The Emergence of Tumor-Initiating Cells in an Advanced Hypopharyngeal Tumor Model Exhibits Enhanced Angiogenesis and Nuclear Factor Erythroid 2-Related Factor 2-Associated Antioxidant Effects.

Aims: Hypopharyngeal cancer (HPC) is associated with the worst prognosis of all head and neck cancers and is typically identified in an advanced stage at the time of diagnosis. While oxidative stress might contribute to the onset of HPC in patients using tobacco or alcohol, the extent of this influence and the characteristics of HPC cells in advanced stage remain to be investigated. In this study, we explored whether HPC cells survived from necrotic xenograft tumors at late stage would display increased tumor resistance along with altered tolerance to oxidative stress. Results: The remnant living HPC cells isolated from a late-stage xenograft tumor, named FaDu ex vivo cells, showed stronger chemo- and radioresistance, tumorigenesis, and invasiveness compared with parental FaDu cells. FaDu ex vivo cells also displayed increased angiogenic ability after re-transplantation in mice visualized by in vivo near infrared-II fluorescence imaging modality. Moreover, FaDu ex vivo cells exhibited significant tumor-initiating cell (TIC)-related properties accompanied by a reduction of the level of reactive oxygen species, which was associated with the upregulation of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Interestingly, inhibition of Nrf2 by the RNA interference and the chemical inhibitor could reduce the TIC-related properties of FaDu ex vivo cells. Innovation: Oxidative stress potentially initiates HPC, but elevation of Nrf2-associated antioxidant mechanisms would be essential to mitigate this effect for promoting and sustaining the stemness of HPC at the advanced stage. Conclusion: Present data suggest that the antioxidant potency of advanced HPC would be a therapeutic target for the design of adjuvant treatment. Antioxid. Redox Signal. 41, 505-521.

Reinforcement learning strategies in cancer chemotherapy treatments: A review.

BACKGROUND AND OBJECTIVE: Cancer is one of the major causes of death worldwide and chemotherapies are the most significant anti-cancer therapy, in spite of the emerging precision cancer medicines in the last 2 decades. The growing interest in developing the effective chemotherapy regimen with optimal drug dosing schedule to benefit the clinical cancer patients has spawned innovative solutions involving mathematical modeling since the chemotherapy regimens are administered cyclically until the futility or the occurrence of intolerable adverse events. Thus, in this present work, we reviewed the emerging trends involved in forming a computational solution from the aspect of reinforcement learning. METHODS: Initially, this survey in-depth focused on the details of the dynamic treatment regimens from a broad perspective and then narrowed down to inspirations from reinforcement learning that were advantageous to chemotherapy dosing, including both offline reinforcement learning and supervised reinforcement learning. RESULTS: The insights established in the chemotherapy-planning problem associated with the Reinforcement Learning (RL) has been discussed in this study. It showed that the researchers were able to widen their perspectives in comprehending the theoretical basis, dynamic treatment regimens (DTR), use of the adaptive control on DTR, and the associated RL techniques. CONCLUSIONS: This study reviewed the recent researches relevant to the topic, and highlighted the challenges, open questions, possible solutions, and future steps in inventing a realistic solution for the aforementioned problem.

Supervised Optimal Chemotherapy Regimen Based on Offline Reinforcement Learning.

In recent years, reinforcement learning (RL) has achieved a remarkable achievement and it has attracted researchers' attention in modeling real-life scenarios by expanding its research beyond conventional complex games. Prediction of optimal treatment regimens from observational real clinical data is being popularized, and more advanced versions of RL algorithms are being implemented in the literature. However, RL-generated medications still need careful supervision of expertise parties or doctors in healthcare. Hence, in this paper, a Supervised Optimal Chemotherapy Regimen (SOCR) approach to investigate optimal chemotherapy-dosing schedule for cancer patients was presented by using Offline Reinforcement Learning. The optimal policy suggested by the RL approach was supervised by incorporating previous treatment decisions of oncologists, which could add clinical expertise knowledge on algorithmic results. Presented SOCR approach followed a model-based architecture using conservative Q-Learning (CQL) algorithm. The developed model was tested using a manually constructed database of forty Stage-IV colon cancer patients, receiving line-1 chemotherapy treatments, who were clinically classified as 'Bevacizumab based patient' and 'Cetuximab based patient'. Experimental results revealed that the supervision from the oncologists has considered the effect to stabilize chemotherapy regimen and it was suggested that the proposed framework could be successfully used as a supportive model for oncologists in deciding their treatment decisions.

Involvement of c-Myc in low dose radiation-induced senescence enhanced migration and invasion of unirradiated cancer cells.

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.

N-Dihydrogalactochitosan Potentiates the Radiosensitivity of Liver Metastatic Tumor Cells Originated from Murine Breast Tumors.

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 γ-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.

Evaluation of the Biological Behavior of a Gold Nanocore-Encapsulated Human Serum Albumin Nanoparticle (Au@HSANP) in a CT-26 Tumor/Ascites Mouse Model after Intravenous/Intraperitoneal Administration.

Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this study, a gold nanocore-encapsulated human serum albumin nanoparticle (Au@HSANP), which is a hybrid protein-inorganic nanoparticle, and its radioactive surrogate 111In-labeled Au@HSANP (111In-Au@HSANP), were developed and their biological behaviors were investigated in a tumor/ascites mouse model. 111In-Au@HSANP was injected either intravenously (iv) or intraperitoneally (ip) in CT-26 tumor/ascites-bearing mice. After ip injection, a remarkable and sustained radioactivity retention in the abdomen was noticed, based on microSPECT images. After iv injection, however, most of the radioactivity was accumulated in the mononuclear phagocyte system. The results of biodistribution indicated that ip administration was significantly more effective in increasing intraperitoneal concentration and tumor accumulation than iv administration. The ratios of area under the curve (AUC) of the ascites and tumors in the ip-injected group to those in the iv-injected group was 93 and 20, respectively. This study demonstrated that the ip injection route would be a better approach than iv injections for applying gold-albumin nanoparticle in peritoneal metastasis treatment.

Presence of Gold Nanoparticles in Cells Associated with the Cell-Killing Effect of Modulated Electro-Hyperthermia.

The efficacy of gold nanoparticle (AuNP)-assisted radiofrequency (RF)-induced hyperthermia employing the Kanzius device remains controversial. Different from the Kanzius device, modulated electro-hyperthermia (mEHT) utilizes the capacitive-impedance coupled 13.56 MHz radiofrequency (RF) current and has been approved for clinical cancer treatment. In this study, we investigated the heating characteristics of spherical-, urchin-, and rod-like AuNPs of a similar 50 nm size upon exposure to a 13.56 MHz radiofrequency using the LabEHY-105CL, an in vivo mEHT device. We found that, regardless of the AuNPs' sphere-, urchin- or rod-like shape, purified gold nanoparticle solution would not promote heat generation. The temperature elevation during radiofrequency irradiation was solely attributed to the ionic background of the solution. The AuNPs present in the medium (≤25 ppm) showed no effect on selective cell killing of malignant cells, whereas the AuNPs incorporated in the cells diminished the cell selectivity as well as cell death and acted as protectors in mEHT cancer treatment. Our study suggested that (1) the temperature elevation induced by 50 nm AuNPs in the 13.56 MHz radiofrequency field was negligible and was shape-independent, and (2) the presence of AuNPs would alter the cell-killing effect of modulated electro-hyperthermia.

Clinical considerations and surgical approaches for low-grade gliomas in deep hemispheric locations: thalamic lesions.

BACKGROUND: Tumors with epicenter in the thalamus occur in about 4 % of pediatric brain tumors. The histological diagnosis is mainly gliomas. Among them, low-grade glioma (LGG) constituted of a significant entity of the tumors (Cuccia et al., Childs Nerv Syst 13:514-521, 1997; Puget et al., J Neurosurg 106:354-362, 2007; Bernstein et al., J Neurosurg 61:649-656, 1984; Bilginer et al., Childs Nerv Syst 30:1493-1498, 2014). Since Kelly's report in 1989, >90 % resection of thalamic tumors were achieved in reported series (Ozek and Ture, Childs Nerv Syst 18:450-6, 2002; Villarejo et al., Childs Nerv Syst 10:111-114, 1994; Moshel et al., Neurosurgery 61:66-75, 2007; Albright, J Neurosurg 100(5 Suppl Pediatrics): 468-472, 2004; Kelly, Neurosurgery 25:185-195, 1989; Drake et al., Neurosurgery 29: 27-33, 1991). MATERIALS AND METHODS: Sixty-nine cases of thalamic tumors in children were retrospectively reviewed. There were 25 cases of LGGs. We analyzed our experience and correlated it with reported series. RESULTS: Summing up of 4 reported series and the present series, there were 267 cases of thalamic tumors in children. Among these tumors, 107 (40.1 %) were LGGs and 91 (34.1 %) were low-grade astrocytomas (LGAs). In the present series, all of the 25 LGGs were LGAs that consisted of 11 pilocytic astrocytomas (PAs) and 14 diffuse astrocytomas (DAs). Six cases received biopsy sampling only. The remaining 19 cases received different degrees of surgical resection via several approaches. Radical (>90 %) resection was achieved better in PAs comparing with DAs. There was no operative mortality. Two patients had increased neurological deficits. In a mean follow-up period of 11.9 years, three patients died of tumor progression and one patient died of anaplastic change. The 5- and 10-year overall survival (OS) was 87.1 and 87.1 %, respectively. CONCLUSION: Thalamic LGGs are mainly LGAs and are indolent. The rate of >90 % resection was relatively low in the present series. By applying contemporary diagnostic MRI studies, surgical facilities, and appropriate approaches in selective cases, we may try maximum neuroprotective radical (>90 %) resection.

Factors affecting survival of medulloblastoma in children: the changing concept of management.

Medulloblastoma (MB) is a type of malignant tumor arising only in the cerebellum that was first defined by Cushing and Bailey in 1920s. In this review paper, we trace the evolution of risk stratification and the correlated changing concept of management in the past years. Outcome analysis of the hospital series of the Taipei Veterans General Hospital, Cheng Hsin General Hospital, and Taipei Medical University Hospital was performed to correlate prognostic indicators with reported studies. The purpose is to provide clues for age-specific and risk-adjusted optimal, effective, but beneficial and protective treatment strategies of these tumors in children.

Over-expression of cofilin-1 suppressed growth and invasion of cancer cells is associated with up-regulation of let-7 microRNA.

Cofilin-1, a non-muscle isoform of actin regulatory protein that belongs to the actin-depolymerizing factor (ADF)/cofilin family is known to affect cancer development. Previously, we found that over-expression of cofilin-1 suppressed the growth and invasion of human non-small cell lung cancer (NSCLC) cells in vitro. In this study, we further investigated whether over-expression of cofilin-1 can suppress tumor growth in vivo, and performed a microRNA array analysis to better understand whether specific microRNA would be involved in this event. The results showed that over-expression of cofilin-1 suppressed NSCLC tumor growth using the xenograft tumor model with the non-invasive reporter gene imaging modalities. Additionally, cell motility and invasion were significantly suppressed by over-expressed cofilin-1, and down-regulation of matrix metalloproteinase (MMPs) -1 and -3 was concomitantly detected. According to the microRNA array analysis, the let-7 family, particularly let-7b and let-7e, were apparently up-regulated among 248 microRNAs that were affected after over-expression of cofilin-1 up to 7 days. Knockdown of let-7b or let-7e using chemical locked nucleic acid (LNA) could recover the growth rate and the invasion of cofilin-1 over-expressing cells. Next, the expression of c-myc, LIN28 and Twist-1 proteins known to regulate let-7 were analyzed in cofilin-1 over-expressing cells, and Twist-1 was significantly suppressed under this condition. Up-regulation of let-7 microRNA by over-expressed cofilin-1 could be eliminated by co-transfected Twist-1 cDNA. Taken together, current data suggest that let-7 microRNA would be involved in over-expression of cofilin-1 mediated tumor suppression in vitro and in vivo.

Continuous production of high-purity fructooligosaccharides and ethanol by immobilized Aspergillus japonicus and Pichia heimii.

High-purity fructooligosaccharides (FOS) were produced from sucrose by an innovative process incorporating immobilized Aspergillus japonicus and Pichia heimii cells. Intracellular FTase of A. japonicus converted sucrose into FOS and glucose, and P. heimii fermented glucose mainly into ethanol. The continuous production of FOS was carried out using a tanks-in-series bioreactor consisting of three stirred tanks. When a solution composed of 1 g L(-1) yeast extract and 300 g L(-1) sucrose was fed continuously to the bioreactor at a dilution rate of 0.1 h(-1), FOS at a purity of up to 98.2 % could be achieved and the value-added byproduct ethanol at 79.6 g L(-1) was also obtained. One gram of sucrose yielded 0.62 g FOS and 0.27 g ethanol. This immobilized dual-cell system was effective for continuous production of high-purity FOS and ethanol for as long as 10 days.

Involvement of p53 R72P polymorphism in the association of MDM2-SNP309 with breast cancer.

The allelic variant MDM2-SNP309 (T>G) has been suggested to influence cancer development, but the clinical correlation between the risk allele and breast cancer remains controversial. The genetic background and the ethnicity of selected subgroups may influence the power of these risk genotypes. In this study, we investigated whether MDM2-SNP309 is associated with p53 R72P genetic polymorphism for the risk of breast cancer development in Asian Taiwanese, which has not been well-studied in this regard. Two hundred and fifty-five patients and 324 cancer-free controls were included, and we found that the MDM2-SNP309 TG and GG genotypes displayed marginally increased risks of breast cancer (GG vs. TT: OR = 1.7, 95% CI = 0.93 to 3.09; TG + TT vs. TT: OR = 1.57, 95% CI = 0.98 to 2.56). The breast cancer risk associated with MDM2-SNP309 was enhanced after stratification for the homozygous GG genotype at p53 codon 72 representing the Arg form of this genotype (GG vs. TT: OR = 3.7, 95% CI = 1.144 to 12.02; TG + GG vs. TT: OR = 2.7, 95% CI = 1.027 to 6.895). Also, the median age at diagnosis of patients with MDM2-SNP309 GG increased from 4 years earlier to 9 years earlier than TT patients after stratification for the GG genotype at p53 codon 72. Moreover, the G-allele of MDM2-SNP309 exhibited a stronger capacity than the T-allele to drive the full-length P2 promoter of the MDM2 gene in several human cell lines, suggesting that the association between MDM2-SNP309 and breast cancer is likely multifactorial rather than due to inconsistent gene expression in different cancer sources.

Interdigitated electrodes based on impedance biosensor for sensing peptide LL-37.

An antimicrobial peptide, LL-37, is found in an innate defense system of humans. Patients who suffer urinary tract infection (UTI) will generate LL-37 and which is released into urine. LL-37 can be used as an indicator for the diagnosis of UTI. We have designed a biosensor with an interdigitated electrode on a printed-circuit board (PCB). The surface of the electrode was modified with 3-mercaptopropionic acid and immobilized with anti-LL37 antibody to improve the specificity of the biosensor. By de-embedding jig impedance, the impedance associated with the change of LL-37 concentration was calculated. The sensitivity of this biosensor for LL-37 in a urine sample can reach 50 µg/mL.