Solid lipid nanoparticles as a drug delivery system to across the blood-brain barrier.

Solid lipid nanoparticles (SLNs) were prepared by biocompatible and biodegradable solid-phase lipids. ß-elemene is a safe natural essential oil with broad-spectrum anti-tumor activity. However, its clinical application has been adversely affected by its poor water solubility and limited bioavailability. SLN incorporation is a potential strategy to bypass the blood-brain barrier, the most important factor limiting the bioactivity of neurotherapeutics. The SLNs-ß has the same efficacy as commercially available elemene in vitro and an enhanced brain drug accumulation in vivo. The survival rate data was promising and acute toxicity experiment proved its safety. All these data suggested that SLN-ß is a safe and effective drug delivery system, especially for brain tumor therapy, and warrants further development.

MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer.

MircroRNAs are emerging as critical regulators in carcinogenesis and chemoresistance in multiple cancer types. In this study, we observed that the miR-944 level was upregulated in breast cancer patients' serum and tumor tissues, suggesting that miR-944 is a tumor promoter in breast cancer. To investigate the role of miR-944, we performed gain- and loss-of-function experiments in vitro. We then demonstrated that miR-944 promotes cell proliferation and tumor metastasis in breast cancer cell lines. Furthermore, we indicated that miR-944 is associated with cisplatin resistance by targeting BNIP3. Knockdown of the miR-944 by specific inhibitors significantly increased the cytotoxicity of cisplatin in cisplatin-resistant MCF-7 cells (MCF-7/R). Importantly, we found that the sensitization of miR-944 inhibitors to cisplatin cytotoxicity was abolished by BNIP3 siRNA which decreased the expression of BNIP3 gene. Finally, we demonstrated that miR-944 inhibitors promoted the loss of mitochondrial membrane potential (MMP) caused by cisplatin in MCF-7/R cells, resulting in the release of mitochondria-derived apoptogenic proteins into cytoplasm, and then, the caspase-3 was activated. In summary, our study showed that miR-944 functions as a novel oncogene and regulates the cisplatin resistance in breast cancer. The miR-944-BNIP3-MMP-caspase-3 pathway might be a novel target for the chemotherapy of breast cancer.

Estradiol induces HOTAIR levels via GPER-mediated miR-148a inhibition in breast cancer.

HOTAIR plays an important role in the regulation of cancer cell proliferation and cancer invasion in breast cancer. The up-regulation of HOTAIR has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. It has been reported that HOTAIR is regulated by estrogen (E2) via ERs in ER-positive breast cancer. However, it is unknown how HOTAIR is regulated in TN breast cancer. In this study, we found that HOTAIR was increased in the peripheral blood mononuclear cells and cancer tissues from breast cancer patients, and was especially higher in patients with metastatic breast cancer. In addition, we found that estrogen promoted HOTAIR through its receptor GPER and estrogen-induced breast cancer cell migration was reversed by deleting HOTAIR in TN breast cancer cells MDA-MB-231and BT549. Furthermore, we identified that E2-GPER induces the level of HOTAIR through the suppression of miR-148a. miR-148a level was negatively correlated with HOTAIR level in breast cancer patients. After the mutation of the predicted miR-148a binding sites in HOTAIR, miR-148a had no effect on HOTAIR. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to increase the HOTAIR level by inhibiting miR-148a in breast cancer.

Quercetin inhibits proliferation and invasion acts by up-regulating miR-146a in human breast cancer cells.

Breast cancer is the most common female malignancies in the world which seriously impacts the female health. In recent years, various studies have been reported to determine the relevance of miRNAs to human cancer. One of these miRNAs, miR-146a has been down-regulated in multiple human cancer types, but up-regulation showed inducing apoptosis. To determine the role of quercetin treated on breast cancer, we investigated the effect of quercetin on cell proliferation in human breast cancer cell lines MCF-7 and MDA-MB-231 with/without transfection of miR-146a mimic or anti-miR-146a. Furthermore, the expressions of bax and cleaved-caspase-3, mainly were increased in control and overexpression miR-146a groups, however, the expression of EGFR was inverse. All the results demonstrated that quercetin exhibited excellent effect on inhibiting cell proliferation in human breast cancer cells, which was performed by up-regulating miR-146a expression, then via inducing apoptosis through caspase-3 activation and mitochondrial-dependent pathways, and inhibiting invasion through down-regulating the expression of EGFR.

GPER mediated estradiol reduces miR-148a to promote HLA-G expression in breast cancer.

Breast cancer is the most common malignant diseases in women. miR-148a plays an important role in regulation of cancer cell proliferation and cancer invasion and down-regulation of miR-148a has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. However, the regulation mechanism of miR-148a is unclear. The role of estrogen signaling, a signaling pathway is important in development and progression of breast cancer. Therefore, we speculated that E2 may regulate miR-148a through G-protein-coupled estrogen receptor-1 (GPER). To test our hypothesis, we checked the effects of E2 on miR-148a expression in ER positive breast cancer cell MCF-7 and TN cancer cell MDA-MB-231. Then we used GPER inhibitor G15 to investigate whether GPER is involved in regulation of E2 on miR-148a. Furthermore, we analyzed whether E2 affects the expression of HLA-G, which is a miR-148a target gene through GPER. The results showed that E2 induces the level of miR-148a in MCF-7 and MDA-MB-231 cells, GPER mediates the E2-induced increase in miR-148a expression in MCF-7 and MDA-MB-231 cells and E2-GPER regulates the expression of HLA-G by miR-148a. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HLA-G expression through inhibiting miR-148a that supports immune evasion in breast cancer.

ChIP-seq analysis of androgen receptor in LNCaP cell line.

The aim of this study was to screen target genes and gene functions of androgen receptor (AR) in LNCaP cell line by ChIP-seq data analysis. We downloaded the gene expression profile GSE14092 from Gene Expression Omnibus database and selected ChIP-seq data (GSM353644) of AR stimulated by androgen R1881 (R1881 stimulation group) and the ChIP-seq data (GSM353643) of AR without R1881 stimulation (control group). MACS peak calling software was used to identify the AR binding cites. After target genes selection and function analysis, motif finding analysis was utilized to predict the AR co-located transcription regulation factors, and we analyzed their functions through GO enrichment analysis. Total 27202 and 2730 AR binding sites were detected in the R1881 stimulation group and the control group, respectively and 398 and 58 target genes were identified in R1881 stimulation group and control group, respectively. Based on GO enrichment analysis, 20 biological processes which AR regulated in the LNCaP cells were enriched, including xenobiotic metabolic process, positive regulation of interleukin-2 production and cellular response to sterol etc. We finally identified 99 transcription factors with high motif enrichment significant levels, and the enrichment of AR co-located transcription factors was significantly enriched in the biological process of regulation of cell proliferation in which 13 transcription factors were involved (FOXJ1, FOXM1, NF1, SOX2, HOXD13, FOXO1, FOXP3, FOXO4, SOX9, PGR, DBP, JUN and TLX1). The analysis of AR target genes and gene functions help us to elucidate the mechanism of the prostate cancer on a molecular level. In addition, it will pave the way to effective therapies for prostatic cancer. However, further experiments are still needed to confirm our results.

A Glutathione-Consuming Bimetallic Nano-Bomb with the Combination of Photothermal and Chemodynamic Therapy for Tumors: An in vivo and in vitro Study.

Background: Chemodynamic therapy (CDT) faces challenges of low catalytic ion efficiency and ROS production. We developed a ROS nano-bomb, Cu/ZIF-8@GA-Fe, to address these issues. Methods: The nano-bomb was synthesized by doping copper into ZIF-8 and assembling Fe3+ and gallic acid (GA). It was tested for reactive oxygen species (ROS) generation in acidic conditions and its photothermal properties. Results: In an acidic micro environment, Cu/ZIF-8@GA-Fe effectively released Fe3+ and Cu2+, depleting GSH and generating ROS. The GA-Fe coating provided photothermal heat and was used to enhance Fenton reactions via dual ions for increasing ROS production. In vivo and in vitro experiments, Cu/ZIF-8@GA-Fe inhibited tumor growth with minimal side effects. Conclusion: Cu/ZIF-8@GA-Fe shows promise for safe and effective CDT, offering a synergistic approach to tumor therapy.

New clinical application of high-intensity focused ultrasound: local control of synovial sarcoma.

High-intensity focused ultrasound (HIFU) is playing an increasingly important role in cancer therapy. Primary synovial sarcomas of the chest wall are extremely rare. We report the first case of noninvasive HIFU therapy for the control of synovial sarcoma. A 51-year-old man was diagnosed with spindle cell sarcoma on the left chest wall through lumpectomy. After four cycles of chemotherapy, local recurrence of the sarcoma was detected. Subsequent extended resection confirmed synovial sarcoma. After five cycles of a new chemotherapy option, the sarcoma relapsed again. Then the patient received five courses of HIFU; this completely ablated the sarcoma without complications. No chemotherapy, radiotherapy, or biological therapy has been applied since. Now the patient is stable and has a high quality of life.

Solid-pseudopapillary neoplasms of the pancreas: clinical and pathological features of 33 cases.

PURPOSE: Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, with a low potential for malignancy. The clinical and pathological features of 33 SPNs were reviewed. METHODS: This study conducted a retrospective analysis of 33 patients who underwent surgery for a pathologically confirmed SPN from 2000 to 2011. RESULTS: Thirty of the 33 patients (91 %) were female, and the median age at diagnosis was 29.2 years (range 12-59). The most common symptom was abdominal discomfort with dull pain (58 %). Others included asymptomatic lesions that were only detected incidentally during imaging (21 %), a palpable abdominal mass (15 %) and indigestion (6 %). All 33 patients underwent surgery with a curative intent and 3 (9 %) underwent laparoscopic surgery. The mean diameter of the tumors was 4.9 cm (range 2-15 cm), and they occurred in the head (9, 27 %), neck (5, 15 %), body or tail (19, 58 %) of the pancreas. One patient had lymph node metastases, one patient had portal venous invasion and 8 patients had perineural invasion. The patient follow-up ranged from 4 to 118 months, and 32 patients were alive and well without recurrence. One patient relapsed 10 months after distal pancreatectomy with splenectomy and underwent a second surgery via laparotomy. Unfortunately, the patient died of multiple organ failure 12 days after the second surgery. CONCLUSION: SPNs are rare neoplasms with malignant potential but excellent prognosis. Adequate surgical resection, including laparoscopic surgery, may therefore be performed safely and is associated with a long-term survival, even in invasive cases.

Enhanced lymph node retrieval from colorectal cancer resections using a simple lymphatic staining method.

BACKGROUND/AIMS: This study evaluated the effect of lymphatic staining on the number of lymph nodes (LNs) examined and staging in patients with colorectal cancer. METHODOLOGY: Sixty-two consecutive specimens from patients with colorectal cancer resected between February 2009 and April 2010 were randomized to the stained group or the control unstained. Differences in the retrieval, number and size of nodes, and time for retrieval were measured. RESULTS: LN harvest differed significantly with 30±12 and 13±5 (p<0.01) nodes in the stained and the control groups, respectively. Insufficient LN harvest (less than 12 nodes) occurred in 14 cases of the control group and only in 1 case of the stained group (p<0.01). Metastases were confirmed in 57 LNs occurring in 17 cases of the stained group and in 39 nodes occurring in 15 cases of the control group. The mean time for LN retrieval in the stained and control groups were comparable, 27.6±6.9min and 24.7±6.0min (p>0.05), respectively, yet there was a significant difference in the number of LNs (<2mm) (294 vs. 59, respectively, p<0.01) as well as in the number of LNs 2-5mm in size (474 vs. 220, respectively, p<0.01). CONCLUSIONS: By lymphatic staining method, more and smaller LNs could be detected, which significantly improved the LN harvest of resected colorectal specimens and reduced cases of insufficient LN harvest.

Neoadjuvant HIFU treatment for malignant fibrous histiocytoma: report of a case.

High-intensity focused ultrasound (HIFU) is an innovative, noninvasive, extracorporeal technique that induces coagulative necrosis of tumor tissue by thermal effects and cavitation. In published studies, HIFU has usually been used as an alternative to surgery, with or without other treatment modalities, to achieve curative tumor ablation or palliative tumor cytoreduction. Neoadjuvant HIFU treatment for primary inoperable malignant fibrous histiocytoma has never been reported, and neoadjuvant radiotherapy, chemoradiation, or chemotherapy is routinely under consideration. This is the first case in which HIFU ablation contributed as a neoadjuvant therapy to facilitate function-sparing resection, not as a replacement for surgery. It suggests that HIFU ablation may have some unique major advantages for treating inoperable huge soft-tissue sarcomas as a neoadjuvant local treatment modality, especially for patients for whom neoadjuvant chemotherapy or radiotherapy is not indicated.

[Corrigendum] Cyclophilin D modulates cell death transition from early apoptosis to programmed necrosis induced by honokiol.

Subsequently to the publication of the above article, the authors have realized that the printed version of Fig. 6 on p. 1661 contained some mistakes. Potential anomalies regarding this figure concerning the duplication of data both within Fig. 6 and comparing data between Figs. 5 and 6 were also drawn to our attention by an interested reader. Specifically, the authors realized that the bands of BCL­xl were erroneously selected from the GAPDH dataset during the process of compiling this figure. The authors subsequently found that the original photographs of these western blot bands had been lost during the time period that had elapsed since these experiments were completed. In order to corroborate the results, the authors repeated the contentious experiments shown in Fig. 6 and obtained similar results, thereby corroborating the results and conclusions reported in this study. A revised version of Fig. 6, containing the newly obtained data, is shown below. The errors made with the assembly of Fig. 6 originally did not have an adverse bearing on the overall conclusions reported in this study. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and all of the authors agree to the publication of this Corrigendum. The authors sincerely apologize for their errors, and apologize to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 42: 1654­1663, 2013; DOI: 10.3892/ijo.2013.1863].

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment.

Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.

Downregulation of miR­200c­3p contributes to the resistance of breast cancer cells to paclitaxel by targeting SOX2.

Acquisition of resistance to paclitaxel is a major obstacle to successful treatment of breast cancer patients, but the molecular mechanisms underlying the development of drug resistance remain largely unclear. The aim of the present study was to investigate the role and mechanism of action of miR­200c­3p in the resistance of breast cancer to paclitaxel. It was observed that miR­200c­3p expression, as determined by reverse transcription­quantitative polymerase chain reaction analysis, was significantly downregulated in paclitaxel­resistant MCF­7/Tax cells compared with parental MCF­7 cells. Overexpression of miR­200c­3p increased the chemosensitivity to paclitaxel and enhanced apoptosis in MCF­7/Tax cells, whereas the downregulation of miR­200c­3p exerted the opposite effect. In addition, upregulation of miR­200c­3p in MCF­7/Tax cells suppressed the expression of sex­determining region Y­box 2 (SOX2) at the mRNA and protein levels. Dual­luciferase reporter assay demonstrated that SOX2 is a target of miR­200c­3p in MCF­7/Tax cells. Moreover, knockdown of SOX2 expression increased chemosensitivity to paclitaxel and upregulated miR­200c­3p expression in MCF­7/Tax cells. Taken together, the results of the present study indicated that miR­200c­3p plays a key role in the development of paclitaxel resistance in breast cancer, possibly partially through regulating SOX2 expression, suggesting that the miR­200c­3p­SOX2 loop may serve as a potential target for the reversal of paclitaxel resistance in breast cancer.

MicroRNA-101 sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis via targeting Mcl-1.

MicroRNAs (miRNAs/miRs) are important regulators of multiple cellular processes, and their dysregulation is a common event in tumorigenesis, including the development of hepatocellular carcinoma (HCC). Studies have shown that certain miRNAs are associated with resistance to chemotherapy or drug sensitization; however, the underlying mechanisms have largely remained elusive. Multiple drug resistance is a major barrier for the treatment of advanced HCC. In the present study, miR-101 was observed to be downregulated in a panel of HCC cell lines, suggesting that it has a tumor suppressor role. Furthermore, transfection of miR-101 significantly enhanced the cytotoxicity of doxorubicin to HepG2 cells. While overexpression of miR-101 did not influence the accumulation of doxorubicin, it promoted the apoptosis-inducing effect of doxorubicin in HepG2 cells. A bioinformatics analysis predicted that miR-101 directly targeted the 3'-untranslated region of myeloid cell leukemia 1 (Mcl-1), which was verified by a luciferase reporter assay. Finally, transfection of HepG2 cells with Mcl-1 expression plasmid inhibited apoptosis caused by doxorubicin plus miR-101 expression. In conclusion, the present study showed that miR-101 is a negative regulator of Mcl-1 in HCC, and the combination of miR-101 expression with doxorubicin may represent a novel approach for the treatment of HCC.

Effect of Age on Breast Cancer Patient Prognoses: A Population-Based Study Using the SEER 18 Database.

BACKGROUND: Age is an important risk factor for breast cancer, but data regarding whether patient age at diagnosis is related to breast cancer survival are conflicting. This population-based study evaluated the effect of age on breast cancer prognosis and identified outcome-related factors. PATIENTS AND METHODS: We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled female primary non-metastatic cases. Patients were subdivided into seven groups, and analyses of the associations between age and overall survival (OS) and breast cancer-specific survival (BCSS) were carried out using the Kaplan-Meier method and Cox regression model, respectively. We also assessed differences in survival among three specific age groups, using the ages of 30 and 50 years as cut-offs. Stratified analyses regarding race, histology, grade, stage and hormone receptor status were also carried out. RESULTS: A total of 133,057 female patients diagnosed with breast cancer from 2004 to 2008 were included in the current study (6.4% <40 years), Women aged 40 to 49 years and 60 to 69 years exhibited significantly better OS and BCSS, respectively (log-rank, p<0.001), than their counterparts in other groups. Middle-aged women exhibited distinctly better OS (log-rank, p<0.001) and BCSS (log-rank, p<0.001) than their counterparts in the other two age groups. Following adjustments for potential confounding factors, middle-age at breast cancer diagnosis was shown to be an independent predictor of favourable outcomes in terms of OS, but not BCSS (for OS, HR, 0.92; 95%CI, 0.87-0.98; p = 0.007; for BCSS, HR, 0.94; 95%CI, 0.80-1.01; p = 0.075, using the young group as reference). Stratified analysis showed that middle-age was significantly associated with increased survival, except among patients with stage III disease, and that elderly women faced worse prognoses than younger patients. CONCLUSION: Our results indicate that younger breast cancer patients exhibit more aggressive disease than older patients. Middle-aged patients exhibit better OS and BCSS than young and elderly patients but exhibit BCSS rates similar to those of young patients after adjustments for confounders. Stratified analysis demonstrated that middle-aged patients exhibited better survival than young patients, with the exception of patients with stage III disease. An age of 60 years or more was a significant independent predictor of a poor prognosis.

MicroRNAs and drug resistance of breast cancer: basic evidence and clinical applications.

Breast cancer is the most common malignancy and leading cause of cancer mortality in women. Drug resistance is a major obstacle in systemic therapy of breast cancer, which leads therapeutic failure, incontrollable disease, and mortality. MiRNAs are an emerging field in cancer research. Recent evidence demonstrates that miRNAs are core regulators in drug resistance of breast cancer. Preclinical research reveals that miRNAs modulate the multidrug-resistant signal transduction network through up-regulated drug efflux transporters and anti-apoptotic proteins, acquisition of epithelial-mesenchymal transition, and formation of cancer stem cells. MiRNAs mediate endocrine resistance through modulating ERα expression, receptor tyrosine kinase signaling, cell survival signaling, and apoptosis. Such emerging evidence indicates that miRNAs could be potential biomarkers for predicting a response to systemic therapy and prognosis in clinical settings. Targeting specific miRNAs of the drug-resistant network is promising in overcoming drug resistance in breast cancer.

Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death.

Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety of human cancer cells through apoptosis and other forms of programmed cell death (such as programmed necrosis). Although much work has been done on its antitumor effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drug­resistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 µg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factor­κB (NF-κB) activation. Our data for the first time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.

Diaphragmatic perforation with colonic herniation due to hepatic radiofrequency ablation: A case report and review of the literature.

Radiofrequency ablation (RFA) has been widely accepted as an alternative treatment for unresectable primary and metastatic hepatic tumors, with satisfactory rates of local response and significant improvements in rates of overall survival. Numerous large series studies have shown that RFA is safe and effective, with a low mortality rate and a low major complication rate. Major complications, including diaphragmatic perforation and hernia, have rarely been previously reported. The current case report presents a case of diaphragmatic hernia with perforation of the incarcerated colon in the thoracic cavity 12 months following hepatic RFA, and reviews nine previously reported cases of diaphragmatic hernia. Comprehensive analysis of the nine cases demonstrated possibilities leading to diaphragmatic hernia following diaphragmatic thermal injury as a consequence of hepatic RFA. Clinicians and radiologists must consider diaphragmatic thermal damage following hepatic RFA for liver tumors adjacent to the diaphragm, particularly for patients with symptoms of ileus, dyspnea, chest pain, pleural effusion and right shoulder pain.

Jejunal intussusception and polyps with different types of malignant transformation in Peutz-Jeghers syndrome: Report of a case.

Intussusception and malignant polyps are complications of Peutz-Jeghers syndrome. Very few cases of intussusception combined with polyps with different types of malignant transformation in Peutz-Jeghers syndrome have been reported to date. In the present study, we describe a case of Peutz-Jeghers syndrome with jejunal intussusception and malignant hamartoma in the jejunum and descending colon, combined with mucinous adenocarcinoma in the sigmoid colon.