A Multifunctional Porous Silicon Nanocarrier for Glioblastoma Treatment.

Clinical treatment of glioblastoma (GBM) remains a major challenge because of the blood-brain barrier, chemotherapeutic resistance, and aggressive tumor metastasis. The development of advanced nanoplatforms that can efficiently deliver drugs and gene therapies across the BBB to the brain tumors is urgently needed. The protein "downregulated in renal cell carcinoma" (DRR) is one of the key drivers of GBM invasion. Here, we engineered porous silicon nanoparticles (pSiNPs) with antisense oligonucleotide (AON) for DRR gene knockdown as a targeted gene and drug delivery platform for GBM treatment. These AON-modified pSiNPs (AON@pSiNPs) were selectively internalized by GBM and human cerebral microvascular endothelial cells (hCMEC/D3) cells expressing Class A scavenger receptors (SR-A). AON was released from AON@pSiNPs, knocked down DRR and inhibited GBM cell migration. Additionally, a penetration study in a microfluidic-based BBB model and a biodistribution study in a glioma mice model showed that AON@pSiNPs could specifically cross the BBB and enter the brain. We further demonstrated that AON@pSiNPs could carry a large payload of the chemotherapy drug temozolomide (TMZ, 1.3 mg of TMZ per mg of NPs) and induce a significant cytotoxicity in GBM cells. On the basis of these results, the nanocarrier and its multifunctional strategy provide a strong potential for clinical treatment of GBM and research for targeted drug and gene delivery.

Serum SALL4 as a predictive biomarker for the prognosis of patients with hepatocellular carcinoma who underwent nonsurgical treatment.

To investigate the role of serum spalt like transcription factor 4 (SALL4) in the hepatocellular carcinoma (HCC) patients with nonsurgical treatment. Serum samples were collected from 101 patients with HCC without surgical treatment, then the SALL4 was detected by enzyme linked immunosorbent assay. According to subsequent treatment, patients were divided into 2 groups, best supportive care (BSC) (58 cases) and nonsurgical anticancer treatment (NSAT) (48 cases). Kaplan-Meier survival analysis and Cox multivariate regression analysis were applied to evaluate the relationship between SALL4 and survival time of 2 groups. In BSC group, there was no significant difference of the survival time between 2 groups (SALL4 < 800 ng/mL or SALL4 ≥ 800 ng/mL) (P = .339). In NSAT group, the survival time of patients with low SALL4 concentration was significantly longer than patients with high SALL4 concentration (P = .005). SALL4 have no predictive effect in BSC patients with HCC. But for patients received NSAT, low SALL4 concentration in serum may indicate longer survival.

Prevalence of left iliac vein compression in an asymptomatic population and patients with left iliofemoral deep vein thrombosis: A multicenter cross-sectional study in southern China.

OBJECTIVE: Population-based epidemiological data on left common iliac vein (LCIV) compression is scarce. This study aimed to investigate the prevalence of LCIV compression in an asymptomatic population and patients with left iliofemoral deep vein thrombosis (IF-DVT). MATERIALS AND METHODS: Nonprobability sampling method was used in this multicenter cross-sectional study. The minimum diameter of LCIV and right common iliac vein minimum were measured. The percentage of LCIV compression (LCIV-CP) was calculated. Compression severity (CS) was classified as mild (CP ≤ 50%), moderate (50% < CP ≤ 70%), and severe (CP > 70%). RESULTS: In all, 896 subjects constituted the asymptomatic population and 93 patients constituted the IF-DVT population. In the asymptomatic population, LCIV-CP ranged from 1.1% to 89.9% (mean 44.0%), and people with mild, moderate, and severe CS accounted for 62.3%, 28.2%, and 9.5%, respectively. In the IF-DVT population, the mean LCIV-CP was 71.1% (range 42.2%-95.2%), and patients with severe CS accounted for 75.3%. Gender and age differences in LCIV-CP and CS distribution were observed in the asymptomatic population. Females, the young- and middle-aged group had higher LCIV-CPs. In the population with moderate-severe CS, the middle-aged group accounted for a larger proportion. Middle-aged females comprised the highest percentage of patients with moderate or severe CS. Sex and age affected the LCIV-CP and CS distribution. No gender and age differences were observed in the IF-DVT population. CONCLUSIONS: LCIV compression is common in population. Middle-aged females are the predominant population with moderate-severe compression. Overlapping of LCIV-CP in the asymptomatic and IF-DVT population is significant and other risk factors should be integrated into the consideration when assessing the risk of IF-DVT secondary to LCIV compression.

Delivering the Promise of Gene Therapy with Nanomedicines in Treating Central Nervous System Diseases.

Central Nervous System (CNS) diseases, such as Alzheimer's diseases (AD), Parkinson's Diseases (PD), brain tumors, Huntington's disease (HD), and stroke, still remain difficult to treat by the conventional molecular drugs. In recent years, various gene therapies have come into the spotlight as versatile therapeutics providing the potential to prevent and treat these diseases. Despite the significant progress that has undoubtedly been achieved in terms of the design and modification of genetic modulators with desired potency and minimized unwanted immune responses, the efficient and safe in vivo delivery of gene therapies still poses major translational challenges. Various non-viral nanomedicines have been recently explored to circumvent this limitation. In this review, an overview of gene therapies for CNS diseases is provided and describes recent advances in the development of nanomedicines, including their unique characteristics, chemical modifications, bioconjugations, and the specific applications that those nanomedicines are harnessed to deliver gene therapies.

Interferon-induced transmembrane protein 2 promotes epithelial-mesenchymal transition by activating transforming growth factor-ß1/small mother against decapentaplegic 2 signaling in gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignancy around the world. Primary tumor cells are enabled to invade and migrate into adjacent normal tissues to form secondary tumors. Epithelial-mesenchymal transitions (EMT) plays a pivotal role in facilitating tumor progression. Abundant evidence suggested that the transforming growth factor-ß1 (TGF-ß1) triggered the process of EMT. Nonetheless, the precise molecular mechanisms underlying EMT requires further elucidation, and there still lacks effective specific therapeutic target. In our recent research, we demonstrated that the interferon (IFN)-induced transmembrane protein 2 (IFITM2) promoted the growth and metastasis of GC. However, it remains unclear whether IFITM2 involves in TGF-ß1 mediated EMT in GC. METHODS AND RESULTS: In the present research, we investigated the functional role of IFITM2 in EMT process and TGF-ß1 signaling pathway in two GC cell lines. We noticed that silencing IFITM2 can effectively inhibit TGF-ß1 signaling mediated EMT by regulating down stream small mother against decapentaplegic (SMAD) 2/3 and transcription factors.This finding was further determined in both tumor tissues from GC patients and normal tissues adjacent to cancer. Our data demonstrated the key role of IFITM2 in TGF-ß1 signaling and EMT in GC. CONCLUSION: The findings enriched our understanding of the underlying mechanism in EMT during the progression of GC. In addition, IFITM2 would be a potential target for treating GC and other malignant tumors.

Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma.

Genome-wide association study recently identified a novel antiviral gene INTS10 (index rs7000921) in suppression of hepatitis B virus (HBV) replication. However, data were lacking on single nucleotide polymorphisms (SNPs) of INTS10 in the context of hepatocellular carcinoma (HCC) induced by HBV infection. Herein, we conducted a case-control study, including 737 HBV-related HCC cases and 750 persistently HBV-infected controls, to investigate the effect of INTS10 SNPs and their gene-environment interactions on HBV-related HCC. In multivariate analysis, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype (adjusted odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p for permutation test = .038). Among the 12 tagSNPs, the rs4268139 yielded a borderline significant association with disease risk under the additive model (adjusted OR = 0.80, 95% CI = 0.63-1.00, p for permutation test = .061). Random forest model further suggested the rs7000921 and rs7822495 as the two-top ranked important SNPs, and thus a weighted genetic risk score (wGRS) was generated from these two SNPs plus rs4268139. The highest tertile of wGRS was associated with an increased risk, with an adjusted OR of 1.36 (95% CI = 1.05-1.75, p for permutation test = .016) compared to the lowest wGRS. Furthermore, an additive interaction was seen between wGRS and drinking (attributable proportion due to interaction [AP] = 0.21, 95% CI = 0.02-0.43, p = .016). The additive interaction between wGRS and smoking approached near significance (AP = 0.15, 95% CI = 0.00-0.32, p = .045). INTS10 polymorphisms may contribute to the progression from HBV infection to HCC. More importantly, INTS10 polymorphisms interact with drinking and smoking to affect the progression.

Genetic variants in STAT4 and their interactions with environmental factors for the incidence of hepatocellular carcinoma.

BACKGROUND: A recent genome-wide association study (GWAS) has posed STAT4 as a promising susceptibility gene for hepatocellular carcinoma (HCC). However, the most significant variant in this GWAS, rs7574865, yielded inconsistent results. OBJECTIVE: This study, in a Southern Chinese population, was aimed to clarify the roles in HCC incidence of the rs7574865 and other two potentially functional variants, rs897200 and rs1031507 in STAT4. METHODS: This study enrolled 631 new HCC cases and 631 cancer-free controls. The genetic association was estimated using the multivariate logistic regression model. The pairwise gene-environment interactions were assessed using the multiplicative term in regression model and the "Delta" method for the additive scale. RESULTS: In the multivariate analysis, the rs7574865 TT genotype conferred a decreased risk of HCC compared to the GG genotype (adjusted OR = 0.62, 95%CI = 0.38∼0.99). The significant association of rs7574865 was also observed under the additive genetic model, with an adjusted OR of 0.81 (95%CI = 0.65∼0.99). Nevertheless, other two variants alone showed no significant association, as well as the haplotypes and genetic risk scores. Further analysis indicated a potential interaction between the rs897200 and alcohol drinking (P= 0.048 and 0.072 for additive and multiplicative interactions, respectively). Drinkers with the rs897200 CT+CC genotypes presented an increased disease-risk, as compared with non-drinkers carrying the TT genotype (adjusted OR = 1.68, 95%CI = 1.11∼2.54). CONCLUSIONS: The variant in STAT4, rs7574865, serves as a potential marker for predicting incidence of HCC. The rs897200 variant possibly interplays with alcohol drinking to alter HCC risk in the Southern Chinese, but warrants further investigation.

Effectiveness of porous silicon nanoparticle treatment at inhibiting the migration of a heterogeneous glioma cell population.

BACKGROUND: Approximately 80% of brain tumours are gliomas. Despite treatment, patient mortality remains high due to local metastasis and relapse. It has been shown that transferrin-functionalised porous silicon nanoparticles (Tf@pSiNPs) can inhibit the migration of U87 glioma cells. However, the underlying mechanisms and the effect of glioma cell heterogeneity, which is a hallmark of the disease, on the efficacy of Tf@pSiNPs remains to be addressed. RESULTS: Here, we observed that Tf@pSiNPs inhibited heterogeneous patient-derived glioma cells' (WK1) migration across small perforations (3 µm) by approximately 30%. A phenotypical characterisation of the migrated subpopulations revealed that the majority of them were nestin and fibroblast growth factor receptor 1 positive, an indication of their cancer stem cell origin. The treatment did not inhibit cell migration across large perforations (8 µm), nor cytoskeleton formation. This is in agreement with our previous observations that cellular-volume regulation is a mediator of Tf@pSiNPs' cell migration inhibition. Since aquaporin 9 (AQP9) is closely linked to cellular-volume regulation, and is highly expressed in glioma, the effect of AQP9 expression on WK1 migration was investigated. We showed that WK1 migration is correlated to the differential expression patterns of AQP9. However, AQP9-silencing did not affect WK1 cell migration across perforations, nor the efficacy of cell migration inhibition mediated by Tf@pSiNPs, suggesting that AQP9 is not a mediator of the inhibition. CONCLUSION: This in vitro investigation highlights the unique therapeutic potentials of Tf@pSiNPs against glioma cell migration and indicates further optimisations that are required to maximise its therapeutic efficacies.

Percutaneous endovenous intervention without vena cava filter for acute proximal deep vein thrombosis secondary to iliac vein compression syndrome: preliminary outcomes.

The aim is to report the preliminary outcomes of percutaneous endovenous intervention (PEVI) for acute proximal deep vein thrombosis (DVT) secondary to iliac vein compression syndrome (IVCS) without inferior vena cava filter (IVCF) placement. Acute DVT patients who underwent PEVI without IVCF were analyzed retrospectively. PEVI consisted of catheter-directed thrombolysis, manual aspiration thrombectomy, balloon angioplasty and stenting. CT was used to evaluate the left common iliac vein (LCIV). Sixty-two consecutive patients (17 men and 45 women, mean age, 59.4 ± 15.2 years) were enrolled. The compression percentage of the LCIV ranged from 51.7% to 95.2% (median 83.2%). Iliac DVT was present in 7 patients; iliofemoral, in 30 patients; and iliofemoropopliteal, in 25 patients. Complete technical success and clinical improvement were obtained in all subjects without the occurrence of symptomatic pulmonary embolism (PE). Five patients experienced recurrent thrombosis. The primary patency rates at 12 and 24 months were 93.8% and 91.4%, respectively, which remained stable at 36, 48 and 60 months. The secondary patency rates at 12 and 24 months were 95.7% and 93.3%, respectively, and there was no change at 60 months. Although limited, our preliminary results suggested that PEVI without IVCF placement seemed to be safe and effective for acute proximal DVT secondary to IVCS without inferior vena cava thrombosis or symptomatic PE.

Preclinical Nanomedicines for Polyglutamine-Based Neurodegenerative Diseases.

Polyglutamine (polyQ) diseases, such as Huntington's disease and several types of spinocerebellar ataxias, are dominantly inherited progressive neurodegenerative disorders and characterized by the presence of expanded CAG trinucleotide repeats in the respective disease locus of the patient genomes. Patients with polyQ diseases currently need to rely on symptom-relieving treatments because disease-modifying therapeutic interventions remain scarce. Many disease-modifying therapeutic agents are now under clinical testing for treating polyQ diseases, but their delivery to the brain is often too invasive (e.g., intracranial injection) or inefficient, owing to in vivo degradation and clearance by physiological barriers (e.g., oral and intravenous administration). Nanoparticles provide a feasible solution for improving drug delivery to the brain, as evidenced by an increasing number of preclinical studies that document the efficacy of nanomedicines for polyQ diseases over the past 5-6 years. In this review, we present the pathogenic mechanisms of polyQ diseases, the common animal models of polyQ diseases for evaluating the efficacy of nanomedicines, and the common administration routes for delivering nanoparticles to the brain. Next, we summarize the recent preclinical applications of nanomedicines for treating polyQ diseases and improving neurological conditions in vivo, placing emphasis on antisense oligonucleotides, small peptide inhibitors, and small molecules as the disease-modifying agents. We conclude with our perspectives of the burgeoning field of "nanomedicines for polyQ diseases", including the use of inorganic nanoparticles and potential drugs as next-generation nanomedicines, development of higher-order animal models of polyQ diseases, and importance of "brain-nano" interactions.

Recent Advances in c-Jun N-Terminal Kinase (JNK) Inhibitors.

c-Jun N-Terminal Kinases (JNKs), members of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, play a key role in the pathogenesis of many diseases including cancer, inflammation, Parkinson's disease, Alzheimer's disease, cardiovascular disease, obesity, and diabetes. Therefore, JNKs represent new and excellent target by therapeutic agents. Many JNK inhibitors based on different molecular scaffolds have been discovered in the past decade. However, only a few of them have advanced to clinical trials. The major obstacle for the development of JNK inhibitors as therapeutic agents is the JNKisoform selectivity. In this review, we describe the recent development of JNK inhibitors, including ATP competitive and ATP non-competitive (allosteric) inhibitors, bidentatebinding inhibitors and dual inhibitors, the challenges, and the future direction of JNK inhibitors as potential therapeutic agents.

Capsular Polysaccharide From Bacteroides fragilis Protects Against Ulcerative Colitis in an Undegraded Form.

The prominent human symbiont Bacteroides fragilis protects animals from intestinal diseases, such as ulcerative colitis, and its capsular polysaccharide plays a key role in reducing inflammation. B. fragilis strain ZY-312 was isolated from the feces of a healthy breast-fed infant, and the zwitterionic capsular polysaccharide zwitterionic polysaccharide, TP2, was extracted. In rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced enteritis, TP2 at an optimal dose of 2.5 mg/kg could significantly alleviate enteritis and reduced the degree of intestinal adhesions, the intestinal ulcer area, and the incidence of ulcers in rats. To understand the underlying mechanism, TP2 was labeled with Fluorescein isothiocyanate and orally administered at a dose of 2.5 mg/kg in rats. TP2 was mainly distributed in the cecum and colorectum, but it was not detected in the blood and other organs except that a compound with a molecular weight greater than that of TP2-FITC was found in liver tissue. During the absorption, distribution, metabolism, and excretion, TP2 was indigestible. These results were further confirmed by investigation in the simulated gastric, intestinal fluid, and colonic fluid with fecal microbiota in vitro, where TP2 remained unaltered at different time points. Furthermore, flora composition was analyzed in simulated colonic fluid with TP2 added and it was found that TP2 increased the abundance of Faecalibacterium, Enterococcus romboutsia, and Ruminococcaceae, whereas the abundance of the phylum Proteobacteria represented by Sutterella, Desulfovibrio, and Enterobacteriaceae was decreased. However, the amount of short-chain fatty acids in the simulated colonic fluid was not changed by intestinal flora post-TP2 addition. In conclusion, these findings confirmed that TP2, a capsular polysaccharide of B. fragilis, protects against ulcerative colitis in an undegraded form.

In Situ Surface Modification of Microfluidic Blood-Brain-Barriers for Improved Screening of Small Molecules and Nanoparticles.

Here, we have developed and evaluated a microfluidic-based human blood-brain-barrier (µBBB) platform that models and predicts brain tissue uptake of small molecule drugs and nanoparticles (NPs) targeting the central nervous system. By using a photocrosslinkable copolymer that was prepared from monomers containing benzophenone and N-hydroxysuccinimide ester functional groups, we were able to evenly coat and functionalize µBBB chip channels in situ, providing a covalently attached homogenous layer of extracellular matrix proteins. This novel approach allowed the coculture of human endothelial cells, pericytes, and astrocytes and resulted in the formation of a mimic of cerebral endothelium expressing tight junction markers and efflux proteins, resembling the native BBB. The permeability coefficients of a number of compounds, including caffeine, nitrofurantoin, dextran, sucrose, glucose, and alanine, were measured on our µBBB platform and were found to agree with reported values. In addition, we successfully visualized the receptor-mediated uptake and transcytosis of transferrin-functionalized NPs. The BBB-penetrating NPs were able to target glioma cells cultured in 3D in the brain compartment of our µBBB. In conclusion, our µBBB was able to accurately predict the BBB permeability of both small molecule pharmaceuticals and nanovectors and allowed time-resolved visualization of transcytosis. Our versatile chip design accommodates different brain disease models and is expected to be exploited in further BBB studies, aiming at replacing animal experiments.

Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.

Design, synthesis, and bioevaluation of pyrazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potent anticancer activities.

A series of Pyrazolo[1,5-a]Pyrimidine analogs were designed and synthesized as novel tubulin inhibitors. Among them, compounds 1a and 1b showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 24.8 nM and 28 nM, respectively. We determined the crystal structures of 1a and 1b in complex with tubulin and confirmed their direct binding to the colchicine site. Compounds 1a and 1b also effectively inhibited tubulin polymerization in vitro, induced cell cycle arrest in G2/M phase, and inhibited cancer cell migration. In addition, compound 1b exhibited high metabolic stability in human liver microsomes. Finally, 1b was highly effective in suppressing tumor growth in a B16-F10 mouse melanoma model without apparent toxicity. In summary, these results suggest that 1b represents a promising tubulin inhibitor worthy of further investigation.

Transferrin-targeted porous silicon nanoparticles reduce glioblastoma cell migration across tight extracellular space.

Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. Nanoparticles hold tremendous promise to overcome the pharmacokinetic challenges and off-target adverse effects. However, an inhibitory effect of nanoparticles by themselves on metastasis has not been explored. In this study, we developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Tf@pSiNP were colloidally stable, biocompatible, and their uptake into GBM cells was enhanced by receptor-mediated internalisation. The migration of Tf@pSiNP-exposed cells across the confined microchannels was suppressed, but unconfined migration was unaffected. The pSiNP-induced destabilisation of focal adhesions at the leading front may partially explain the migration inhibition. More corroborating evidence suggests that pSiNP uptake reduced the plasticity of GBM cells in reducing cell volume, an effect that proved crucial in facilitating migration across the tight confined tracts. We believe that the inhibitory effect of Tf@pSiNP on cell migration, together with the drug-delivery capability of pSiNP, could potentially offer a disruptive strategy to treat GBM.

SHCBP1 promotes cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway.

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting ß-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy.

Systematic Evaluation of Transferrin-Modified Porous Silicon Nanoparticles for Targeted Delivery of Doxorubicin to Glioblastoma.

There is a dire need to develop more effective therapeutics to combat brain cancer such as glioblastoma multiforme (GBM). An ideal treatment is expected to target deliver chemotherapeutics to glioma cells across the blood-brain barrier (BBB). The overexpression of transferrin (Tf) receptor (TfR) on the BBB and the GBM cell surfaces but not on the surrounding cells renders TfR a promising target. While porous silicon nanoparticles (pSiNPs) have been intensely studied as a delivery vehicle due to their high biocompatibility, degradability, and drug-loading capacity, the potential to target deliver drugs with transferrin (Tf)-functionalized pSiNPs remains unaddressed. Here, we developed and systematically evaluated Tf-functionalized pSiNPs (Tf@pSiNPs) as a glioma-targeted drug delivery system. These nanoparticles showed excellent colloidal stability and had a low toxicity profile. As compared with nontargeted pSiNPs, Tf@pSiNPs were selective to BBB-forming cells and GBM cells and were efficiently internalized through clathrin receptor-mediated endocytosis. The anticancer drug doxorubicin (Dox) was effectively loaded (8.8 wt %) and released from Tf@pSiNPs in a pH-responsive manner over 24 h. Furthermore, the results demonstrate that Dox delivered by Tf@pSiNPs induced significantly enhanced cytotoxicity to GBM cells across an in vitro BBB monolayer compared with free Dox. Overall, Tf@pSiNPs offer a potential toolbox for enabling targeted therapy to treat GBM.

Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway.

Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. However, it is unclear whether Ku80 regulates tumor growth in human melanoma. In this study, we screened a siRNA library targeting 6024 human genes and identified Ku80 as a potential therapeutic target in melanoma cells. Knockdown of Ku80 significantly suppressed melanoma cell proliferation and induced apoptosis, as well as enhanced the antitumor effect of melatonin in melanoma in vitro and in vivo. Overexpression of Ku80, however, promoted melanoma growth and increased the insensitivity of melanoma cells to melatonin. Mechanistically, we found that Ku80 bound to the PDK1 promoter and activated the transcription of PDK1. Moreover, we showed that the binding of Ku80 at the PDK-1 promoter was HIF1-α dependent, and melatonin degraded HIF1-α in melanoma cells. Furthermore, clinical data revealed that the expression of Ku80 and PDK-1 proteins were positively correlated and elevated in the tumor tissues of melanoma patients, and high expression of Ku80 predicted a poor prognosis in melanoma. Collectively, our study demonstrated that Ku80 promoted melanoma growth and regulated antitumor activity of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway, suggesting that Ku80 may be a potential molecular target for melanoma treatment.

TRIP4 promotes tumor growth and metastasis and regulates radiosensitivity of cervical cancer by activating MAPK, PI3K/AKT, and hTERT signaling.

Thyroid hormone receptor interactor 4 (TRIP4), a subunit of the tetrameric nuclear activating signal co-integrator 1 (ASC-1) complex, exerts pro-tumorigenic effects. The role for TRIP4 in the regulation of cervical cancer growth and radiation resistance is presently unknown. In this study, TRIP4 was found to be highly expressed in cervical cancer cells and tumor tissues. Knockdown of TRIP4 significantly suppressed cervical cancer cell proliferation and epithelial-mesenchymal transition (EMT), accompanied by inactivation of PI3K/AKT and MAPK/ERK signaling. TRIP4 was also found to target hTERT signaling by regulating its binding to the hTERT promoter. Moreover, the knockdown of TRIP4 increased cell sensitivity to radiation, concomitant with downregulation of Rad51 and p-H2AX. We also demonstrated in an in vivo study that the knockdown of TRIP4 effectively suppressed cervical cancer growth and progression in a xenograft tumor model, and these effects were concomitant with the downregulation of p-AKT, p-ERK, p-MEK1/2, MMP-9 and hTERT expression. Immunohistochemical analysis of tumor tissue microarrays showed that TRIP4 overexpression predicted poor prognosis in patients with cervical cancer. Collectively, these results show that TRIP4 plays an essential role in cervical cancer growth and survival.