LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes.

BACKGROUND: Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB. METHODS: The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms. RESULTS: Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-ß2. Knockdown of TGF-ß2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions. CONCLUSIONS: This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-ß2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.

Guard Cell-Inspired Ion Channels: Harnessing the Photomechanical Effect via Supramolecular Assembly of Cross-Linked Azobenzene/Polymers.

Stimuli-responsive ion nanochannels have attracted considerable attention in various fields because of their remote controllability of ionic transportation. For photoresponsive ion nanochannels, however, achieving precise regulation of ion conductivity is still challenging, primarily due to the difficulty of programmable structural changes in confined environments. Moreover, the relationship between noncontact photo-stimulation in nanoscale and light-induced ion conductivity has not been well understood. In this work, a versatile design for fabricating guard cell-inspired photoswitchable ion channels is presented by infiltrating azobenzene-cross-linked polymer (AAZO-PDAC) into nanoporous anodic aluminum oxide (AAO) membranes. The azobenzene-cross-linked polymer is formed by azobenzene chromophore (AAZO)-cross-linked poly(diallyldimethylammonium chloride) (PDAC) with electrostatic interactions. Under UV irradiation, the trans-AAZO isomerizes to the cis-AAZO, causing the volume compression of the polymer network, whereas, in darkness, the cis-AAZO reverts to the trans-AAZO, leading to the recovery of the structure. Consequently, the resultant nanopore sizes can be manipulated by the photomechanical effect of the AAZO-PDAC polymers. By adding ionic liquids, the ion conductivity of the light-driven ion nanochannels can be controlled with good repeatability and fast responses (within seconds) in multiple cycles. The ion channels have promising potential in the applications of biomimetic materials, sensors, and biomedical sciences.

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. METHODS: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. RESULTS: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. CONCLUSIONS: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.

Bridging geographical disparities across 368 townships with healthcare system and socioeconomic factors in Taiwan.

A universal health insurance program such as the National Health Insurance in Taiwan offers a wide coverage and increased access to healthcare services. Despite its ongoing efforts to enhance healthcare accessibility, differences in health for people living in urban and resource-deprived areas remain substantial. To investigate the longitudinal impact of the healthcare system and other potential structural drivers such as education and economic development on geographical disparities in health, we designed a panel study with longitudinal open secondary data, covering all 368 townships in Taiwan between 2013 and 2017. Our findings indicated higher mortality rates in the mountainous and rural areas near the east and south regions of the island in both years. Multivariate analyses showed an increase in the density of primary care physicians (PCP) was associated with lower all-cause mortality (ß = - 0.72, p < 0.0001) and cardiovascular disease mortality (ß = - 0.41, p < 0.0001). Effect of PCP is evident, but merely focusing on access to healthcare is still not enough. Additional measures are warranted to address the health disparities existing between urban and underprivileged areas.

Photoswitchable and Solvent-Controlled Directional Actuators: Supramolecular Assembly and Crosslinked Polymers.

Untethered small actuators have drawn tremendous interest owing to their reversibility, flexibility, and widespread applications in various fields. For polymer actuators, however, it is still challenging to achieve programmable structural changes under different stimuli caused by the intractability and single-stimulus responses of most polymer materials. Herein, multi-stimuli-responsive polymer actuators that can respond to light and solvent via structural changes are developed. The actuators are based on bilayer films of polydimethylsiloxane (PDMS) and azobenzene chromophore (AAZO)-crosslinked poly(diallyldimethylammonium chloride) (PDAC). Upon UV light irradiation, the AAZO undergoes trans-cis-trans photoisomerization, causing the bending of the bilayer films. When the UV light is off, a shape recovery toward an opposite direction occurs spontaneously. The reversible deformation can be repeated at least 20 cycles. Upon solvent vapor annealing, one of the bilayer films can be selectively swollen, causing the bending of the bilayer films with the directions controlled by the solvent vapors. The effects of different parameters, such as the weight ratios of AAZO and film thicknesses, on the bending angles and curvatures of the polymer films are also analyzed. The results demonstrate that multi-stimuli-responsive actuators with fast responses and high reproducibility can be fulfilled.

Targeting Castration-Resistant Prostate Cancer Using Mesenchymal Stem Cell Exosomes for Therapeutic MicroRNA-let-7c Delivery.

BACKGROUND: Castration-resistant prostate cancer (PCa; CRPC) has a poor response to androgen deprivation therapy and is considered an incurable disease. MicroRNA (miR)-lethal 7c (let-7c) was implied to be a tumor suppressor in PCa, and treatment with exogenous let-7c targets both cancer cells and their associated mesenchymal stem cells (MSCs) to prevent CRPC progression and metastasis. Exosomes are nanometer-sized membrane-bound vesicles which have an absolute predominance in biocompatibility for drug delivery and gene therapy by mediating cell-to-cell communication. By utilizing the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of MSC-derived exosomes as an exogenous miR delivery system to target CRPC, using miR let-7c as an example. METHODS: Bioinformatics analysis was performed to observe miR-let-7c expression in clinical samples by utilizing the GEO database. MSC-derived exosomes were collected from a human bone marrow-derived MSC cell line after cell transfection with either a pre-miR negative control or pre-miR-let-7c, and further characterized through nanoparticle tracking analysis and Western blotting. miR-let-7c expression was determined using RT-qPCR, and the phenotypic effects of both naked and MSC-exosome-encapsulated let-7c on CRPC cells (PC3 and CWR22Rv1) were determined by WST-1 cell proliferation assay and wound healing migration assay. RESULTS: miR-let-7c was downregulated in metastatic PCa and high grade group patients. miR-let-7c expression was confirmed to be downregulated in PCa cell lines, with massively decreased in most metastatic CRPC-like cells. Exogenous miR-let-7c can be successfully packaged into MSC exosomes. Treatment with either naked or MSC-exosome-encapsulated miR-let-7c resulted in significant reductions in cell proliferation and migration in CRPC-like PC3 and CWR22Rv1 cells. CONCLUSIONS: MSC-derived exosomes could serve as a therapeutic let-7c delivery system to target CRPC.

Non-cell-autonomous activation of hedgehog signaling contributes to disease progression in a mouse model of renal cystic ciliopathy.

Polycystic kidney disease (PKD) is a ciliopathy characterized by fluid-filled epithelial cysts in the kidney. Although it is well established that the primary cilium is essential for hedgehog (HH) signaling and HH signaling is abnormally activated in multiple PKD models, the mechanism and function of HH activation in PKD pathogenesis remain incompletely understood. Here we used a transgenic HH reporter mouse line to identify the target tissue of HH signaling in Arl13f/f;Ksp-Cre mutant kidney, in which the cilia biogenesis gene Arl13b is specifically deleted in epithelial cells of the distal nephron. In addition, we used a co-culture system to dissect cross-talk between epithelial and mesenchymal cells in the absence of expanding cysts. Finally, we treated Arl13bf/f;Ksp-Cre mice with the GLI inhibitor GANT61 and analyzed its impact on PKD progression in this model. We found that deletion of Arl13b in epithelial cells in the mouse kidney, in vivo, led to non-cell-autonomous activation of the HH pathway in the interstitium. In vitro, when co-cultured with mesenchymal cells, Arl13b-/- epithelial cells produced more sonic hedgehog in comparison to cells expressing Arl13b. Reciprocally, HH signaling was activated in mesenchymal cells co-cultured with Arl13b-/- epithelial cells. Finally, whole body inhibition of the HH pathway by GANT61 reduced the number of proliferating cells, inhibited cyst progression and fibrosis and preserved kidney function in Arl13bf/f;Ksp-Cre mice. Our results reveal non-cell-autonomous activation of HH signaling in the interstitium of the Arl13bf/f;Ksp-Cre kidney and suggest that abnormal activation of the HH pathway contributes to disease progression.

Enrichment of Tumor-Infiltrating B Cells in Group 4 Medulloblastoma in Children.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is classified into core molecular subgroups (wingless activated (WNT), sonic hedgehog activated (SHH), Group 3 (G3), and Group 4 (G4)). In this study, we analyzed the tumor-infiltrating immune cells and cytokine profiles of 70 MB patients in Taiwan using transcriptome data. In parallel, immune cell composition in tumors from the SickKids cohort dataset was also analyzed to confirm the findings. The clinical cohort data showed the WNT and G4 MB patients had lower recurrence rates and better 5-year relapse-free survival (RFP) compared with the SHH and G3 MB patients, among the four subgroups of MB. We found tumor-infiltrating B cells (TIL-Bs) enriched in the G4 subgroups in the Taiwanese MB patients and the SickKids cohort dataset. In the G4 subgroups, the patients with a high level of TIL-Bs had better 5-year overall survival. Mast cells presented in G4 MB tumors were positively correlated with TIL-Bs. Higher levels of CXCL13, IL-36γ, and CCL27 were found compared to other subgroups or normal brains. These three cytokines, B cells and mast cells contributed to the unique immune microenvironment in G4 MB tumors. Therefore, B-cell enrichment is a G4-subgroup-specific immune signature and the presence of B cells may be an indicator of a better prognosis in G4 MB patients.

Arrestin Facilitates Rhodopsin Dephosphorylation in Vivo.

Deactivation of G-protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G-protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (ARR1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether ARR1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking ARR1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For WT mice, rhodopsin dephosphorylation was nearly complete by 1 h in darkness. Surprisingly, we observed that, in the Arr1 KO rods, rhodopsin remained phosphorylated even after 3 h. Delayed dephosphorylation in Arr1 KO rods cannot be explained by cell stress induced by persistent signaling, since it is not prevented by the removal of transducin, the visual G-protein, nor can it be explained by downregulation of protein phosphatase 2A, the putative rhodopsin phosphatase. We further show that cone arrestin (ARR4), which binds light-activated, phosphorylated rhodopsin poorly, had little effect in enhancing rhodopsin dephosphorylation, whereas mice expressing binding-competent mutant ARR1-3A showed a similar time course of rhodopsin dephosphorylation as WT. Together, these results reveal a novel role of ARR1 in facilitating rhodopsin dephosphorylation in vivoSIGNIFICANCE STATEMENT G-protein-coupled receptors (GPCRs) are transmembrane proteins used by cells to receive and respond to a broad range of extracellular signals that include neurotransmitters, hormones, odorants, and light (photons). GPCR signaling is terminated by two sequential steps: phosphorylation and arrestin binding. Both steps must be reversed when GPCRs are recycled and reused. Dephosphorylation, which is required for recycling, is an understudied process. Using rhodopsin as a prototypical GPCR, we discovered that arrestin facilitated rhodopsin dephosphorylation in living mice.

The ADAM9/UBN2/AKR1C3 axis promotes resistance to androgen-deprivation in prostate cancer.

Metastatic and castration-resistant disease is a fatal manifestation of prostate cancer (PCa). The mechanism through which resistance to androgen deprivation in PCa is developed remains largely unknown. Our understanding of the tumor microenvironment (TME) and key signaling pathways between tumors and their TME is currently changing in light of the generation of new knowledge with regard to cancer progression. A disintegrin and metalloproteinase domain-containing protein 9 (ADAM9) is a membranous bridge forming cell-cell and cell-matrix connections that regulate tumor aggressiveness and metastasis. However, it is not known whether ADAM9 expressed in the TME contributes to the CRPC phenotype. In this study, we aimed to investigate the expression patterns of ADAM9 in prostate cancer-associated fibroblasts (CAFs). We also intended to elucidate the effects of both stromal cell- and cancer cell-derived ADAM9 on the progression of CRPC and the implicated molecular pathways. By using both clinical specimens and cell lines, we herein showed that unlike the membrane anchored ADAM9 overexpressed by both PCa cells and prostate CAFs, the secreted isoform of ADAM9 (sADAM9) was strongly detected in CAFs, but rarely in tumor cells, and that could be a serum marker for PCa patients. We demonstrated that functionally sADAM9 are characterized as chemoattractant for the directed movement of androgen-independent PCa cells through integrin downstream FAK/AKT pathway, supporting that elevated sADAM9 by prostate CAFs could be responsible for the promotion of CRPC metastasis. Moreover, by stimulating PCa cells with sADAM9, we found that ubinuclein-2 (UBN2) expression was increased. A positive correlation of ADAM9 and UBN2 expression was observed in androgen receptor-expressing PCa cell lines and further confirmed in clinical PCa specimens. Using a genetic modification approach, we identified UBN2 as a downstream target gene of ADAM9 that is critical for the survival of androgen-dependent PCa cells in response to androgen deprivation, through the induction and effect of the aldo-keto reductase family 1 member C3 (AKR1C3). Collectively, our results reveal a novel action of ADAM9 on the transition of androgen-dependent PCa cells into an androgen-independent manner through the UBN2/AKR1C3 axis; the aforementioned action could contribute to the clinically-observed acquired androgen-deprivation therapy resistance.

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment.

Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept.

Extracellular and intracellular intermittent magnetic-fluid hyperthermia treatment of SK-Hep1 hepatocellular carcinoma cells based on magnetic nanoparticles coated with polystyrene sulfonic acid.

The use of magnetic nanoparticles (MNPs) magnetized on applying an alternating magnetic field (AMF) to stimulate the thermal characteristics and to induce tumor apoptosis is a currently active area of research in cancer treatment. In previous work, we developed biocompatible and superparamagnetic polystyrene-sulfonic-acid-coated magnetic nanoparticles (PSS-MNPs) as applications for magnetically labeled cell trapping, but without assessment of treatment effects on tumor diseases. In the present work, we examined PSS-MNP-induced magnetic fluid hyperthermia (MFH) on SK-Hep1 hepatocellular carcinoma (HCC) cells for lethal thermal effects with a self-made AMF system; an adjustable AMF frequency generated a variable intensity of magnetic field and induced MNP relaxation. The extracellular and intracellular MFH treatments on a SK-Hep1 cell line were implemented in vitro; the result indicates that the lethal effects were efficient and caused a significantly decreased cell viability of SK-Hep1 cells. As the PSS-MNP concentration decreased, especially in intracellular MFH treatments, the MFH effects on cells, however, largely decreased through heat spreading to the culture medium. On controlling and decreasing the volume of culture medium, the problem of heat spreading was solved. It can be consequently expected that PSS-MNPs would be a prospective agent for intracellular cancer magnetotherapy.

The Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis.

SETDB1 is a histone-lysine N-methyltransferase critical for germline development. However, its function in early meiotic prophase I remains unknown. Here, we report that Setdb1 null spermatocytes display aberrant centromere clustering during leptotene, bouquet formation during zygotene, and subsequent failure in pairing and synapsis of homologous chromosomes, as well as compromised meiotic silencing of unsynapsed chromatin, which leads to meiotic arrest before pachytene and apoptosis of spermatocytes. H3K9me3 is enriched in centromeric or pericentromeric regions and is present in many sites throughout the genome, with a subset changed in the Setdb1 mutant. These observations indicate that SETDB1-mediated H3K9me3 is essential for the bivalent formation in early meiosis. Transcriptome analysis reveals the function of SETDB1 in repressing transposons and transposon-proximal genes and in regulating meiotic and somatic lineage genes. These findings highlight a mechanism in which SETDB1-mediated H3K9me3 during early meiosis ensures the formation of homologous bivalents and survival of spermatocytes.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan.

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22-2.18) or absence (HR: 2.31, 95% CI = 1.40-3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

Synthesis and characterization of magnetic nanoparticles coated with polystyrene sulfonic acid for biomedical applications.

The development of novel magnetic nanoparticles (MNPs) with satisfactory biocompatibility for biomedical applications has been the subject of extensive exploration over the past two decades. In this work, we synthesized superparamagnetic iron oxide MNPs coated with polystyrene sulfonic acid (PSS-MNPs) and with a conventional co-precipitation method. The core size and hydrodynamic diameter of the PSS-MNPs were determined as 8-18 nm and 50-200 nm with a transmission electron microscopy and dynamic light scattering, respectively. The saturation magnetization of the particles was measured as 60 emu g-1 with a superconducting quantum-interference-device magnetometer. The PSS content in the PSS-MNPs was 17% of the entire PSS-MNPs according to thermogravimetric analysis. Fourier-transform infrared spectra were recorded to detect the presence of SO3 - groups, which confirmed a successful PSS coating. The structural properties of the PSS-MNPs, including the crystalline lattice, composition and phases, were characterized with an X-ray powder diffractometer and 3D nanometer-scale Raman microspectrometer. MTT assay and Prussian-blue staining showed that, although PSS-MNPs caused no cytotoxicity in both NIH-3T3 mouse fibroblasts and SK-HEP1 human liver-cancer cells up to 1000 µg mL-1, SK-HEP1 cells exhibited significantly greater uptake of PSS-MNPs than NIH-3T3 cells. The low cytotoxicity and high biocompatibility of PSS-MNPs in human cancer cells demonstrated in the present work might have prospective applications for drug delivery.

Progress in Delivery of siRNA-Based Therapeutics Employing Nano-Vehicles for Treatment of Prostate Cancer.

Prostate cancer (PCa) accounts for a high number of deaths in males with no available curative treatments. Patients with PCa are commonly diagnosed in advanced stages due to the lack of symptoms in the early stages. Recently, the research focus was directed toward gene editing in cancer therapy. Small interfering RNA (siRNA) intervention is considered as a powerful tool for gene silencing (knockdown), enabling the suppression of oncogene factors in cancer. This strategy is applied to the treatment of various cancers including PCa. The siRNA can inhibit proliferation and invasion of PCa cells and is able to promote the anti-tumor activity of chemotherapeutic agents. However, the off-target effects of siRNA therapy remarkably reduce its efficacy in PCa therapy. To date, various carriers were designed to improve the delivery of siRNA and, among them, nanoparticles are of importance. Nanoparticles enable the targeted delivery of siRNAs and enhance their potential in the downregulation of target genes of interest. Additionally, nanoparticles can provide a platform for the co-delivery of siRNAs and anti-tumor drugs, resulting in decreased growth and migration of PCa cells. The efficacy, specificity, and delivery of siRNAs are comprehensively discussed in this review to direct further studies toward using siRNAs and their nanoscale-delivery systems in PCa therapy and perhaps other cancer types.

The In Vivo Radiosensitizing Effect of Magnolol on Tumor Growth of Hepatocellular Carcinoma.

BACKGROUND/AIM: Radiation (RT) induced ERK/NF-κB in hepatocellular carcinoma (HCC) has been reported in our previous works; it weakens the toxicity of RT or triggers a radioresistance effect. Thus, combining RT with a suitable NF-κB inhibitor may sensitize HCC to RT. Magnolol, a bioactive compound, was known to have anti-inflammatory and anti-tumor functions. Here, we aimed to investigate whether magnolol may enhance anti-HCC efficacy of RT in vivo. MATERIALS AND METHODS: We established a Hep3B bearing mouse to evaluate the efficacy of the combination treatment of magnolol and RT. RESULTS: Most significantly, tumor volume and tumor weight inhibition was found in the combination group. Tumor immunohistochemistry staining also illustrated the suppression of RT-induced ERK/NF-κB-related proteins expression by magnolol. In addition, intrinsic apoptosis-related proteins, such as caspase-3 and -9, were markedly increased in the combination group. CONCLUSION: Magnolol may effectively enhance anti-HCC ability of RT by downregulating the expression of ERK/NF-κB-related proteins and increasing the expression of apoptosis-related proteins.

MIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA.

MIWI, a murine member of PIWI proteins mostly expressed during male meiosis, is crucial for piRNA biogenesis, post-transcriptional regulation, and spermiogenesis. However, its meiotic function remains unknown. Here, we report that MIWI deficiency alters meiotic kinetochore assembly, significantly increases chromosome misalignment at the meiosis metaphase I plate, and causes chromosome mis-segregation. Consequently, Miwi-deficient mice show elevated aneuploidy in metaphase II and spermatid death. Furthermore, in Miwi-null and Miwi slicer-deficient mutants, major and minor satellite RNAs from centromeric and pericentromeric satellite repeats accumulate in excess. Over-expression of satellite repeats in wild-type spermatocytes also causes elevated chromosome misalignment, whereas reduction of both strands of major or minor satellite RNAs results in lower frequencies of chromosome misalignment. We show that MIWI, guided by piRNA, cleaves major satellite RNAs, generating RNA fragments that may form substrates for subsequent Dicer cleavage. Furthermore, Dicer cleaves all satellite RNAs in conjunction with MIWI. These findings reveal a novel mechanism in which MIWI- and Dicer-mediated cleavage of the satellite RNAs prevents the over-expression of satellite RNAs, thus ensuring proper kinetochore assembly and faithful chromosome segregation during meiosis.