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Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays an essential role in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions.

Ionizing radiation is known to cause cell apoptosis at high dose range, but little is known about the cellular response to low dose radiation. In this study, we found that conditioned medium harvested from WI-38 lung fibroblasts and H1299 lung adenocarcinoma cells exposed to 0.1Gy to 1Gy could enhance the migration and invasion of unirradiated H1299 cells in both 2D and 3D culturing circumstances. Low dose radiation did not induce apoptosis, but induced senescence in irradiated cells. We next examined the expression of immediately early genes including c-Myc and K-Ras. Although both genes could be up-regulated by low dose radiation, induction of c-Myc was more specific to low dose range (0.5Gy) at transcriptional and translational levels. Knockdown of c-Myc by shRNA could repress the senescence induced by low dose radiation. The conditioned medium of irradiated cells induced migration of unirradiated cells was also repressed by knockdown of c-Myc. The c-Myc inhibitor 10058-F4 could suppress low dose radiation induced cell senescence, and the conditioned medium harvested from irradiated cells pretreated with 10058-F4 also lost the ability to enhance the migration of unirradiated cells. The cytokine array analysis revealed that immunosuppressive monocyte chemoattractant protein-1 increased by low dose radiation could be repressed by 10058-F4. We also showed that 10058-F4 could suppress low dose radiation induced tumor progression in a xenograft tumor model. Taken together, current data suggest that -Myc is involved in low dose radiation induced cell senescence and potent bystander effect to increase the motility of unirradiated cells.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity., P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.

The functional connectivity of the default-mode network (DMN) monitored by functional magnetic resonance imaging (fMRI) in Alzheimer's disease (AD) patients has been found weaker than that in healthy participants. Since breathing and heart beating can cause fluctuations in the fMRI signal, these physiological activities may affect the fMRI data differently between AD patients and healthy participants. We collected resting-state fMRI data from AD patients and age-matched healthy participants. With concurrent cardiac and respiratory recordings, we estimated both physiological responses phase-locked and non-phase-locked to heart beating and breathing. We found that the cardiac and respiratory physiological responses in AD patients were 3.00 ± 0.51 s and 3.96 ± 0.52 s later (both p < 0.0001) than those in healthy participants, respectively. After correcting the physiological noise in the resting-state fMRI data by population-specific physiological response functions, the DMN estimated by seed-correlation was more localized to the seed region. The DMN difference between AD patients and healthy controls became insignificant after suppressing physiological noise. Our results indicate the importance of controlling physiological noise in the resting-state fMRI analysis to obtain clinically related characterizations in AD.

Metastasis is the leading cause of death in non-small cell lung cancer patients (NSCLC). Actin cytoskeletal rearrangement is frequently accompanied by cancer cell invasion and metastasis induced by the epithelial-mesenchymal transition (EMT). The expression levels of the actin-associated protein cofilin-1 and the crucial EMT molecule Twist-1 in NSCLC tissues were investigated in this work. Immunohistochemical (IHC) staining was used to identify 67.4% of tissue locations that had reciprocal amounts of cofilin-1 and Twist-1 using lung cancer tissue arrays. This reciprocal expression pattern was also found in 10 out of 15 NSCLC cell lines and 21 out of 25 clinicopathological NSCLC tissue sections. Furthermore, in tissue arrays and clinicopathological tissue samples, high levels of cofilin-1 and low levels of Twist-1 accounted for 80% and 71.5% of the reciprocal expression pattern, respectively. This pattern was also found in normal lung tissues, lung cancer tissues in stages I and II, and NSCLC tissues with adenocarcinoma subtypes. Despite the fact that cofilin-1 and Twist-1 were expressed in opposite directions, there was a positive association between the two proteins in normal lung tissues and lung tumor tissues. In addition, induced expression of cofilin-1 in H1299 NSCLC cells may suppress Twist-1 expression. A public microarray dataset with a maximum of 1,926 NSCLC samples were made accessible through an online Kaplan-Meier survival analytic tool. The investigators discovered that high levels of expression of both the cofilin-1 and Twist-1 genes were linked to lower NSCLC patient survival, particularly in the adenocarcinoma subtype. The multivariate Cox regression model was used in the analysis. Even though more data is required to confirm the reciprocal relationship between cofilin-1 and Twist-1 expression levels and NSCLC survival rates, it could be a useful indication of NSCLC progression.

Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remains to be addressed. Here, we demonstrated, after a survey of various actin-binding proteins, that the post-translational up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization morphological enlargement in senescent cells. Additionally, up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form, according to the 2D gel immunoblotting assay. The up-regulation of cofilin-1 was also detected in aged mammalian tissues. The over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with an increased cell size. Additionally, senescent phenotypes were also reduced by knockdown of total cofilin-1, which led to a decrease in phosphorylated cofilin-1. The senescence induced by the over-expression of cofilin-1 was dependent on p27Kip1 , but not on the p53 and p16INK4 expressions. The knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that the over-expression of cofilin-1 induced the expression of p27Kip1 through transcriptional suppression of the transcriptional enhancer factors domain 1 (TEAD1) transcription factor. The TEAD1 transcription factor played a transrepressive role in the p27Kip1 gene promoter, as determined by the promoter deletion reporter gene assay. Interestingly, the down-regulation of TEAD1 was accompanied by the up-regulation of cofilin-1 in senescence. The knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and senescent phenotypes, respectively. Taken together, the current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest.

Human head and neck squamous cell carcinoma (HNSCC) is usually treated with chemoradiotherapy, but the therapeutic efficacy could be hampered by intrinsic radioresistance and early relapse. Repeated administrations of rhenium-188 (188Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of 188Re-liposome, the liposome-encapsulated 188Re nanoparticles exhibited significant killing effects on HNSCC FaDu cells and SAS cells but not on OECM-1 cells. To investigate the biological and pharmaceutical responses of high 188Re-liposomal dosage in vivo, repeated doses of 188Re-liposome was injected into the orthotopic tumor model. FaDu cells harboring luciferase reporter genes were implanted in the buccal positions of nude mice followed by intravenous injection of 188Re-liposome. The Cerenkov luminescence imaging (CLI) was performed to demonstrate an increased accumulation of 188Re-liposome in the tumor lesion of nude mice with repeated doses compared to a single dose. Repeated doses also enhanced tumor growth delay and elongated the survival of tumor-bearing mice. These observations were associated with significant loss of Ki-67 proliferative marker and epithelial–mesenchymal transition (EMT) markers in excised tumor cells. The body weights of mice were not significantly changed using different doses of 188Re-liposome, yet repeated doses led to lower blood counts than a single dose. Furthermore, the pharmacokinetic analysis showed that the internal circulation of repeated 188Re-liposomal therapy was elongated. The biodistribution analysis also demonstrated that accumulations of 188Re-liposome in tumor lesions and bone marrow were increased using repeated doses. The absorbed dose of repeated doses over a single dose was about twofold estimated for a 1 g tumor. Together, these data suggest that the radiopharmacotherapy of 188Re-liposome can enhance tumor suppression, survival extension, and internal circulation without acute toxicity using repeated administrations.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

The effects of particle size, pretreatment (acid pretreatment and steam explosion), and catalysis of aluminum oxide (Al2O3) on heating efficiency, product distribution, and gaseous product composition of corn stover pyrolysis using microwave heating were investigated in this study. Both maximum temperature and heating rate increased with decreasing particle size of corn stover. The heating efficiency was also improved over Al2O3 and by applying both pretreatment methods. Adding 10-mesh Al2O3 increased the gaseous yield but decreased the liquid yield. However, this phenomenon did not exist when 50-mesh Al2O3 was used. This may be attributable to that small catalyst particles are encapsulated by other catalyst and biomass particles to reduce their catalytic activity. Applying acid pretreatment substantially decreased the gaseous yield but increased the liquid yield, whereas the effect of steam explosion was not significant. Approximately half of CO was produced during the first 5 min of experiment, but the yields of H2, CH4, and CO2 produced from microwave pyrolysis of corn stover pretreated by acid were relatively small or even none during this initial period. The reaction kinetics for microwave pyrolysis of corn stover was analyzed by using the first- and second-order reaction models.

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and &gamma, H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors.

Fisetin (3,7,3′,4′-tetrahydroxyflavone), which belongs to the flavonoid group of polyphenols and is found in a wide range of plants, has been reported to exhibit a number of biological activities in human cancer cells, including antioxidant, anti-inflammatory, antiangiogenic, anti-invasive and antiproliferative effects. Although previous in vitro studies have shown that fisetin treatment increases the apoptotic rate and enhances the radiosensitivity of human colorectal cancer cells, the in vivo effects of fisetin on tumor growth remain unclear. In the present study a murine xenograft tumor model was employed to investigate the therapeutic effects of fisetin in combination with radiation on CT-26 colon cancer cells and human HCT116 colorectal cancer cells. This revealed that intratumoral injection of fisetin significantly suppressed the growth of CT-26 tumors compared with the untreated control group, but had little effect on the growth of HCT116 tumors. However, fisetin in combination with 2-Gy radiation enhanced tumor suppressor activity in murine colon and human colorectal xenograft tumors, as compared with 2-Gy fractionated radiation administered alone for 5 days and fisetin alone. Interestingly, fisetin downregulated the expression of the oncoprotein securin in a p53-independent manner. However, securin-null HCT116 tumors showed only moderate sensitivity to fisetin treatment, and the combination of fisetin and radiation did not significantly suppress securin-null HCT116 tumor growth compared with normal HCT116 tumors. Therefore, the role of securin in mediating the effect of fisetin on colorectal cancer growth warrants further investigation. In conclusion, the results of the current study provide important preclinical data for evaluating the efficacy of fisetin and radiation combination treatment as an adjuvant chemoradiotherapy for human colorectal cancers.

// Liang-Ting Lin 1, 2 , Chun-Yuan Chang 1 , Chih-Hsien Chang 3 , Hsin-Ell Wang 1 , Shih-Hwa Chiou 2, 4, 5 , Ren-Shyan Liu 1 , Te-Wei Lee 3 , Yi-Jang Lee 1, 6 1 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 2 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan 3 Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan 4 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 5 Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan 6 Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan Correspondence to: Te-Wei Lee, email: tewei123456@gmail.com Yi-Jang Lee, email: yjlee2@ym.edu.tw Keywords: 188 Re-liposome, HNSCC, orthotopic tumor model, microarray analysis, let-7 microRNA Received: May 20, 2016 Accepted: August 13, 2016 Published: August 29, 2016 ABSTRACT Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188 Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188 Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188 Re-liposome significantly accumulated in the tumor lesion compared to free 188 Re. The circulation time and tumor targeting of 188 Re-liposome were also longer than that of free 188 Re in tumor-bearing mice. The tumor growth was suppressed by 188 Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188 Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188 Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188 Re-liposome mediated suppression of tumor growth in vivo . Our data suggest that 188 Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.

Metastasis is the primary cause of mortality in patients with non‑small cell lung cancer (NSCLC). Actin cytoskeletal reorganization is usually accompanied by the epithelial‑mesenchymal transition (EMT)‑induced invasion and metastasis of cancer cells. In the present study, expression levels of the actin‑associated protein cofilin‑1 and of the pivotal EMT molecule Twist‑1 were determined in NSCLC tissues. Using lung cancer tissue arrays, the identification of 67.4% of tissue spots that exhibited reciprocal levels of cofilin‑1 and Twist‑1 was achieved by immunohistochemical (IHC) staining. This reciprocal expression pattern was also detected in 21 out of 25 clinicopathological NSCLC tissue sections, and in 10 out of 15 NSCLC cell lines. In addition, high levels of cofilin‑1 and low levels of Twist‑1 accounted for 80 and 71.5% of the reciprocal expression pattern in tissue arrays and clinicopathological tissue samples, respectively. This pattern was also detected in normal lung tissues, stage I and II lung cancer tissues, and adenocarcinoma subtypes of NSCLC tissues. Although cofilin‑1 and Twist‑1 were expressed inversely, a positive correlation of these two proteins was present in normal lung tissues and lung tumor tissues. Furthermore, enforced expression of cofilin‑1 suppressed the expression level of Twist‑1 in NSCLC H1299 cells. An on‑line Kaplan‑Meier survival analytic tool allowed access to a public microarray dataset with a maximum of 1,926 NSCLC samples. The analysis revealed that high expression levels of both cofilin‑1 (CFL1) and Twist‑1 (TWIST1) genes were associated with decreased survival of NSCLC patients, notably with regard to the adenocarcinoma subtype. The analysis was conducted using the multivariate Cox regression model. Although the reciprocal association of the expression levels of cofilin‑1 and Twist‑1 with the survival rate of NSCLC patients requires additional information, it may be a significant indicator of the progression of NSCLC.

Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remains to be addressed. Here, we demonstrated, after a survey of various actin‐binding proteins, that the post‐translational up‐regulation of cofilin‐1 was essential for the reduced rate of actin depolymerization morphological enlargement in senescent cells. Additionally, up‐regulated cofilin‐1 mainly existed in the serine‐3 phosphorylated form, according to the 2D gel immunoblotting assay. The up‐regulation of cofilin‐1 was also detected in aged mammalian tissues. The over‐expression of wild‐type cofilin‐1 and constitutively phosphorylated cofilin‐1 promoted cell senescence with an increased cell size. Additionally, senescent phenotypes were also reduced by knockdown of total cofilin‐1, which led to a decrease in phosphorylated cofilin‐1. The senescence induced by the over‐expression of cofilin‐1 was dependent on p27Kip1, but not on the p53 and p16INK4 expressions. The knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that the over‐expression of cofilin‐1 induced the expression of p27Kip1 through transcriptional suppression of the transcriptional enhancer factors domain 1 (TEAD1) transcription factor. The TEAD1 transcription factor played a transrepressive role in the p27Kip1 gene promoter, as determined by the promoter deletion reporter gene assay. Interestingly, the down‐regulation of TEAD1 was accompanied by the up‐regulation of cofilin‐1 in senescence. The knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and senescent phenotypes, respectively. Taken together, the current data suggest that cofilin‐1/TEAD1/p27Kip1 signaling is involved in senescence‐related morphological change and growth arrest., Triggers of senescence, such as replicative stress or oxidative stress, can induce the expression of cofilin‐1 to influence of cell morphology. Up‐regulated cofilin‐1 would enhance the expression of p27kip1 gene by suppressing the TEAD‐1 that transrepresses p27kip1 and lead to senescence‐associated growth delay.

The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response to environmental stimulation, CFL-1 enters the nucleus to regulate the actin dynamics. Although the purpose of this cytoplasm-nucleus transition remains unclear, it is speculated that the interaction between CFL-1 and DNA may influence various biological responses, including DNA damage repair. In this review, we will discuss the possible involvement of CFL-1 in DNA damage responses (DDR) induced by ionizing radiation (IR), and the implications for cancer radiotherapy.

Ultrafast functional magnetic resonance imaging (fMRI) can measure blood oxygen level dependent (BOLD) signals with high sensitivity and specificity. Here we propose a novel method: simultaneous multi-slice inverse imaging (SMS-InI) — a combination of simultaneous multi-slice excitation, simultaneous echo refocusing (SER), blipped controlled aliasing in parallel imaging echo-planar imaging (EPI), and regularized image reconstruction. Using a 32-channel head coil array on a 3 T scanner, SMS-InI achieves nominal isotropic 5-mm spatial resolution and 10 Hz sampling rate at the whole-brain level. Compared with traditional inverse imaging, we found that SMS-InI has higher spatial resolution with lower signal leakage and higher time-domain signal-to-noise ratio with the optimized regularization parameter in the reconstruction. SMS-InI achieved higher effective resolution and higher detection power in detecting visual cortex activity than InI. SMS-InI also detected subcortical fMRI signals with the similar sensitivity and localization accuracy like EPI. The spatiotemporal resolution of SMS-InI was used to reveal that presenting visual stimuli with 0.2 s latency between left and right visual hemifield led to 0.2 s relative hemodynamic response latency between the left and right visual cortices. Together, these results indicate that SMS-InI is a useful tool in measuring cortical and subcortical hemodynamic responses with high spatiotemporal resolution.

Arsenic trioxide (ATO) is a traditional Chinese medicine that can induce oxidative stress for treatment of cancer cells. However, ATO may generate anti-oxidative responses to compromise the cytotoxic effect, but the underlying mechanisms remain unclear. Here we found that ATO could inhibit miR-182-5p expression in patient-derived primary S1 glioblastoma (GBM) cells accompanied by up-regulation of Sestrin-2 (SESN2) mRNA, a known anti-oxidant molecule. This phenomenon was also detected in a U87MG glioma cell line, human lung adenocarcinoma H1299 cell line and A549 cell line. Pretreatment with a free radical scavenger N-acetylcysteine (NAC) reduced the oxidative stress induced by ATO. Concomitantly, ATO mediated suppression of miR-182-5p and enhancement of SESN2 expression were also compromised. The MTT assay further showed that ATO induced cytotoxicity was enhanced by transfection of miR-182-5p mimics. Overexpression of miR-182-5p mimics significantly suppressed the expression of SENS2 and a firefly luciferase reporter gene fused to 3’- untranslated region (UTR) of SESN2 mRNA. Use of ribonucleoprotein immunoprecipitation (RNP-IP), ATO mediated suppression of miR-182-5p led to the stabilization of SESN2 mRNA as a result of Argonaute-2 (AGO2) dependent gene silencing. Furthermore, high expression of miR-182-5p and low expression of SESN2 mRNA tend to be associated with longer survival of glioma or lung cancer patients using public available gene expression datasets and online tools for prediction of clinical outcomes. Taken together, current data suggest that the miR-182-5p/SENS2 pathway is involved in ATO induced anti-oxidant responses, which may be important for the design of novel strategy for cancer treatment.

Morphological change is an explicit characteristic of cell senescence, but the underlying mechanisms remain to be addressed. Here we demonstrated, after a survey of various actin-binding proteins, that up-regulation of cofilin-1 was essential for the reduced rate of actin depolymerization in senescent cells, as well as their morphological enlargement . Additionally, the up-regulated cofilin-1 mainly existed in the serine-3 phosphorylated form according to the 2D gel immunoblotting assay. Accumulation of cofilin-1 in senescent cells depended on the post-translational mechanism, as the ubiquitin-proteasomal degradation of cofilin-1 was reduced without any change in mRNA level. Up-regulation of cofilin-1 was not only found in replicative senescence but also in oxidative stress- and K-Ras oncogene-induced senescence. Over-expression of wild-type cofilin-1 and constitutively phosphorylated cofilin-1 promoted cell senescence with increased cell size. Additionally, senescent phenotypes were reduced by knockdown of total cofilin-1. The senescence induced by over-expression of cofilin-1 was dependent on p27Kip1 but not p53 and p16INK4 expression. Knockdown of p27Kip1 alleviated cell senescence induced by oxidative stress or replicative stress. We also found that over-expression of cofilin-1 induced expression of p27Kip1 through transcriptional suppression of the TEAD1 transcription factor. The TEAD1 transcription factor played a transrepressive role on the p27Kip1 gene promoter as determined by the promoter deletion reporter gene assay. Interestingly, TEAD1 down-regulation was accompanied by up-regulation of cofilin-1 in senescence. Knockdown and restoration of TEAD1 in young cells and old cells could induce and inhibit p27Kip1 and cell senescence, respectively. Furthermore, senescence induced by the over-expression of cofilin-1 could be alleviated by ectopic expression of TEAD1. Taken together, current data suggest that cofilin-1/TEAD1/p27Kip1 signaling is involved in senescence-related morphological change and growth arrest. Keywords: Cofilin-1, TEAD1, p27Kip1, morphology, growth arrest, senescence Citation Format: Yi-Jang Lee, Cheng-Han Tsai, Chun-Yuan Chang. The cofilin-TEAD1-p27Kip1 pathway ablates cell senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 893.

Purpose188Re-liposome has been used for evaluating the theranostic efficacy in various human cancers. However, whether the therapeutic efficacy of 188Re-liposome directly related to microRNAs regulation and specific signaling pathways are largely unknown. In this project, we investigated the 188Re-liposome induced systemic microRNA expressive responses in human head and neck cancer (HNSCC) cells. Methods The FaDu-3R cells were implanted into the nude mice at the position of buccal cavity. After two weeks of implantation, the tumors were palpable and the bioluminescent imaging indicated the location of this orthotopic tumor model. The PEGylated 188Re-liposome was intravenously injected single and dual dose respectively. We harvested all of the tumors after 188Re-liposome injection one month ago, and used Taqman Openarray MicroRNA (Thermo, USA) to detect the expression of miRNAs in different groups. The dataset we observed was further analyzed by using Ingenuity Pathway Analysis (IPA) software to establish the molecular signaling pathway of 188Re-liposome radiopharmaceutical. Results Quantification of the photon signals showed that the tumor growth of the dual 188Re-liposome treated mice was slower than that of control ones. The survival rate of 188Re-liposome treated animals were also better than control ones. The microRNA Openarray showed that, compared to untreated control, 17 miRNA were significantly changed in expressive levels over 5 fold after 188Re-liposome treatment. Subsequently, we used IPA to determine the role of these miRNA, and found these miRNA with oncogenic and tumor suppressive properties were down-regulated and up-regulated, respectively. Among them, we focused on miR-152-5p that is closed related to cancer occurrence and development, and showed that knockdown of miR-152-5p could decreased the effects of 188Re-liposome on suppressing the growth of HNSCC xenograft tumors. Conclusion HNSCC tumor model treated with dual dose of 188Re-liposome exhibited significant response to this radiopharmaceutical. We also found that 17 miRNA could be gsignificantly re-regulated, and miR-152-5p is one example to be involved in mediating the efficacy of 188Re-liposome. Targeting on specific miRNA may enhance the application value of 188Re-liposome.in cancer treatment. Citation Format: Bing-Ze Lin, Chun-Yuan Chang, Chih-Hsien Chang, Yi-Jang Lee. Openarray profiling of the systemic change of microRNAs in rhenium-188 liposome treated human head and neck cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1803.

Background and Purpose— The study aimed to assess whether onset headache is an ominous sign in patients with first-ever ischemic stroke. Methods— A large population of ischemic stroke patients was obtained from the Taiwan Stroke Registry. Stroke subtypes were classified by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of the International Classification of Headache Disorders, second version, onset headache was defined as a new headache that developed at the onset of ischemic stroke. Clinical features and impact on stroke outcomes, including in-hospital stroke in evolution, changes in National Institutes of Health Stroke Scale on discharge, and Barthel index and modified Rankin scale ≤6 months after stroke were compared between those with and without onset headache. Results— Among 11 523 patients with first-ever ischemic stroke, 848 had onset headache (7.4%). Patients with specific cause, large-artery atherosclerosis, or cardioembolism were more likely to have onset headache. Patients with onset headache were younger, predominantly female, and more likely to have posterior circulation ischemic lesions. Compared with patients without onset headache, those with onset headache had a lower frequency of stroke in evolution (4.5% versus 6.7%; adjusted relative risk, 0.64; 95% confidence interval, 0.52–0.79), greater improvement in National Institutes of Health Stroke Scale score on discharge (0.08 versus −0.20; P =0.02), higher mean Barthel index scores (86.5±20.0 versus 83.9±23.3; adjusted difference, 1.43; 95% confidence interval, 0.28–2.89), and a lower frequency of modified Rankin scale higher than 2 (27.6% versus 31.5%; adjusted relative risk, 0.85; 95% confidence interval, 0.72–0.95) at 1-month follow-up. There was also a trend for better functional outcome in 3- and 6-month follow-ups. Conclusions— By adopting standard classification criteria, this large-scale study demonstrated that onset headache was associated with modest but significantly better outcomes after ischemic stroke.

The spread of forest fire is a complex adaptive system. The spread could be seen as the result of fire agents continuous learning, adaptation and co-ordination. This paper founded an Agent-based model for forest fire spread, modeled the generating of fire spread rules based on Genetic Algorithms. Created the spread rules with effect of wind and topography independently for forest fire, designed the fitness function, and took the genetic operation on the rules, which created new rules. Implemented the adaptive algorithm on Repast S, and used it in the Agent-based model of forest fire spread. The result of models running indicated the adaptive algorithm could improve the adaptive ability of fire agent.

Aim Effects of radiofrequency ablation (RFA) combining immunoadjuvant glycated chitosan (GC) on tumor control and potent cytokine responses were investigated in a syngeneic breast tumor model. Materials and methods Murine 4T1 breast carcinoma cells harboring the luciferase reporter gene were used to evaluate the tumor growth rate and metastasis in vivo using bioluminescent imaging. Plasma of RFA/GC-treated tumor-bearing mice was collected for ex vivo cytotoxicity analysis and mouse chemokine array assays. Results Tumor growth and systemic metastasis were suppressed by combined RFA and GC when tumor size reached 300 mm3, not detected, however, when tumor size reached 800 mm3 The survival rate of mice bearing small tumors was also higher than that of large ones after RFA-GC treatment. Plasma extracted from RFA-GC-treated small tumor-bearing mice exhibited cytotoxicity on cultured 4T1 cells. Moreover, reduced tumor growth-related cytokines and increased antitumor-related cytokines were detected in the plasma collected. Conclusion RFA combining GC could control tumor progression with induced potent antitumor cytokine responses.

Forest fire fighting is very complex, the simulation using linear method is impossible. This paper proposed an Agent-based model for forest firefighting, designed the properties and behaviors of Fire Agent, Fighter Agent, and Commander Agent, simulated the fire spread and firefighting in forest by the three kinds of Agent’s actions, evolutions, and interactions; Developed the simulation software on Repast, which is composed of fire context, Agents, display, statistics and analysis etc; Simulated fighting with different number of Fighter Agent. The simulation’s statistics and analysis of Agents support both theory and practice for forest firefighting.

G1 to S phase transition is strictly regulated to avoid uncontrolled growth in mammalian cells. Although DNA replication initiates in S phase, licensing of DNA replicative origins substantially begins from late M to G1 phase. Interference of replicative origins licensing will lead to genomic instability and cell death. In addition, integral actin organization is required for G1 phase to S phase transition. Whether actin architectures will influence the licensing of DNA replicative origins is unclear. Previously, we found that over-expression of cofilin-1, a member of actin depolymerizing factor (ADF)/cofilin family could destabilize actin cytoskeleton and cause G1 phase arrest. The microarray assay further showed that minichromosome maintenance complex 2-7 (MCM2-7) helicase involved in the establishment of licensing was regulated by cofilin-1. In this study, we aim to investigate whether cofilin-1 would affect the expression of MCM2-7 complexes and the initiation of replicative origins licensing. First, we exploited a double thymidine blockage assay to demonstrate that the cofilin-1 expression was down-regulated during G1 to S phase transition. Use of H1299/tet-on-cofilin-1 cells, we also found that doxycycline induced exogenous cofilin-1 could inhibit the expression of MCM2-7 complex in both dose and time-dependent manners. Chromatin fractionation for analyzing the replicative origin licensing was performed to confirm these observations. DNA fiber analysis for determining the interorigin distance (IOD) was applied to investigate the IOD after the overexpression of cofilin-1 in H1299/tet-on-cofilin-1 cells. Taken together, current results revealed a novel finding that cofilin-1 could regulate MCM2-7 complex for mediating the replicative origin licensing and cell cycle progression. Since MCM2-7 complex has been regarded a prognostic marker of several human cancers, this study may contribute to designing of new therapeutic strategy for cancer treatment. Citation Format: Yi-Jang Lee, Chun-Yuan Chang. Cofilin-1 is associated with replicative origins licensing through regulation of MCM2-7 helicase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4296.