The role of TRPV4 in programmed cell deaths.

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.

[Retracted] MicroRNA­338­3p functions as tumor suppressor in breast cancer by targeting SOX4.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the GAPDH control western blotting assay data shown in Figs. 5D and 6B, the cell­cycle data in Fig. 4A, the cell apoptotic data in Fig. 4B and the Transwell cell invasion assay in Fig. 3B were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to International Journal of Oncology, or were under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published previously, the Editor of International Journal of Oncology has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 47: 1594­1602, 2015; DOI: 10.3892/ijo.2015.3114].

Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.

Targeted Nanodrugs to Destroy the Tumor Extracellular Matrix Barrier for Improving Drug Delivery and Cancer Therapeutic Efficacy.

One of the main reasons why most cancer patients do not respond well to chemotherapy is that drugs cannot accumulate in tumors at an optimal dose, eventually resulting in failure to prevent cancer cell growth. To improve drug delivery efficiency, we engineered a highly efficient tumor-targeted and stroma-breaking nanocarrier by the modification of iron oxide nanoparticles (IONPs) with a tumor-targeting peptide c(RGDyK) and a hyaluronidase (HAase) on the surface. The yielding nanocomplex, c(RGDyK)-HAase-IONP, targeted the tumor by binding integrin αvß3 and went deeply into the tumors by the degradation of hyaluronic acid (HA), which was highly expressed in the tumor extracellular matrix (ECM). Good biostability and a low pH preferred drug release profile were characterized for c(RGDyK)-HAase-IONP carrying DOX in vitro. c(RGDyK)-HAase-IONP showed an improved tumor-targeting (2.5 times higher) effect after intravenous injection in the MC38 tumor-bearing mice model, as determined by whole-body fluorescence imaging compared to the non-targeted IONPs without HAase. After 5 systemic treatments, c(RGDyK)-HAase-IONP/DOX (5 mg/kg of equivalent dose of DOX) significantly inhibited MC38 tumor growth (22.1 ± 7.4 times relative to the non-treated group). Elevated apoptosis and reduced proliferation in the tumor cell were detected in the c(RGDyK)-HAase-IONP/DOX treated tumors compared to the control groups. Overall, the highly efficient targeted nanocarrier c(RGDyK)-HAase-IONP demonstrated tremendous potency for improving drug delivery and tumor therapy efficacy by targeted degradation of the dense HA barrier in the tumor ECM. We determined that such a tumor stroma-degrading nanosystem was capable of reducing tumor recurrence and drug resistance and could ultimately improve clinical tumor treatment responses.

Enzyme and Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanocomplex for Tumor Chemo-Photodynamic Therapy.

Introduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy. Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5ß-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy. Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model. Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.

A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma.

This study aimed to examine B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) in gastric adenocarcinoma (GAC) and its association with the maximal standard uptake value (SUVmax) of preoperative fluorine-18-fludeoosyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinicopathological data were retrospectively collected from 60 primary GAC patients. The Bmi-1 protein expression in GAC and adjacent noncancerous tissues was examined by immunohistochemistry and western blot analysis. Pearson's correlation analysis was conducted to assess the correlation between Bmi-1 expression and the SUVmax. The Bmi-1 protein levels were significantly greater in GAC versus noncancerous tissues, and higher Bmi-1 was significantly correlated with a lower degree of tumor differentiation, higher tumor stages, more lymph node metastasis, and depth of invasion. The SUVmax value was significantly correlated with the T stage, N stage, and clinical stage, but not with age, gender, tumor size, histological differentiation degree, or Lauren classification. Moreover, a significant positive correlation between Bmi-1 and SUVmax was observed in GAC tissues. In conclusion, our findings demonstrate a novel correlation between Bmi-1 and preoperative SUVmax in GAC patients who did not receive radiotherapy, chemotherapy, or targeted treatment before surgery, and both are positively correlated with unfavorable prognostic factors and a higher grade of malignancy.

Hyaluronidase responsive second near-infrared fluorescent nanocomplex for combined HER2 blockade and chemotherapy of HER2+ breast cancer.

The human epidermal growth factor receptor-2-positive (HER2+) type is aggressive and has poor prognosis. Although anti-HER2 therapy alone or in combination with other treatment regimens showed significant improvement in survival outcomes, breast cancer patients are still suffering from tumor relapse and severe dose-limiting side effects. Thus, there is still an unmet challenge to develop effective therapeutic agents for HER2+ breast cancer treatment with minimized side effects. Herein, we produced a stimuli-responsive and tumor-targeted hyaluronic acid (HA) nanocomplex that combined HER2 blockade and chemotherapy for effective HER2+ breast cancer therapy. A hydrophobic NIR-II dye, IR1048, was covalently linked with HA to form a spherical HA-IR1048 nanoparticle (HINP), with Herceptin conjugated on the surface and paclitaxel (PTX) encapsulated inside. The fluorescent signals from the yielding Her-HINP/PTX are quenched originally, but a strong NIR-II signal is generated when HINP is degraded by the hyaluronidase that is overexpressed in breast tumors, thus allowing the tracking and visualization of Herceptin and PTX accumulation. Her-HINP/PTX peaked in HER2+ tumors at 24 h post injection as imaged by NIR-II fluorescent imaging. A significantly improved tumor growth inhibition effect was observed after five systemic treatments compared to single PTX (3.71 ± 0.41 times) or Herceptin (5.98 ± 0.51 times) treatment in a HER2-overexpressed breast cancer mouse model with prolonged survival. Collectively, the designed Her-HINP/PTX presents a new hyaluronidase-responsive and HER2 blockade nanoformulation that can visualize the accumulation of nanocomplexes and release drugs inside tumors for combined HER2+ breast cancer therapy with a great promise for translational study. STATEMENT OF SIGNIFICANCE: The high expressions of a protein called human epidermal growth factor receptor 2 (HER2) in breast tumors make this subtype of cancer aggressive. Currently, chemotherapy combined with a HER2 antibody, Herceptin, is a preferred approach for HER2-positive breast cancer therapy. However, these breast cancer patients still suffer from tumor relapse and severe side effects because various therapeutic agents have inherent different biodistributions, resulting in insufficient treatment effects and unfavorable normal organ uptake of these therapeutic agents. Herein, we produced a nanocomplex carrying both Herceptin and chemotherapy drug to simultaneously deliver two drugs into tumors for efficient HER2+ tumor treatment with minimized side effects, providing new insights for designing a combined therapy strategy.

Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma.

This study aimed to investigate whether and how Moloney murine leukemia virus integration site 1 (Bmi-1) plays a role in the regulation of glucose transporter 1 (GLUT1) in gastric adenocarcinoma (GAC). GAC and matched noncancerous tissues were obtained from GAC patients who underwent surgical treatment at the China-Japan Union Hospital, Jilin University (Changchun, Jilin, China). The human GAC cell line AGS and the gastric epithelial cell line GES-1 were used for in vitro studies. BALB/c nude mice were used for in vivo studies. The Bmi-1 and GLUT1 protein levels were significantly greater in human tissues from GAC patients and AGS cells in comparison with controls. Silencing of Bmi-1 resulted in significant decrease in glucose uptake, lactate levels, and GLUT1 expression. In vivo 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging studies indicated that the nude mice bearing xenografts of AGS cells treated with Bmi-1-specific small interfering RNA (siRNA) had a significantly lower maximum standardized uptake value (SUVmax) in comparison with the control mice. Thus, Bmi-1 directly upregulates GLUT1 gene expression, through which it is involved in enhancing glucose uptake in GAC. The results also provide scientific evidence for 18F-FDG PET/CT imaging to evaluate Bmi-1 and glucose uptake in GAC.

Three-dimensional imaging for the localization of related anatomical structures during surgery on the internal auditory canal.

BACKGROUND: The Fisch infra-temporal fossa approach (Fisch's method), first proposed in 1970, is commonly used during internal auditory canal (IAC) surgery with an approach that advances through the middle cranial fossa. This study was designed to address the technical difficulties encountered in recognizing and localizing the arcuate eminence with respect to the superior semicircular canal (SSC). METHODS: Forty men and 40 women (18-57 years of age) without space-occupying lesions in the petrous part of the temporal bone were selected for the study. In total, 160 samples were obtained from both sides of the temporal bone. The temporal bone in these 160 samples was scanned using computed tomography, and a three-dimensional coordinate system was established to measure the three-dimensional coordinate values of structures adjacent to the arcuate eminence, the SSC, and the IAC. RESULTS: The results showed that the shape of the arcuate eminence is highly variable. Approximately 23.12% of samples had no obvious arcuate eminence, which prevented the use of Fisch's method to localize the SSC. The arcuate eminence was difficult to identify in 37 samples. CONCLUSIONS: Analysis samples showed that the SSC was located in a fan ring centered at the midpoint of the upper edge of the petrous portion of the temporal bone. The arcuate eminence did not correspond directly with the SSC, as the former was located posterolateral to the latter in 85.83% of samples. The angle between the SSC and the IAC ranged from 0° to 60° degrees, as reported previously by Fisch. However, the angle typically ranged from 10-30° in our study.

LTB4 Promotes Acute Lung Injury via Upregulating the PLCε-1/TLR4/NF-κB Pathway in One-Lung Ventilation.

BACKGROUND: Mechanical ventilation (MV) can provoke acute lung injury (ALI) by increasing inflammation activation and disrupting the barrier in lung tissues even causing death. However, the inflammation-related molecules and pathways in MV-induced ALI remain largely unknown. Hence, the purposes of this study are to examine the role and mechanism of a novel inflammation-related molecule, leukotriene B4 (LTB4), in ALI. METHODS: The functions of LTB4 in one-lung ventilation (OLV) model were detected by the loss-of-function experiments. H&E staining was used to examine the pathologic changes of lung tissues. Functionally, PLCε-1 knockdown and Toll-like receptor 4 (TLR4)/NF-κB pathway inhibitor were used to detect the regulatory effects of LTB4 on the phospholipase Cε (PLCε-1)/TLR4/nuclear factor-kappa B (NF-κB) pathway. The levels of genes and proteins were determined by RT-qPCR and western blotting assay. The levels of inflammation cytokines and chemokines were measured by ELISA. RESULTS: Here, we found LTA4H, leukotriene B (4) receptor 1 (BLT1), LTB4, and PLCε-1 upregulated in OLV rats and associated with inflammatory activation and lung permeability changes of lung tissues. Inhibition of LTB4 alleviated the OLV-induced ALI by inhibiting inflammatory activation and lung permeability changes of lung tissues. For mechanism analyses, LTB4 promoted OLV-induced ALI by activating the PLCε-1/TLR4/NF-κB pathway. CONCLUSION: LTB4 induced ALI in OLV rats by activating the PLCε-1/TLR4/NF-κB pathway. Our findings might supply a new potential therapeutic for OLV-induced ALI.

NIR-II Fluorescent Activatable Drug Delivery Nanoplatform for Cancer-Targeted Combined Photodynamic and Chemotherapy.

Nanotheranostics with integrated imaging functions can help monitor nanoparticle accumulation in tumors, thus achieving synergism and higher therapeutic accuracy in cancer therapy. However, it remains challenging to monitor the release of therapeutic drugs in real time from a nanoparticulate drug delivery system (nano-DDS) in the body. Herein, we developed a nano-DDS for fluorescence imaging in the second near-infrared window (NIR-II) region, which can be used for monitoring the responsive release of drugs and cancer-targeted combined photodynamic and chemotherapy. There is a linear correlation between the cumulative release of the drug and the NIR-II fluorescence intensity. Moreover, hyaluronidase/glutathione dual-response RGD-SS-DOX/Ce6@HA-IR-1061 (RSSDCHI) exhibited a higher tumor-to-normal-tissue ratio in NIR-II fluorescence imaging and enhanced antitumor efficacy in vivo. This makes it possible to visualize drug release at the cellular level by the nanocomposites and to predict the treatment effect according to the NIR-II fluorescence intensity in the tumor site, serving as a promising nanoplatform for precision nanomedicine.

Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine-Refractory Differentiated Thyroid Cancer: The REALITY Randomized Clinical Trial.

IMPORTANCE: Patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options. OBJECTIVE: To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020. INTERVENTIONS: Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib. MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy. RESULTS: Of the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])-none of which occurred in the placebo group. CONCLUSIONS AND RELEVANCE: The REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03048877.

[Retracted] miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Figs. 4C, 5B and 6D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 34: 2202­2210, 2015; DOI: 10.3892/or.2015.4165].

An Integrin-αvß6/α5ß1-Bitargeted Probe for the SPECT Imaging of Pancreatic Adenocarcinoma in Preclinical and Primary Clinical Studies.

Pancreatic adenocarcinoma (PA) is one of the deadliest human malignancies. However, early detection, prediction of surgical resectability, and prognosis of PA are challenging with current conventional imaging technologies in the clinic. Molecular imaging technologies combined with novel imaging probes could be useful for early detection and accurate staging of PA. Integrin αvß6 and α5ß1 are found to be overexpressed in PA. In this study, integrin αvß6/α5ß1-bitargeted probes 99mTc-HYNIC-isoDGR (99mTc-isoDGR) and 99mTc-HYNIC-PEG4-PisoDGR2 (99mTc-3PisoDGR2) were prepared and evaluated in the BxPC-3 human pancreatic tumor model. Both subcutaneous and in situ BxPC-3 tumors could be clearly visualized by 99mTc-isoDGR nanoScan SPECT/CT imaging with a high ratio of tumor to background. The blocking study with excess nonradioactive peptide showed a significantly reduced tumor uptake, which confirmed the specificity of 99mTc-isoDGR. Biodistribution results confirmed the imaging results. The dimer tracer 99mTc-3PisoDGR2 significantly enhanced tumor uptake compared with 99mTc-isoDGR, and the spontaneous PA lesion in the mouse model could be clearly visualized by 99mTc-3PisoDGR2. The primary clinical study also verified the ability of 99mTc-3PisoDGR2 for detection of PA. Therefore, SPECT/CT imaging using the integrin αvß6/α5ß1-bitargeted 99mTc-3PisoDGR2 provided a potential approach for the noninvasive detection of PA.

Silencing long non-coding RNA MEG8 inhibits the proliferation and induces the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Even though long non-coding RNA (lncRNA) MEG8 plays vital roles in carcinogenesis of malignances, its roles and mechanisms in hemangioma remain unknown. Therefore, we evaluate the oncogenic roles of MEG8 in hemangioma. Small interfering RNA (siRNA)-mediated depletion of MEG8 inhibited the proliferation and increased MDA level in human hemangioma endothelial cells (HemECs). The inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) abolished the MEG8 silence induced cell viability loss. Knockdown of MEG8 increased the miR-497-5p expression and reduced the mRNA and protein levels of NOTCH2. Using a dual-luciferase assay, we confirmed the binding between MEG8 and miR-497-5p, and between the miR-497-5p and 3'UTR of NOTCH2. We further found that silencing MEG8 significantly decreased the expressions of SLC7A11 and GPX4 both in mRNA and protein level and had no effect on the level of AIFM2. Importantly, blocking miR-497-5p abrogated the effects of MEG8 loss on cell viability, MDA level and expression levels of NOTCH2, SLC7A11 and GPX4 in HemECs. Taken together, our results suggested that knockdown of long non-coding RNA MEG8 inhibited the proliferation and induced the ferroptosis of hemangioma endothelial cells by regulating miR-497-5p/NOTCH2 axis.

Ultrathin gold nanowires to enhance radiation therapy.

BACKGROUND: Radiation therapy is a main treatment option for cancer. Due to normal tissue toxicity, radiosensitizers are commonly used to enhance RT. In particular, heavy metal or high-Z materials, such as gold nanoparticles, have been investigated as radiosensitizers. So far, however, the related studies have been focused on spherical gold nanoparticles. In this study, we assessed the potential of ultra-thin gold nanowires as a radiosensitizer, which is the first time. METHODS: Gold nanowires were synthesized by the reduction of HAuCl4 in hexane. The as-synthesized gold nanowires were then coated with a layer of PEGylated phospholipid to be rendered soluble in water. Spherical gold nanoparticles coated with the same phospholipid were also synthesized as a comparison. Gold nanowires and gold nanospheres were first tested in solutions for their ability to enhance radical production under irradiation. They were then incubated with 4T1 cells to assess whether they could elevate cell oxidative stress under irradiation. Lastly, gold nanowires and gold nanoparticles were intratumorally injected into a 4T1 xenograft model, followed by irradiation applied to tumors (3 Gy/per day for three days). Tumor growth was monitored and compared. RESULTS: Our studies showed that gold nanowires are superior to gold nanospheres in enhancing radical production under X-ray radiation. In vitro analysis found that the presence of gold nanowires caused elevated lipid peroxidation and intracellular oxidative stress under radiation. When tested in vivo, gold nanowires plus irradiation led to better tumor suppression than gold nanospheres plus radiation. Moreover, gold nanowires were found to be gradually reduced to shorter nanowires by glutathione, which may benefit fractionated radiation. CONCLUSION: Our studies suggest that gold nanowires are a promising type of radiosensitizer that can be safely injected into tumors to enhance radiotherapy. While the current study was conducted in a breast cancer model, the approach can be extended to the treatment of other cancer types.

Modulation of TRPV4 and BKCa for treatment of brain diseases.

As a member of transient receptor potential family, the transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which belongs to non-voltage gated Ca2+ channel. Large-conductance Ca2+-activated K+ channel (BKCa) represents a unique superfamily of Ca2+-activated K+ channel (KCa) that is both voltage and intracellular Ca2+ dependent. Not surprisingly, aberrant function of either TRPV4 or BKCa in neurons has been associated with brain disorders, such as Alzheimer's disease, cerebral ischemia, brain tumor, epilepsy, as well as headache. In these diseases, vascular dysfunction is a common characteristic. Notably, endothelial and smooth muscle TRPV4 can mediate BKCa to regulate cerebral blood flow and pressure. Therefore, in this review, we not only discuss the diverse functions of TRPV4 and BKCa in neurons to integrate relative signaling pathways in the context of cerebral physiological and pathological situations respectively, but also reveal the relationship between TRPV4 and BKCa in regulation of cerebral vascular tone as an etiologic factor. Based on these analyses, this review demonstrates the effective mechanisms of compounds targeting these two channels, which may be potential therapeutic strategies for diseases in the brain.

Barium tungstate nanoparticles to enhance radiation therapy against cancer.

High-Z nanoparticles have emerged as a novel type of radiosensitizers due to their relatively large X-ray cross-section and ability to enhance radical production under irradiation. Recently, CaWO4 nanoparticles have been prepared and their potential as a radiosensitizer has been demonstrated. Herein, we investigated BaWO4 nanoparticles as a novel type of alkaline-earth metal tungstate radiosensitizer for radiotherapy (RT). We synthesized BaWO4 nanoparticles using hydrothermal reaction and coated them with polyvinylpyrrolidone (PVP). We found that BaWO4 nanoparticles could more efficiently enhance hydroxyl radical production under irradiation than CaWO4 nanoparticles. When tested in vitro, BaWO4 nanoparticles showed lower toxicity than CaWO4 nanoparticles in the absence of irradiation, but induced more significant oxidative stress under irradiation. When tested in vivo, BaWO4 nanoparticles led to more efficient tumor inhibition without causing systemic toxicity. Overall, our results suggest that BaWO4 nanoparticles can efficiently enhance RT and hold great potential as a novel type of radiosensitizing agent.