YTHDC1-Mediated lncRNA MSC-AS1 m6A Modification Potentiates Laryngeal Squamous Cell Carcinoma Development via Repressing ATXN7 Transcription.

Laryngeal squamous cell carcinoma (LSCC) has the highest mortality rate among head and neck squamous cell carcinoma. This study was designed to investigate the biological effect of long noncoding RNA (lncRNA) MSC antisense RNA 1 (MSC-AS1) on LSCC development and the underlying mechanism. The expression and prognostic value of lncRNAs in head and neck squamous cell carcinoma were predicted in the bioinformatics tools. The overexpression of MSC-AS1 in LSCC patients predicted a poor prognosis. Depletion of MSC-AS1 using shRNA repressed the malignant phenotype of AMC-HN-8 and TU-177 cells. MSC-AS1, mainly localized in the nucleus, interacted closely with the transcription factor CCCTC-binding factor (CTCF). CTCF played anti-tumor effects in vitro and in vivo. Ataxin-7 (ATXN7) was predicted to be a downstream target of CTCF, whose expression was negatively controlled by MSC-AS1. MSC-AS1 was found to block the expression of CTCF, thereby repressing ATXN7. Finally, MSC-AS1 overexpression in LSCC was governed by YTH domain-containing protein 1 (YTHDC1)-mediated m6A modification. In summary, our research identified the YTHDC1/MSC-AS1/CTCF/ATXN7 axis in LSCC development, which indicated that MSC-AS1 is an attractive biomarker in the LSCC treatment.

Oridonin inhibited epithelial-mesenchymal transition of laryngeal carcinoma by positively regulating LKB1/AMPK signaling.

Oridonin is the main bioactive component of Rabdosia rubescens, and its anticancer activity has been reported in a variety of cancers. However, the molecular mechanism of oridonin in laryngeal carcinoma remains unclear. In the present study, the cytotoxic effect of oridonin on laryngeal carcinoma Hep-2 and TU212 cell lines were initially detected by modified MTT assay. The results showed that oridonin had a dose-dependent anti-proliferative effect on laryngeal carcinoma Hep-2 and TU212 cells. Next, we found that oridonin significantly inhibited the migration and invasion of human laryngeal carcinoma Hep-2 and TU212 cell lines by wound healing assay and transwell assay. Subsequently, the results of quantitative real-time PCR assay and western blotting assay confirmed that oridonin upregulated the expression of E-cadherin while downregulated the expression of N-cadherin in a concentration-dependent manner at mRNA and protein levels. In addition, phosphorylation levels of liver kinase B1 (p-LKB1) and AMP-activated protein kinase (p-AMPK) were also elevated upon oridonin treatment. To further verify the role of LKB1/AMPK signaling pathway in laryngeal carcinoma, overexpression of LKB1 was constructed by plasmid transfection. The data exhibited that overexpression of LKB1 could further reinforce the increase of E-cadherin level and decrease of N-cadherin level mediated by oridonin. Additionally, AMPK inhibitor compound C could reverse anti-metastatic effect of oridonin on laryngeal carcinoma, and antagonise EMT expression. In contrast, AMPK activator AICAR presented the opposite effect. In conclusion, our study revealed that oridonin could remarkably reverse the epithelial-mesenchymal transition of laryngeal carcinoma by positively regulating LKB1/AMPK signaling pathway, which suggested that oridonin may be a potential candidate for the treatment of laryngeal carcinoma in the future.

[Corrigendum] Thymoquinone inhibits epithelial­mesenchymal transition in prostate cancer cells by negatively regulating the TGF­ß/Smad2/3 signaling pathway.

After the publication of the article, an interested reader drew to the authors' attention that the Du145 'Control' migration panel in Fig. 2C appeared to overlap with the Du145 'Control' invasion panel in Fig. 5A; furthermore, two of the Du145 panels in Fig. 5A also appeared to overlap. The authors have consulted their original data, and realize that these figures were inadvertently assembled incorrectly. The corrected versions of Figs. 2 and 5, incorporating the correct data for the Du145 'Control' panel in Fig. 2C, and the TQ­/TGF­ß OE­ invasion and migration panels, and the TQ+/TGF­ß OE+ migration panel, in Fig. 5A, are shown on the next page. These further corrections do not grossly affect the results or the conclusions reported in this work. The authors all agree to this Corrigendum, and are grateful to the Editor of Oncology Reports for granting them the opportunity to correct the errors that were made during the assembly of these figures. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [Oncology Reports 38: 3592­3598, 2017; DOI: 10.3892/or.2017.6012].

LKB1 inhibits proliferation, metastasis and angiogenesis of thyroid cancer by upregulating SIK1.

Purpose: Liver kinase B1 (LKB1), also known as serine/threonine kinase 11, was considered as a tumor suppressor, which exhibited anti-cancer activity in a variety of cancers. However, the effect of LKB1 in thyroid cancer remains unclear. Methods: In the study, MTT assay, colony formation assay, flow cytometry, western blot analysis, wound healing assay, transwell assays, quantitative real-time PCR, HUVEC migration assay, ELISA assay, tube formation assay and nude mice xenograft were used to investigate the anti-cancer capacity of LKB1 in thyroid cancer in vitro and in vivo. Results: In the present study, we found that the expression of LKB1 was lower in thyroid cancer tissues and cell lines, compared with the adjacent normal tissue and thyroid epithelial cell. After construction of stable clone cells with ectopic LKB1 overexpression, the findings revealed that LKB1 overexpression exerted anti-proliferative and pro-apoptotic property in thyroid cancer TPC-1 and BCPAP cells. In addition, LKB1 overexpression could inhibit migration and invasion, downregulate MMP2 and MMP9 expressions, and reverse EMT in thyroid cancer cells. Furthermore, overexpression of LKB1 attenuated HUVEC recruitment, decreased the expression of VEGFA and inhibited the formation of new vessels in thyroid cancer cells. To validate the underlying mechanism of LKB1 in thyroid cancer, the results showed that LKB1 could positively regulate SIK1 in thyroid cancer TPC-1 and BCPAP cells. Additionally, the SIK1 inhibitor HG-9-91-01 could partially abrogate the anti-proliferative and anti-metastatic effect of LKB1, and reverse MET (mesenchymal-to-epithelial transition) mediated by LKB1 overexpression. Ultimately, the results in vivo revealed that LKB1 overexpression exhibited a strong inhibitory effect of tumorigenicity and presented anti-angiogenic characteristic in nude mice xenograft model. Conclusion: the results demonstrated that LKB1 could inhibit proliferation, metastasis phenotype and angiogenesis, and reverse EMT in thyroid cancer in vitro and vivo via the upregulation of SIK1, suggesting that LKB1 could be considered as a potential therapeutic target for the treatment of thyroid cancer.

Oridonin represses epithelial-mesenchymal transition and angiogenesis of thyroid cancer via downregulating JAK2/STAT3 signaling.

Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to exert anticancer activity in various cancers. However, the molecular mechanism of oridonin in thyroid cancer has not yet been elucidated. In the present study, oridonin was found to significantly inhibit migration and invasion of thyroid cancer TPC-1 and BCPAP cells, as evidenced by wound healing assay, transwell migration assay and Matrigel invasion assay. In addition, oridonin could partially impede epithelial-mesenchymal transition by upregulating E-Cadherin expression and downregulating N-Cadherin and vimentin expressions in a concentration-dependent manner. Accumulating evidence indicated that JAK2 (Janus kinase-2)/STAT3 (Signal Transducer and Activator of Transcription 3) signaling pathway was associated with epithelial-mesenchymal transition. As expected, the protein levels of phosphorylated-JAK2 and phosphorylated-STAT3 were dramatically reduced upon oridonin treatment in thyroid cancer TPC-1 and BCPAP cells. Subsequently, the findings revealed that JAK2 overexpression could weaken the anti-metastatic effect and partially attenuate MET (mesenchymal-to-epithelial transition) by oridonin, while AG490, a JAK2 antagonist, enhanced the above process in thyroid cancer cells. The subsequent results showed that oridonin inhibited angiogenesis and VEGFA expression in thyroid cancer cells by tube formation assay, western blot and ELISA assay. Meanwhile, AG490 could further attenuate oridonin-treated VEGFA protein level. In addition, the in vivo results further confirmed that oridonin inhibited tumorigenicity in thyroid cancer xenograft. In conclusion, the results demonstrated that oridonin repressed metastatic phenotype, angiogenesis and modulated EMT (epithelial-mesenchymal transition) of thyroid cancer cells via the inactivation of JAK2/STAT3 signaling pathway, suggesting that JAK2 may be a novel therapeutic target of oridonin against thyroid cancer.

Long non-coding RNA AGAP2-AS1 promotes proliferation and metastasis in papillary thyroid cancer by miR-628-5p/KLF12 axis.

Long non-coding RNA (lncRNA) AGAP2-AS1 acts as an oncogene in several types of cancers. However, the role and mechanism of AGAP2-AS1 in papillary thyroid carcinoma (PTC) remain unclear. Thus, in this study, we aimed to explore the role of AGAP2-AS1 in PTC. Our results showed that AGAP2-AS1 was significantly upregulated in PTC tissues. Knockdown of AGAP2-AS1 inhibited the proliferation, migration and invasion of PTC cells. In vivo experiment showed that AGAP2-AS1 knockdown inhibited the tumorigenesis of PTC. MiR-628-5p was found to act as a target miRNA of AGAP2-AS1 in PTC. The expression level of miR-628-5p in PTC tissues was negatively associated with that of AGAP2-AS1. Inhibition of miR-628-5p attenuated the effects of AGAP2-AS1 knockdown on PTC. Moreover, miR-628-5p directly bound to the 3'UTR of KLF12 and inhibited the expression of KLF12. Knockdown of KLF12 enhanced the inhibitory effects of miR-628-5p on PTC cell proliferation and metastasis. In conclusion, these findings indicated that AGAP2-AS1 exerted an oncogenic role in PTC progression and metastasis. The effects of AGAP2-AS1 might be mediated by the regulation of miR-628-5p/KLF12 axis.

Oridonin inhibits epithelial-mesenchymal transition of human nasopharyngeal carcinoma cells by negatively regulating AKT/STAT3 signaling pathway.

Oridonin, derived from Rabdosia rubescens, has exhibited anticancer activity in a variety of cancers. However, few studies have explored the effect of oridonin (ORI) on migration, invasion and epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma. In our study, the results demonstrated that oridonin significantly inhibited migration and invasion of human nasopharyngeal carcinoma CNE-2Z and HNE-1 cell lines, as depicted by wound healing and Transwell assays. In addition, oridonin increased the expression of E-Cadherin while decreased the expressions of vimentin and twist1 at the mRNA and protein levels in a dose-dependent manner. Interestingly, oridonin also decreased cell mobility in nasopharyngeal carcinoma. The subsequent results of western blotting uncovered that the phosphorylation levels of AKT and signal transducer and activator of transcription 3 (STAT3) were decreased upon oridonin treatment. Furthermore, co-treatment with the AKT activator SC-79 attenuated the anti-metastatic effect of oridonin on nasopharyngeal carcinoma and partially abolished the high expression of E-cadherin and the low expression of twist1 mediated by oridonin. In conclusion, the results revealed that oridonin could repress metastatic phenotype and reverse epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma by negatively regulating AKT/STAT3 signaling pathway, suggesting that AKT/STAT3 signaling may be the potential therapeutic target of oridonin against nasopharyngeal carcinoma.

Helical nanofibers of N-(perfluorooctanoyl)cysteine ethyl ester in coordination polymers of Ag.

We propose using the formation of coordination polymers of Ag+ to probe differences between the perfluorinated alkyl chain and the alkyl chain by deriving a thiol ligand, N-(perfluoroalkanoyl)cysteine. Rapid formation in EtOH of P-/M-helical nanofibrils of high thermostability was found for N-(perfluorooctanoyl)-l-/d-cysteine ethyl esters at the µM level upon mixing with Ag+, but not for the octanoyl counterpart. This difference was also observed in terms of circular dichroism-enantiomeric excess dependence.

Oridonin Induces Apoptosis of Laryngeal Carcinoma via Endoplasmic Reticulum Stress.

PURPOSE: Oridonin, a bioactive diterpenoid derived from Rabdosia rubescens, has been widely reported to exhibit anticancer activity in multiple types of cancer. However, the molecular mechanism of oridonin in human laryngeal carcinoma has not been clearly elucidated. This study investigated the function of oridonin in laryngeal carcinoma to provide a research basis for laryngeal carcinoma therapy. METHODS: The proliferation of laryngeal carcinoma Hep-2 and TU212 cells treated with oridonin was determined by MTT assay. The apoptotic induction effect of oridonin on Hep-2 and TU212 cells was analyzed by flow cytometry, Western blot analysis and caspase3 activity assay. In addition, the caspase inhibitor, Z-VAD-fmk, was synergistically treated with oridonin to detect the function of caspase cascade in oridonin-mediated apoptosis. Then, the expressions of endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated-PERK, phosphorylated-eIF2α and CHOP) were measured in Hep-2 and TU212 cells by Western blotting. The cells were treated with 4-PBA (an ER stress inhibitor) or knockdown of CHOP to explore the role of ER stress in oridonin-mediated apoptosis in laryngeal carcinoma. Subsequently, a nude mouse xenograft model was constructed to confirm the function of oridonin in laryngeal carcinoma in vivo. RESULTS: Oridonin was found to significantly inhibit the proliferation of laryngeal carcinoma Hep-2 and TU212 cells in a concentration-dependent manner. Then, we confirmed that oridonin could induce apoptosis in human laryngeal carcinoma cells. The caspase inhibitor, Z-VAD-fmk, could partially reverse the pro-apoptotic effect of oridonin on human laryngeal carcinoma cells. Subsequently, Western blotting analysis demonstrated that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated-PERK, phosphorylated-eIF2α and CHOP) were up-regulated in Hep-2 and TU212 cells exposed to oridonin. In addition, 4-PBA (an ER stress inhibitor) or knockdown of CHOP could antagonize oridonin-induced apoptosis. Oridonin significantly decreased the tumorigenicity of Hep-2 cells in a nude mouse xenograft model. CONCLUSION: Oridonin-induced apoptosis of human laryngeal carcinoma through the activation of ER stress.

Downregulation of microR-147b represses the proliferation and invasion of thyroid carcinoma cells by inhibiting Wnt/ß-catenin signaling via targeting SOX15.

microRNA-147b (miR-147b) is a newly identified tumor-related miRNA that is dysregulated in multiple cancer types. Yet, the role of miR-147b in thyroid carcinoma remains unknown. Herein, we found that miR-147b expression was upregulated in thyroid carcinoma tissues and cell lines. miR-147b inhibition decreased the proliferation, colony formation, and invasion of thyroid carcinoma cells. The tumor suppressive gene SRY-related high-mobility-group box gene 15 (SOX15) was predicted as a miR-147b target gene. SOX15 expression was markedly decreased in thyroid carcinoma tissues and inversely correlated with the miR-147b expression. SOX15 overexpression repressed the proliferation and invasion of thyroid carcinoma cells associated with downregulation of Wnt/ß-catenin signaling. SOX15 knockdown abolished the miR-147b-inhibition-mediated antitumor effect. miR-147b inhibition or SOX15 overexpression retarded the tumor growth of thyroid carcinoma cells in vivo. Overall, our study suggests that miR-147b inhibition restrains the proliferation and invasion of thyroid carcinoma cells through upregulation of SOX15 and inhibition of Wnt/ß-catenin signaling.

Large-Area Exfoliated Lead-Free Perovskite-Derivative Single-Crystalline Membrane for Flexible Low-Defect Photodetectors.

Wide applications of personal consumer electronics have tended to cause a huge demand for smart and portable electronics, featuring mechanical flexibility, lightweight, and environmental friendliness. However, most of the recently reported flexible photodetectors based on microcrystalline and amorphous components commonly suffer from severe drawbacks, including plenty of grains, boundaries, and surface defects. Here, we present a new lead-free chiral perovskite-derivative light absorber of (aminoguanidinium)3Bi2I9 (AG3Bi2I9), which displays a narrow direct band gap of about 1.89 eV. High-quality bulk single crystals were successfully grown with dimensions up to 24 × 12 × 5 mm3. Emphatically, as-grown bulk single crystals are easy to be exfoliated for large-area ultrathin wafers with an exfoliated area up to 0.6 cm2, showing promise for low-defect flexible optoelectronic applications. The remarkable surface smoothness and crystalline quality of single-crystalline thin layers were further confirmed by TEM, HRTEM, AFM, single-crystalline X-ray diffraction, and space-charge limited current (SCLC) measurements. As expected, the planar photodetectors based on flexible exfoliated wafers are first fabricated and exhibit notable photoelectric performance. This work represents an important step forward as it offers an effective strategy for the fabrication of high-quality large-area flexible exfoliated wafer devices.

Thymoquinone inhibits metastatic phenotype and epithelial­mesenchymal transition in renal cell carcinoma by regulating the LKB1/AMPK signaling pathway.

Thymoquinone, isolated from the seeds of Nigella sativa, has exhibited antitumor properties in a variety of cancer types. However, few studies have investigated the effect of thymoquinone (TQ) on migration and invasion in renal cell carcinoma (RCC). In the present study, our results confirmed that TQ significantly inhibited the migration and invasion of the human RCC 769­P and 786­O cell lines, as demonstrated by wound healing and Transwell assays. Additionally, TQ upregulated the expression of E­cadherin and downregulated the expression of Snail, ZEB1 and vimentin at the mRNA and protein levels in a concentration­dependent manner. Subsequently, the phosphorylation levels of liver kinase B1 (LKB1) and AMP­activated protein kinase (AMPK) were increased upon TQ treatment. To further validate the role of LKB1/AMPK signaling, we revealed that TQ­mediated increase of E­cadherin level and reduction of Snail level could be further enhanced by LKB1 overexpression. Furthermore, co­treatment with the AMPK inhibitor Compound C attenuated the anti­metastatic effect of TQ on RCC and partially abrogated the high expression of E­cadherin and the low expression of Snail mediated by TQ. In contrast, the AMPK activator AICAR demonstrated the opposite effect. Collectively, the present study revealed that TQ could markedly suppress the metastatic phenotype and reverse the epithelial­mesenchymal transition in RCC by regulating the LKB1/AMPK signaling pathway, indicating that TQ may be a potential therapeutic candidate against RCC.

MicroRNA-30e protects the heart against ischemia and reperfusion injury through autophagy and the Notch1/Hes1/Akt signaling pathway.

The aim of the present study was to determine the cardioprotective mechanisms by which micro (mi)RNA-30e protects the heart from myocardial ischemia/reperfusion injury (MI/R) and to explore the signaling pathways that may confer protection for the heart and be potential therapeutic targets. It was demonstrated that miRNA­30e expression was decreased in patients with MI/R. In H9C2 cells, silencing (si)miRNA­30e significantly inhibited cellular apoptosis, the expression of apoptosis regulator BAX (Bax) and caspase­3 activity. It also significantly increased the expression of microtubule­associated proteins 1A/1B light chain 3B, p62, Beclin­1, neurogenic locus notch homolog protein­1 (Notch1), Hes1 and phosphorylated­protein kinase B (p­Akt), and decreased the expression of inducible NO synthase (iNOS) and proteins associated with oxidative stress. The inhibition of autophagy following treatment with 3­methyladenine significantly reversed the effect of si­miRNA­30e on apoptosis, Bax, caspase­3, iNOS and oxidative stress in H9C2 cells. The promotion of Notch1 expression increased the effect of si­miRNA­30e on apoptosis, Bax, caspase­3, iNOS, Notch1, Hes1 and p­Akt protein expression and oxidative stress in H9C2 cells. Taken together, these results indicate that miRNA­30e protects the heart from MI/R via autophagy and the Notch1/Hes1/Akt signaling pathway.

Clinical application of different operative approach of total knee replacement in knee valgus patients. Retrospective cohort study.

PURPOSE: According to the severity of knee valgus, different operative approaches were applied in total knee replacement. Hence, we assessed the safety and efficacy of different operative approaches in the level IV study. METHODS: From May 2011 to March 2014, a retrospectively analysis was conducted among 31 patients with knee valgus (mild in 10 cases, moderate in 8 cases and severe in 13 cases based on Keblish grade). Medial approach trip knee replacement was performed in mild and moderate patients, which were assigned as medial approach group. Lateral approach was performed in severe patients, which was assigned as lateral approach group. Relevant results were compared between medial approach group and lateral approach group, including valgus corrected angle, postoperative knee joint activity and Kss score. Furthermore, operative time, postoperative blood loss, patellar trajectory and anterior knee pain were also compared between the two groups. RESULTS: All operations were successful without obvious complications. In medial approach group, postoperative knee valgus angle was (7 ±â€¯1)°. Three months after operation, degree of knee joint activity was (85.2 ±â€¯5.2)°, and KSS score of knee joint was (80.1 ±â€¯5.2). Significant differences were detected in these compared with preoperative data (all P < .05). Moreover, similar results were found in lateral approach group with postoperative knee valgus angle as (8.2 ±â€¯2.3)°, degree of knee joint activity three months after operation as (85.2 ±â€¯5.3)°, and KSS score of knee joint as (80.3 ±â€¯3.2). However, no significant differences were found among these three groups in operative time, postoperative blood loss, patellar trajectory or anterior knee pain. CONCLUSIONS: Different operative approaches in total knee replacement according to the severity of knee valgus were proved as effective and safe procedures, which deserved further application.

HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-ß/Smad2 signaling pathway.

High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E­cadherin level was upregulated, while N­cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786­O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-ß and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-ß overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-ß deficiency impeded the pro­metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-ß-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.

Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells.

Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra is a traditional Chinese medicine and exerts anticancer capacity in various types of cancers. Previous studies have shown that tetrandrine induces apoptosis in bladder cancer cells via activation of the caspase cascade. However, the underlying mechanism has not yet been reported. Autophagy is a cellular process involved in the degradation of broken proteins and aging organelles to maintain homeostasis. Recent studies indicate that autophagy is implicated in cancer therapy. Thus, we focused on the correlation between autophagy and apoptosis upon tetrandrine treatment in human bladder cancer cells. Firstly, our results observed a marked increase in autophagic double-membrane vacuoles and fluorescent puncta of red fluorescence protein-green fluorescence protein-LC3 (GRP-RFP-LC3) upon tetrandrine treatment, as evidenced by transmission electron microscopy and confocal fluorescence microscopy. Secondly, the expression of LC3-II was increased in tetrandrine-treated T24 and 5637 cells in a time- and concentration-dependent manner. Subsequently, downregulation of p62 and LC3 turnover assay further confirmed that tetrandrine induced autophagic flux in bladder cancer T24 and 5637 cells. Thirdly, the protein levels of phosphorylated-AMP-activated protein kinase (AMPK) and phosphorylated-acetyl-coenzyme A carboxylase (ACC) were upregulated in the tetrandrine-treated cells, while the mammalian target of rapamycin (mTOR)-related proteins were downregulated. Moreover, AICAR, a common AMPK activator, further increased the expression the LC3-II, while AMPK inhibitor compound C partially reversed the LC3-II protein levels in bladder cancer T24 cells. Finally, AICAR significantly reinforced the growth inhibition and apoptosis induction of tetrandrine in T24 and 5637 cells, while compound C had an opposite effect, suggesting that AMPK-mediated autophagy enhanced the cytotoxic and pro-apoptosis effect of tetrandrine in human bladder cancer cells. Taken together, the present study showed that tetrandrine induced autophagy in human bladder cancer cells by regulating the AMPK/mTOR signaling pathway, which contributed to the apoptosis induction by tetrandrine, indicating that tetrandrine may be a potential anticancer candidate for the treatment of bladder cancer, and autophagy may be a possible mechanism for cancer therapy.

Thymoquinone inhibits epithelial-mesenchymal transition in prostate cancer cells by negatively regulating the TGF-ß/Smad2/3 signaling pathway.

Thymoquinone, a major ingredient of black seed oil (Nigella sativa), has been shown to exhibit anticancer capacity in various types of cancers. However, there are few studies concerning the correlation between thymoquinone and epithelial-to-mesenchymal transition (EMT) in prostate cancer. In the present study, we firstly found that thymoquinone showed antimetastatic capacity in prostate cancer DU145 and PC3 cells. Additionally, thymoquinone reversed EMT by increasing E-cadherin expression and decreasing vimentin and Slug expression in a concentration-dependent manner. Recent studies have shown that the transforming growth factor-ß (TGF-ß) signaling pathway may be associated with EMT. Intriguingly, the expression of TGF-ß, Smad2 and Smad3 at the mRNA and protein levels was notably reduced upon thymoquinone treatment in prostate cancer DU145 and PC3 cells. Subsequently, we confirmed that thymoquinone repressed metastasis and EMT of prostate cancer through downregulation of the TGF-ß/Smad2/3 signaling pathway, which may be partially reversed by TGF-ß overexpression. In summary, our findings demonstrated that thymoquinone suppressed the metastatic phenotype and reversed EMT of prostate cancer cells by negatively regulating the TGF-ß/Smad2/3 signaling pathway. These findings suggest that thymoquinone is a potential therapeutic agent against prostate cancer which functions by targeting TGF-ß.

A mathematical optimization model for efficient assignment of inpatients in an oncology center in China.

This paper addresses a problem for assignment of chemo-receiving inpatients in an oncology care center, which has not been addressed in the literature. Chemotherapy is regarded as one of the most effective treatments for cancer. In recent years, as cancer incidence increased, the number of patients admitted to a cancer treatment center has also been rising. How to balance the workload of medical service resources by planning admission of patients has become an essential problem that must be given consideration by policy- makers. The allocation of chemotherapy patients, different from that of the routine inpatients, is restrained by treatment agreements of patients and presents periodic features. Therefore, the allocation of chemotherapy patients is much more difficult than that of routine patients. A mixed integer programming (MIP) model was first formulated for this problem in order to maximize the usage of beds. Specific features of chemotherapy, such as chemotherapy protocols, were integrated into this model. The inpatient assignment problem was proved to be non-deterministic polynomial- complete and we propose an exact method to solve it. Numerical experiments on suitable use-case scenarios and a practical Chinese oncology center were performed to test and evaluate this model. The obtained results demonstrated the effectiveness of our method. Some useful managerial implication are provided for policy-makers through the analysis of obtained results. The models and methods suggested here can be effectively applied in similar departments of other countries and regions.

Integer programming for improving radiotherapy treatment efficiency.

BACKGROUND AND PURPOSE: Patients received by radiotherapy departments are diverse and may be diagnosed with different cancers. Therefore, they need different radiotherapy treatment plans and thus have different needs for medical resources. This research aims to explore the best method of scheduling the admission of patients receiving radiotherapy so as to reduce patient loss and maximize the usage efficiency of service resources. MATERIALS AND METHODS: A mix integer programming (MIP) model integrated with special features of radiotherapy is constructed. The data used here is based on the historical data collected and we propose an exact method to solve the MIP model. RESULTS: Compared with the traditional First Come First Served (FCFS) method, the new method has boosted patient admission as well as the usage of linear accelerators (LINAC) and beds. CONCLUSIONS: The integer programming model can be used to describe the complex problem of scheduling radio-receiving patients, to identify the bottleneck resources that hinder patient admission, and to obtain the optimal LINAC-bed radio under the current data conditions. Different management strategies can be implemented by adjusting the settings of the MIP model. The computational results can serve as a reference for the policy-makers in decision making.