposes, various conventional phase-based EPT reconstruction methods were used that ignore B 1 + magnitude information, such as Savitzky-Golay kernel combined with Gaussian filter (S-G Kernel), phase-based convection-reaction EPT (cr-EPT), magnitude-weighted polynomial-fitting phase-based EPT (Poly-Fit), and integral-based phase-based EPT (Integral-based). From the in-silico experiments, quantitative analysis showed that the proposed method provides more accurate and improved quality (e.g., high structural preservation) conductivity maps compared to conventional reconstruction methods. Representatively, in the healthy brain in-silico phantom experiment, the proposed method yielded mean conductivity values of 1.97 ± 0.20 S/m for CSF, 0.33 ± 0.04 S/m for WM, and 0.52 ± 0.08 S/m for GM, which were closer to the ground-truth conductivity (2.00, 0.30, 0.50 S/m) than the integral-based method (2.56 ± 2.31, 0.39 ± 0.12, 0.68 ± 0.33 S/m). In-vivo ANN-based conductivity reconstructions were also of improved quality compared to conventional reconstructions and demonstrated network generalizability and robustness to in-vivo data and pathologies. The reported in-vivo brain conductivity values were in agreement with literatures. In addition, the proposed method was observed for various SNR levels (SNR levels = 10, 20, 40, and 58) and repeatability conditions (the eight acquisitions with the number of signal averages = 1). The preliminary investigations on brain tumor patient datasets suggest that the network trained on simulated dataset can generalize to unforeseen in-vivo pathologies, thus demonstrating its potential for clinical applications.

Effects of extracellular vesicles derived from steroids-primed oviductal epithelial cells on porcine in vitro embryonic development.

Extracellular vesicles (EVs) play an active role in regulating different physiological events, however, endocrine control of EVs cargo contents remain poorly understood. In this study, we aimed to isolate EVs from the porcine oviductal epithelial cells (POECs) that were primed with steroid hormones including estradiol (E2) and progesterone (P4), mimicking the in vivo conditions of the reproductive cycle and studied their effects on in vitro produced embryonic development. For this purpose, POECs were treated either with 0 concentration (control) or two different combinations of E2 and P4 including 50 pg/mL E2 + 0.5 ng/mL P4 (group H1), and 10 pg/mL E2 + 35 ng/mL P4 (group H2). Embryos were prepared after in vitro maturation either by parthenogenetic activation or somatic cell nuclear transfer (SCNT) technique. Treating parthenogenetic embryo with EVs, led a significantly higher rate of the blastocyst formation in the group supplemented with each EVs, compared to the control group. In addition, TUNEL assay and gene expression level analysis revealed that apoptosis was significantly reduced in the H2 EVs group. Furthermore, EVs from hormone-primed POECs improved the formation rate of porcine SCNT embryos compared to the control group. While in each EVs supplemented group (control EVs, H1 EVs, H2 EVs), the expression of cell reprogramming-related genes in cloned embryos showed a tendency of increase, the effect was stronger in H1 EVs and H2 EVs. In conclusion, EVs derived from POECs cultured in hormonal conditions simulating the in vivo environment had a positive effect on porcine blastocysts formation, which will likely facilitate in the production of cloned embryos.

Correlation between standardized uptake value of 18F-FDG PET/CT and conductivity with pathologic prognostic factors in breast cancer.

We investigated the correlation between standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and conductivity parameters in breast cancer and explored the feasibility of conductivity as an imaging biomarker. Both SUV and conductivity have the potential to reflect the tumors' heterogeneous characteristics, but their correlations have not been investigated until now. Forty four women diagnosed with breast cancer who underwent breast MRI and 18F-FDG PET/CT at the time of diagnosis were included. Among them, 17 women received neoadjuvant chemotherapy followed by surgery and 27 women underwent upfront surgery. For conductivity parameters, maximum and mean values of the tumor region-of-interests were examined. For SUV parameters, SUVmax, SUVmean, and SUVpeak of the tumor region-of-interests were examined. Correlations between conductivity and SUV were evaluated, and among them, the highest correlation was observed between mean conductivity and SUVpeak (Spearman's correlation coefficient = 0.381). In a subgroup analysis for 27 women with upfront surgery, tumors with lymphovascular invasion (LVI) showed higher mean conductivity than those without LVI (median: 0.49 S/m vs 0.06 S/m, p < 0.001). In conclusion, our study shows a low positive correlation between SUVpeak and mean conductivity in breast cancer. Furthermore, conductivity showed a potential to noninvasively predict LVI status.

Peli3 ablation ameliorates acetaminophen-induced liver injury through inhibition of GSK3ß phosphorylation and mitochondrial translocation.

The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3-/- knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3ß were decreased in primary hepatocytes obtained from Peli3-/- KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3ß compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3ß. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3-/- KO hepatocytes restored the mitochondrial translocation of GSK3ß, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3ß polyubiquitination.

Technical note: Multi-receiver combination method for phase-based electrical property tomography of the breast.

BACKGROUND: Phase-based electrical property tomography (EPT) is a technique that allows conductivity reconstruction with only phase of the B1 field under the assumption that the magnitude of the B1 fields are homogeneous. The more this assumption is violated, the less accurate the reconstructed conductivity. Thus, a method that ensures homogeneity of | B 1 - | $| {{\rm{B}}_1^ - } |$ field is important for breast image using multi-receiver coil. PURPOSE: To develop a method for multi-receiver combination for phase-based EPT usable for breast EPT imaging in the clinic. METHODS: Theory of the proposed method is presented. To validate the proposed method, the phantom and in-vivo experiments were conducted. Conductivity images were reconstructed using the transceive phase of the combined image and results were compared with another combination method. RESULTS: The proposed method's conductivity results were more stable than those of the previous method when | B 1 + | $| {{\rm{B}}_1^ + } |$ was not homogeneous and when the homogeneous contrast region was small. The phantom and in-vivo results indicate that the proposed method produces improved conductivity images than the previous method. The proposed combination method also increased the conductivity contrast between benign and cancerous tissues. CONCLUSION: The proposed method produced more stable multi-receiver combination for phase-based EPT of the breast in a clinical environment.

Comparing the Electronic Structure of Iron, Cobalt, and Nickel Compounds That Feature a Phosphine-Substituted Bis(imino)pyridine Chelate.

It was recently discovered that (Ph2PPrPDI)Mn (PDI = pyridine diimine) exists as a superposition of low-spin Mn(II) that is supported by a PDI dianion and intermediate-spin Mn(II) that is antiferromagnetically coupled to a triplet PDI dianion, a finding that encouraged the synthesis and electronic structure evaluation of late first row metal variants that feature the same chelate. The addition of Ph2PPrPDI to FeBr2 resulted in bromide dissociation and the formation of [(Ph2PPrPDI)FeBr][Br]. Reduction of this precursor using excess sodium amalgam afforded (Ph2PPrPDI)Fe, which possesses an Fe(II) center that is supported by a dianionic PDI ligand. Similarly, reduction of a premixed solution of Ph2PPrPDI and CoCl2 yielded the cobalt analog, (Ph2PPrPDI)Co. EPR spectroscopy and density functional theory calculations revealed that this compound features a high-spin Co(I) center that is antiferromagnetically coupled to a PDI radical anion. The addition of Ph2PPrPDI to Ni(COD)2 resulted in ligand displacement and the formation of (Ph2PPrPDI)Ni, which was found to possess a pendent phosphine group. Single-crystal X-ray diffraction, CASSCF calculations, and EPR spectroscopy indicate that (Ph2PPrPDI)Ni is best described as having a Ni(II)-PDI2- configuration. The electronic differences between these compounds are highlighted, and a computational analysis of Ph2PPrPDI denticity has revealed the thermodynamic penalties associated with phosphine dissociation from 5-coordinate (Ph2PPrPDI)Mn, (Ph2PPrPDI)Fe, and (Ph2PPrPDI)Co.

Characteristics and Prevalence of Early Chronic Obstructive Pulmonary Disease in a Middle-Aged Population: Results from a Nationwide-Representative Sample.

INTRODUCTION: Few studies have examined the prevalence and associated factors of early chronic obstructive pulmonary disease (COPD) in Asians. OBJECTIVE: To evaluate the prevalence of early COPD and its associated factors among non-institutionalized middle-aged Korean adults. METHODS: A total of 3195 participants aged 40-49 years from the 2016-2018 Korea National Health and Nutrition Examination Survey were included in this study. Patients (1) aged less than 50 years, (2) with a minimum of 10 pack-years of smoking, and (3) with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) below the lower limit of normal were diagnosed with early COPD. The prevalence and odds ratio (OR) for early COPD were measured using multivariate logistic regression analysis, and the demographic data, anthropometric measurements, socioeconomic status, and lifestyle factors were considered covariates. RESULTS: The overall prevalence of early COPD among the middle-aged Korean population was 2.4% (4.4% in men and 0.4% in women), while that in participants with ≥10 pack-years was 8.2% (8.1% in men and 11.3% in women). A multivariate logistic regression model showed that male sex, urban residence, chronic sputum production, and hypertriglyceridemia were associated with increased ORs for early COPD in middle-aged, non-institutionalized Korean adults. CONCLUSION: Early COPD is prevalent among middle-aged smokers in Korea. Efforts are needed to reduce the potential negative effects of early COPD on public health in Korea and other Asian countries.

IL-6 and IL-10 Levels, Rather Than Viral Load and Neutralizing Antibody Titers, Determine the Fate of Patients With Severe Fever With Thrombocytopenia Syndrome Virus Infection in South Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne viral disease, and most SFTS virus (SFTSV) infections occur via bites from the tick Haemaphysalis longicornis; however, SFTSV transmission can also occur through close contact with an infected patient. SFTS is characterized by acute high fever, thrombocytopenia, leukopenia, elevated serum hepatic enzyme levels, gastrointestinal symptoms, and multiorgan failure and has a 16.2 to 30% mortality rate. In this study, we found that age, dyspnea rates, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, multiorgan dysfunction score (MODS), viral load, IL-6 levels, and IL-10 levels were higher in patients with fatal disease than in patients with nonfatal disease during the initial clinical course of SFTS. In addition, we found that IL-6 and IL-10 levels, rather than viral load and neutralizing antibody titers, in patients with an SFTSV infection strongly correlated with outcomes (for severe disease with an ultimate outcome of recovery or death).

Near-infrared Transillumination and Photodynamic Therapy Using Hypericin in Animal Laryngeal Tumors.

BACKGROUND: We aimed to validate a pilot study of photodiagnosis using near infrared (NIR) transillumination and assess the clinical efficacy of hypericin-mediated photodynamic therapy (HYP-PDT) in a rabbit laryngeal cancer model in order to develop a novel therapeutic modality with complete remission and preservation of the functional organ. METHODS: (1) In vitro study: VX tumor cells were subcultured and subjected to HYP-PDT. (2) In vivo study: A laryngeal cancer model was developed in which 12 rabbits were inoculated with a VX tumor suspension in the submucosal area of the left vocal fold using a transoral approach. All rabbits underwent NIR transillumination using light with a wavelength of 780 nm. The survival periods of the three treatment groups (6 rabbits in Group A: HYP-PDT, 3 each in Groups B and C: laser irradiation or HYP administration only) were analyzed. RESULTS: The higher the HYP concentration, the lower the VX cell viability in response to HYP-PDT using 590 nm LED. Following HYP-PDT, small tumors in Group A-1 rabbits healed completely and the animals demonstrated a long survival period, and larger tumors in Group A-2 healed partially with a survival period that extended over 3 weeks after inoculation. The survival of Groups B and C were not different over the first 3 weeks of the study, and were shorter than in Group A. CONCLUSION: We found HYP-PDT could be a curative therapy for early-stage cancers that may also preserve organ function, and may inhibit tumor progression and metastasis during advanced stages of laryngeal cancer.

Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma.

The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development.

Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia.

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

Noncontrast-Enhanced MR-Based Conductivity Imaging for Breast Cancer Detection and Lesion Differentiation.

BACKGROUND: There is increasing interest in noncontrast-enhanced MRI due to safety concerns for gadolinium contrast agents. PURPOSE: To investigate the clinical feasibility of MR-based conductivity imaging for breast cancer detection and lesion differentiation. STUDY TYPE: Prospective. SUBJECTS: One hundred and ten women, with 112 known cancers and 17 benign lesions (biopsy-proven), scheduled for preoperative MRI. FIELD STRENGTH/SEQUENCE: Non-fat-suppressed T2-weighted turbo spin-echo sequence (T2WI), dynamic contrast-enhanced MRI and diffusion-weighted imaging (DWI) at 3T. ASSESSMENT: Cancer detectability on each imaging modality was qualitatively evaluated on a per-breast basis: the conductivity maps derived from T2WI were independently reviewed by three radiologists (R1-R3). T2WI, DWI, and pre-operative digital mammography were independently reviewed by three other radiologists (R4-R6). Conductivity and apparent diffusion coefficient (ADC) measurements (mean, minimum, and maximum) were performed for 112 cancers and 17 benign lesions independently by two radiologists (R1 and R2). Tumor size was measured from surgical specimens. STATISTICAL TESTS: Cancer detection rates were compared using generalized estimating equations. Multivariable logistic regression analysis was performed to identify factors associated with cancer detectability. Discriminating ability of conductivity and ADC was evaluated by using the areas under the receiver operating characteristic curve (AUC). RESULTS: Conductivity imaging showed lower cancer detection rates (20%-32%) compared to T2WI (62%-71%), DWI (85%-90%), and mammography (79%-88%) (all P < 0.05). Fatty breast on MRI (odds ratio = 11.8, P < 0.05) and invasive tumor size (odds ratio = 1.7, P < 0.05) were associated with cancer detectability of conductivity imaging. The maximum conductivity showed comparable ability to the mean ADC in discriminating between cancers and benign lesions (AUC = 0.67 [95% CI: 0.59, 0.75] vs. 0.84 [0.76, 0.90], P = 0.06 (R1); 0.65 [0.56, 0.73] vs. 0.82 [0.74, 0.88], P = 0.07 (R2)). DATA CONCLUSION: Although conductivity imaging showed suboptimal performance in breast cancer detection, the quantitative measurement of conductivity showed the potential for lesion differentiation. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Application of Polarization Sensitive-Optical Coherence Tomography to the Assessment of Phase Retardation in Subpleural Cancer in Rabbits.

BACKGROUND: Polarization sensitive-optical coherence tomography (PS-OCT) provides the unique advantage of being able to measure the optical characteristics of tissues by using polarized light. Although the well-organized fibers of healthy muscle can change the polarization states of passing light, damaged tissue has different behaviors. There are studies on optical imaging methods applied to the respiratory organs; however, they are restricted to structural imaging. In particular, the intercostal muscle situated under the pleura is very challenging to visualize due to the difficulty of access. METHOD: In this study, PS-OCT was used to identify subpleural cancer in male New Zealand white rabbits (3.2-3.4 kg) and to assess the phase retardation changes in normal and cancerous chest walls. VX2 cell suspension was injected between the intercostal muscle and parietal pleura and a tented area was observed by thoracic scope. A group of rabbits (n = 3) were sacrificed at day 7 after injection and another group (n = 3) at day 14. RESULTS: In the PS-OCT images, pleura thickness changes and muscle damage were criteria to understand the stages of the disease. The results of image and phase retardation analysis matched well with the pathologic examinations. CONCLUSION: We were able to visualize and analyze subpleural cancer by PS-OCT, which provided structural and functional information. The measured phase retardation could help to identify the margin of the tumor. For further studies, various approaches into other diseases using polarization light are expected to have positive results.

Investigation of the Clinical Potential of Polarization-Sensitive Optical Coherence Tomography in a Laryngeal Tumor Model.

BACKGROUND: The vocal cord tissue consists of three anatomical layers from the surface to deep inside: the epithelium that contains almost no collagen, the lamina propria that is composed of abundant collagen, and the vocalis muscle layer. It is clinically important to visualize the tissue microstructure using a non-invasive method, especially in the case of vocal cord nodules or cancer, since histological changes in each layer of the vocal cord cause changes in the voice. Polarization-sensitive optical coherence tomography (PS-OCT) enables phase retardation measurement to evaluate birefringence of tissue with varied organization of collagen fibers in different tissue layers. Therefore, PS-OCT can visualize structural changes between normal and abnormal vocal cord tissue. METHOD: A rabbit laryngeal tumor model with different stages of tumor progression was investigated ex-vivo by PS-OCT. A phase retardation slope-based analysis, which quantifies the birefringence in different layers, was conducted to distinguish the epithelium, lamina propria, and muscle layers. RESULTS: The PS-OCT images showed a gradual decrease in birefringence from normal tissue to advanced tumor tissue. The quantitative analysis provided a more detailed comparison among different stages of the rabbit laryngeal tumor model, which was validated by the corresponding histological findings. CONCLUSION: Differences in tissue birefringence was evaluated by PS-OCT phase retardation measurement. It is also possible to indirectly infer the dysplastic changes based on the mucosal and submucosal alterations.

Mechanical Properties and Sulfate Resistance of High Volume Fly Ash Cement Mortars with Air-Cooled Slag as Fine Aggregate and Polypropylene Fibers.

The depletion of natural sand and production of the huge amount of cement in the construction industry are serious threats to the environment, which can be reduced by the utilization of by-products as cement replacement material. In this study, cement was replaced with fly ash up to 45% (by weight). In addition, the natural fine aggregate was replaced with air-cooled blast furnace slag aggregate (here referred to as "slag aggregate") at a level of 50% and 100% (by weight). Polypropylene fiber was also added, at a dosage of 0.25% of binder weight. Mortar specimens were prepared and analyzed using tests for compressive, flexure, and splitting tensile strength, as well as for microhardness, and ultrasonic pulse velocity. In addition, the specimens were exposed to sulfate solution and investigated for changes in length, mass, and compressive strength. Electron microscopy and X-ray diffraction analysis were performed to examine the microstructure and phase changes of mortar specimens exposed to sulfate solution. The results indicate that mortar specimens made with 50% slag aggregate and 0.25 % fiber showed enhanced mechanical properties. The performance of slag aggregate mortars under sulfate attack was improved significantly.

A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-ß signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-peroxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368-381.

Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion.

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407-21. ©2018 AACR.

A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1.

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-ß1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3ß (GSK3ß), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-ß1-induced EMT and metastasis of basal-like breast cancers.