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The process of shock wave focusing can make the strength of shock waves be continuously accumulated and turned into detonation wave in Pulse Detonation Engine (PDE). However, its effective application needs the inlet jets be in high temperature and velocity, which is difficult to be satisfied under certain conditions. Therefore, in this paper, metal magnesium assisted detonation initiation is proposed and the effect of magnesium particle addition on the shock wave focusing process in a kerosene-fueled PDE with cavity configuration is investigated through numerical simulation. The result showed that when the temperature of the premixed fuel/air jets injected in opposite direction was set as 650 K, the collision of leading shock waves on the central axis was the main source of energy deposition and the shock wave focusing could make the detonation be initiated in the cavity. When the temperature of jets is reduced to 550 K, fuel ignition and detonation could not be achieved through shock wave focusing. Then adding metal magnesium particles into the combustor made the energy deposition be enhanced and the detonation be induced. The diffusion of metal particles can significantly change the structure, motion, merging and dissipation of vortices in the flow field. Generally, the shock wave focusing process is basically not affected with metal particles injection. Therefore, this method can be successfully employed for detonation initiation in the cavity when the fuel/air premixed jet temperature is not high for PDE.

The anisotropic fibers of wood will lead to a macroscopic anisotropic property in both mechanical strength and heat transfer. Previous experimental studies of wood materials were mainly focused on the mechanical property while their anisotropic thermal property is still lacking. In this research, the anisotropic thermal performance of spruce wood is studied at different temperature, humidity and mechanical load. The one-dimensional steady-state method and the transient plane source method are adopted to conduct the test. The thermal conductivity both in-plane and outside-of-plane of spruce wood at temperature ranging from 25 to 422 ℃, relative humidity ranging from 30–90% RH and mechanical load ranging from 0 to 20 MPa are obtained. The accuracy of the TPS method is validated using the 1D steady-state method. Both methods can be utilized to gauge the anisotropic thermal conductivity of spruce wood. Due to the unidirectional distribution of fiber, spruce wood has an outside-of-plane thermal conductivity that is roughly three times greater than its in-plane thermal conductivity. Among environmental conditions of temperature, humidity and mechanical load, the thermal conductivity of spruce wood are varied with temperature more significantly, which is followed by humidity and mechanical load. The measurement uncertainty is also discussed.

Ibrutinib significantly sensitizes ABCB1-overexpressing cells to vincristine and colchicine.

Ibrutinib significantly sensitizes ABCC10-overexpressing cells to vincristine.

Cytotoxicity assays of ibrutinib alone in the drug-resistant and parental cells.

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.

Table S1. Key reagents used in the experiments described in this manuscript are listed. Table S2. Major driver mutations in colon cancer cell lines described in this manuscript are listed. Figure S1. BETi induced expression of DR5, DCR1, and DCR2, but not DR4, in HCT116 colon cancer cells. The induction of DR5 by BETi did not require p53, but involved CHOP induction and eIF2-alpha phosphorylation. Figure S2. BRD4 knockdown or inhibition in combination with 5-FU or oxaliplatin markedly suppressed the growth of colon cancer cells. The combination treatments strongly induced apoptosis and caspase activation. Caspase inhibition by z-VAD-fmk suppressed the effects of the combination treatments. Figure S3. DR5-KO in HCT116 and RKO colon cancer cells abrogated the chemosensitization effects of BRD4 knockdown and BETi. Apoptosis and caspase activation were suppressed in DR5-KO HCT116 and RKO cells. Figure S4. Transfecting BRD4 siRNA induced DR5 and CHOP expression in SPOP-mutant SNU-407 and NCI-H508 cells. Figure S5. Transfecting HCT116 and RKO cells with E47A or E50K mutant SPOP increased BETi sensitivity, and enhanced BETi-induced apoptosis and caspase activation. The effects of SPOP mutants were suppressed in DR5-KO HCT116 and RKO cells. Figure S6. 5-FU/JQ1 combination suppressed the growth of PDX tumors without affecting animal weight. The combination treatment enhanced cell death analyzed by TUNEL staining.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal cancer (CRC). However, the mechanism by which NSAIDs suppress colorectal tumorigenesis remains unclear. We previously showed that NSAIDs selectively kill emerging tumor cells via death receptor (DR) signaling and a synthetic lethal interaction mediated by the proapoptotic Bcl-2 family protein BID. In this study, we found NSAIDs induce endoplasmic reticulum (ER) stress to activate DR signaling and BID in tumor suppression. Importantly, our results unveiled an ER stress- and BID-dependent immunogenic effect of NSAIDs, which may be critical for tumor suppression. NSAID treatment induced hallmarks of immunogenic cell death (ICD) in CRC cells and colonic epithelial cells upon loss of APC tumor suppressor, and elevated tumor-infiltrating lymphocytes (TILs) in the polyps of APCMin/+ mice. ER stress inhibition or BID deletion abrogated the antitumor and immunogenic effects of NSAIDs. Furthermore, increased ER stress and TILs were detected in human advanced adenomas from NSAID-treated patients. Together, our results suggest that NSAIDs induce ER stress- and BID-mediated ICD to restore immunosurveillance and suppress colorectal tumor formation.

PurposeDrawing on leader-member exchange theory and regulatory focus theory, the purpose of this study is to explore the effects of hotel employees’ regulatory foci on their voice behavior and the moderating role of leader-member exchange.Design/methodology/approachThe questionnaire includes demographics, regulatory foci, leader-member exchange and voice behavior sections. The data was collected via a survey of 10 international tourist hotels in Taiwan and 479 valid questionnaires were completed. Confirmatory factor analysis and path analysis were used to test the composite reliability, discriminant validity and convergent validity. Multiple regression analysis was used to test the hypotheses.FindingsThe outcome of this study indicates that both promotion focus and prevention focus can benefit employees’ voice behavior; however, prevention-focused employees have more positive voice behavior than promotion-focused employees. In addition, the leader-member exchange can moderate the relationship between regulatory foci and voice behavior.Originality/valueThis is an empirical study in the hotel field to examine the moderating effects of leader-member exchange on the relationships between regulatory foci and voice behavior. This research is contributed toward human resource management literature in the hospitality and tourism domain. Practices for managers and suggestions for future research are discussed.

Supplemental material, sj-docx-1-jtr-10.1177_00472875211067548 for The Matching Effect of Destinations��� Crisis Communication by Jiangchi Zhang, Chaowu Xie, Yanying Chen, You-De Dai and Wang Yi-Jun in Journal of Travel Research

Two new coordination polymers, [Zn(3-NDI)0.5(NDC)(DMF)]n (1) and {[Zn1.5(3-NDI)0.5(BDC)1.5]·2.5DMF}n (2), were synthesized based on naphthalenediimide and aromatic dicarboxylic acids (3-NDI = N,N′-bis (3-pyridine methyl)-1,4,5,8-naphthalenediimide, H2NDC = 1,4-naphthalenedicarboxylic acid, H2BDC = terephthalic acid, and DMF = N,N′-dimethylformamide). Complex 1 is a two-dimensional structure, whereas complex 2 is a three-dimensional structure with a hex topology. Both complexes feature photochromic behaviors, which are proved by single-crystal X-ray diffraction, UV-vis spectroscopy and EPR characterization. Furthermore, both complexes have obvious fluorescence quenching behaviors upon irradiation by using a xenon lamp.

Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Furthermore, cromolyn and F-cromolyn augment neurite outgrowth in PC12 neuronal cells in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.

To investigate the value of CD44Flow cytometry was used to detected the proportion of CD44The percentage of CD44HCD44CD44探讨CD44用流式细胞仪检测44例AML患者诱导化疗后14 d，外周血CD44MRDHCD44

Cromolyn is a known mast cell stabilizer and is approved for treatment of asthma and for other allergic indications. Cromolyn, in a new redesigned dry powder formulation, is being tested in a pivotal clinical trial in combination with low dose ibuprofen to treat early Alzheimer’s Disease (AD) subjects. To better understand the mechanistic effect cromolyn has in slowing down or halting the neuroinflammatory response associated with AD progression, we tested the effect of cromolyn to dampen the inflammatory response in the human HMC3 microglia cell line. The direct effect of cromolyn on HMC3 microglia is on cytokines and chemokines production following their activation by the inflammatory cytokine TNF-α. Cromolyn and a new fluorinated analog dramatically reduced the secretion of a wide spectrum of inflammatory mediators, which included cytokines such as IL-1β, IL-6, IL-8 and IFN-γ, and chemokines such as CXCL10, CCL2, CCL3 and CCL4. These results bolster our understanding of how our cromolyn platform modulates toxic microglia behavior as a dynamic future treatment option for neurodegenerative disorders.

To detect the relationship between leukocytes derived microparticle (CD45The expression of CD45The percentages of CD45High level of CD45白细胞来源微泡与急性髓系白血病微小残留病及预后的相关性.探讨白细胞来源微泡与急性髓系白血病（AML）微小残留病（MRD）及预后的相关性。方法：。结果：。结论：。.用流式细胞仪检测47例AML患者诱导化疗后，21 d外周血的CD45MRD高水平CD45

BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.

ObjectiveTo establish a risk prediction model for pancreatic fistula according to the pancreatic fistula standards of the 2016 edition.MethodsClinical data from 182 patients with PD admitted to Tianjin Third Central Hospital from January 2016 to February 2020 were retrospectively analyzed. Patients were divided into modeling (01/2016 to 12/2018) and validation (01/2019 to 02/2020) sets according to the time of admission. The risk factors for postoperative pancreatic fistula (POPF) were screened by univariate and multivariate logistic regression analyses, and a risk prediction model for POPF was established in the modeling set. This score was tested in the validation set.ResultsLogistic regression analysis showed that the main pancreatic duct index and CT value were independent risk factors according to the 2016 pancreatic fistula grading standard, based on which a risk prediction model for POPF was established. Receiver operating characteristic curve analysis showed that the area under the curve was 0.788 in the modeling set and 0.824 in the validation set.ConclusionThe main pancreatic duct index and CT value of the pancreas are closely related to the occurrence of pancreatic fistula after PD, and the established risk prediction model for pancreatic fistula has good prediction accuracy.

Objective To establish a risk prediction model for pancreatic fistula according to the pancreatic fistula standards of the 2016 edition. Methods Clinical data from 223 patients with PD admitted to Tianjin Third Central Hospital from January 2016 to December 2020 were retrospectively analyzed. Patients were divided into modeling (January 2016 to December 2018) and validation (January 2019 to December 2020) sets according to the time of admission. The risk factors for postoperative pancreatic fistula (POPF) were screened by univariate and multivariate logistic regression analyses, and a risk prediction model for POPF was established in the modeling set. This score was tested in the validation set. Results Logistic regression analysis showed that the main pancreatic duct index and CT value were independent risk factors according to the 2016 pancreatic fistula grading standard, based on which a risk prediction model for POPF was established. Receiver operating characteristic curve analysis showed that the area under the curve was 0.775 in the modeling set and 0.848 in the validation set. Conclusion The main pancreatic duct index and CT value of the pancreas are closely related to the occurrence of pancreatic fistula after PD, and the established risk prediction model for pancreatic fistula has good prediction accuracy.

Cromolyn is a known mast cell stabilizer and is approved for treatment of asthma and for other allergic indications. Cromolyn, in a new redesigned dry powder formulation, is being tested in a pivotal clinical trial in combination with low dose ibuprofen to treat early Alzheimer’s Disease (AD) subjects. To better understand the mechanistic effect cromolyn has in slowing down or halting the neuroinflammatory response associated with AD progression, we tested the effect of cromolyn to dampen the inflammatory response in the human HMC3 microglia cell line. The direct effect of cromolyn on HMC3 microglia is on cytokines and chemokines production following their activation by the inflammatory cytokine TNF-α. Cromolyn and a new fluorinated analog dramatically reduced the secretion of a wide spectrum of inflammatory mediators, which included cytokines such as IL-1β, IL-6, IL-8 and IFN-γ, and chemokines such as CXCL10, CCL2, CCL3 and CCL4. These results bolster our understanding of how our cromolyn platform modulates toxic microglia behavior as a dynamic future treatment option for neurodegenerative disorders.

One of the major mediators of multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) is the overexpression of ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we conducted in vitro and in vivo experiments to determine whether PD153035, an inhibitor of EGFR, could reverse ABCG2-mediated MDR in human NSCLC and transfected cells overexpressing ABCG2. The efficacy of SN-38, topotecan, and mitoxantrone (MX) were significantly increased by PD153035, PD153035 significantly reversed ABCG2-mediated MDR by attenuating the efflux activity of this transporter. In addition, PD153035 significantly down-regulated the expression of the ABCG2 transporter protein. Furthermore, a combination of PD153035 and topotecan, exhibited significant synergistic anticancer activity against mice xenografted with human H460/MX20 cells. These results, provided that they can be extrapolated to humans, suggest that the combination of topotecan and PD153035 could be a promising therapeutic strategy to attenuate the resistance to topotecan, as well as other anticancer drugs, mediated by the overexpression of ABCG2.

ObjectiveThere is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.Design and resultsA total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI −12.59 to −2.50; p=0.0018), respectively.ConclusionsThis is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.Trial registrationNCT01770431; Post-results.

Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.

Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.

// Jun Li 1, 2, * , Priyank Kumar 1, * , Nagaraju Anreddy 1 , Yun-Kai Zhang 1 , Yi-Jun Wang 1 , Yanglu Chen 1, 3 , Tanaji T. Talele 1 , Kanav Gupta 1, 4 , Louis D. Trombetta 1 and Zhe-Sheng Chen 1 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, New York, 11439, USA 2 Department of Otolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China 3 Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA 4 Jericho High School, Jericho, NY, 11753, USA * These authors have contributed equally to this work Correspondence to: Zhe-Sheng Chen, email: chenz@stjohns.edu Louis D. Trombetta, email: trombetl@stjohns.edu Keywords: quizartinib, ABCG2, ABCC1, MDR, reversal Received: April 25, 2017 Accepted: June 26, 2017 Published: September 16, 2017 ABSTRACT Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 μM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR. Results also showed that quizartinib reversed MDR not by reducing the expression of ABCG2 protein, but by antagonizing the drug efflux function and increasing the intracellular accumulation of substrate anticancer drugs in ABCG2-overexpressing cells. Importantly, quizartinib at 30 mg/kg strongly enhanced the effect of topotecan (3 mg/kg) in ABCG2-overexpressing (H460/MX20) xenografts in athymic nude mice. These results demonstrated that quizartinib potentiates the antineoplastic activity of wild-type and R482T mutant ABCG2 substrates. These findings may be useful in clinical practice for cancer combination therapy with quizartinib.

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021–30. ©2017 AACR.

The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100 ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.

Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5 μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI–H460/MX20 cells, and sensitized NCI–H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.

A scanning prism with polymer-stabilized blue phase liquid crystals (PS-BPLCs) was demonstrated with an impulsive blinking backlight system of high-resolution three-dimensional (3-D) display. The fast switching PS-BPLC prism, whose response time was less than 1 ms, may solve the resolution degradation problem for the autostereoscopic display. Also, the impulsive blinking backlight system may improve the dynamic crosstalk for 3-D perception. By optimizing the device structure and backlight system, the scanning prism-type autostereoscopic display may achieve low crosstalk, about 14%, for high-resolution 3-D display.

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.

Background Prostate cancer (PCa) is a prevalent human malignancy in males. Circular RNA circCRKL (Hsa_circ_0001206) was reported to be lowly expressed in PCa tissues. However, the regulatory role of circCRKL in PCa is poorly defined. Methods Levels of circCRKL, microRNA-141 (miR-141), and Kruppel-like factor (KLF5) were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Cell cycle progression, apoptosis, migration, and invasion were examined by Flow cytometry, Wound healing, and transwell assays. The underlying relationship between miR-141 and circCRKL or KLF5 was predicted by starBase, and then verified by a dual-luciferase reporter, RNA Immunoprecipitation (RIP), and RNA pull-down assays. The protein level of KLF5 was assessed by western blot assay. The biological role of circCRKL was detected by a xenograft tumor model in vivo. Results CircCRKL and KLF5 were decreased, and miR-141 was increased in PCa tissues and cells. The functional analysis discovered that the overexpression of circCRKL repressed cell cycle progression, migration, invasion, and boosted apoptosis of PCa cells. Mechanically, circCRKL could positively regulate KLF5 expression by sponging miR-141. In addition, circCRKL upregulation could hinder PCa tumor growth in vivo. Conclusion These findings revealed that circCRKL inhibited the progression of PCa through upregulating KLF5 expression by sponging miR-141, elucidating a novel regulatory pathway in PCa cells. Our research suggested an underlying circRNA-targeted therapy for PCa.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Approximately 15% of CRCs have defects in DNA mismatch repair (MMR) genes, which lead to frequent mutations in repetitive genomic sequences known as microsatellites. This kind of genomic instability, referred to as microsatellite instability (MSI), contributes to the emergence of highly immunogenic neoantigen peptides that can stimulate an antitumor response. As such, a subset of CRC patients with deficient MMR has a positive response to immune checkpoint blockade immunotherapy. However, the molecular basis of MSI-induced antitumor immune response is not well understood. To address this issue, we used CRISPR to genetically inactivate MutL homolog 1 (MLH1), a key MMR protein, in two microsatellite stable (MSS) murine colorectal cancer cell lines, CT26 and MC-38, which enabled us to directly compare isogenic MSI and MSS tumors in mice with an immuno-deficient or -competent microenvironment. The growth of MLH1-KO cells was comparable to the parental cells in immunocompromised mice. Upon transplantation into syngeneic, immunocompetent mice, the parental CT26 and MC-38 tumors rapidly proliferate. In contrast, the MLH1-KO tumors grew poorly under the same conditions, which was accompanied by apoptotic cell death, upregulation of inflammatory cytokines, and tumor infiltration of CD8+ T lymphocytes. Blocking apoptosis by caspase inhibition suppressed cytokine induction and T lymphocyte infiltration, suggesting a key role of apoptosis in triggering an antitumor immune response. Our current efforts are towards elucidating the mechanism of cell death and defining the associated immune signatures. Ultimately, a better understanding of the immunological consequences of MSI status in CRCs may help to develop more effective CRC therapies. Citation Format: Darleny Y. Lizardo, Yi-Jun Wang, Liheng Yang, Jian Yu, Lin Zhang. Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1622.

Background. Prostate cancer (PCa) is the ninth most common cause of cancer death globally. Many studies have investigated aspirin exposure and mortality risk among PCa patients, returning inconsistent results. We conducted a comprehensive meta-analysis to explore the association between aspirin exposure and mortality risk among PCa patients and to investigate potential dose/duration/frequency-response relationships. Methods and Results. Studies published from 1980 to 2018 of PubMed and EMBASE databases were searched. We included 14 studies with 110,000 participants. Multivariate-adjusted odds ratios (ORs) were pooled using random-effect models. Potential dose/duration/frequency-response relationships were evaluated for aspirin exposure and prostate cancer-specific mortality (PCSM) risk. We did not detect an association between the highest aspirin exposure and mortality risk (PCSM of prediagnostic aspirin exposure, OR: 0.96, 95% confidence interval [CI]: 0.87-1. 07, I2 = 0%; PCSM of postdiagnostic aspirin exposure, OR:0.92, 95% CI: 0.77-1.10, I2 = 56.9%; all-cause mortality [ACM] of prediagnostic aspirin exposure, OR: 0.96, 95% CI: 0.88-1.04, I2 = 9.4%; ACM of postdiagnostic aspirin exposure, OR: 0.95, 95% CI: 0.73-1.23, I2 = 88.9%). There was no significant dose/frequency-response association observed for aspirin exposure and PCSM risk. On duration-response analysis, we found that short-term postdiagnostic aspirin exposure (shorter than 2.5 years) increased the risk of PCSM. Conclusions. Our meta-analysis suggests that there is no association between aspirin exposure and PCSM risk. Nor is there an association between the highest aspirin exposure and ACM risk among PCa patients. More studies are needed for a further dose/duration/frequency-response meta-analysis.

Nitric oxide (NO) is a well-known signaling molecular that plays a significant role in stress tolerance of plants to heavy metals. However, the detoxification mechanism of NO has not been well studied. Here, we examined the absorbing and transporting characteristics of copper (Cu) and cadmium (Cd) in tomato seedlings through nutrient solution culture and its response to exogenous NO under Cu and/or Cd stress. Results showed that Cu and Cd with the concentration of 50Mgr;mol·L一氧化氮(NO)作为信号分子,在抵御重金属胁迫中起重要作用,但对不同离子胁迫下的解毒机制尚缺乏研究.本研究采用营养液培养法,研究了铜(Cu)、镉(Cd)单一或复合胁迫下,番茄幼苗对Cu、Cd的吸收转运特性及对外源NO的响应机制.结果表明: 50 μmol·L

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.

BACKGROUND Prostate cancer is a common type of malignant tumor invading the male reproductive-urinary system, which has increasing incidence worldwide. Androgen receptor variant 7 (AR-V7) participates in regulating prostate cancer cell proliferation and gene expression. This study aimed to investigate the expression of AR-V7 in circulated tumor cells (CTCs) in patients with prostate cancer and to assess its correlation with drug sensitivity against enzalutamide or abiraterone. MATERIAL AND METHODS Blood samples of prostate cancer patients were collected for separating CTCs, in which mRNA expression level of full-length AR and AR-V7 was measured to analyze their correlation with enzalutamide or abiraterone resistance. Progression-free survival (PFS) of patients with different AR-V7 expression levels was compared. AR-V7 was overexpressed in transfected prostate cancer cells, and its effects on proliferation were analyzed by clonal formation assay. RESULTS qRT-PCR showed AR-V7 overexpression in a total of 13 patients; 76.92% of these patients developed drug resistance, the distal metastasis of which was significantly higher than that in the group with AR-V7 downregulation, with lower PFS (p

Inflammation plays a critical role in the development of acute kidney injury (AKI). Neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation used to predict the prognostic outcome of several diseases. We conducted a retrospective cohort study to investigate if NLR can be used as a biomarker to predict the mortality of AKI.Records of critically ill patients with AKI were extracted from the Medical Information Mart for Intensive Care Database III version 1.3 (MIMIC-III v1.3). The primary outcome was 30-day mortality and the two secondary outcomes were in hospital and 90-day mortality. We used the Cox proportional hazards models to assess the association between different categories of NLR and outcomes. This analysis included data for 13,678 eligible subjects, with a total of 2,588 30-day, 2,224 in-hospital and 3,545 90-day deaths during the follow-up period. For 30-day mortality, an increased risk of mortality was associated with a higher level of NLR. The HR (95% confidence interval [CI]) of upper tertile (NLR 12.14) was 1.37 (1.17-1.60) in a multivariate model when compared with that of the lower tertile (NLR 5.55). In the quintile analysis, we confirmed the upward trend with HR (95% CI) of the fifth quintile (NLR 17.4) of 1.35 (1.08, 1.69) in a multivariate model compared to the first quintile (NLR 3.82). A similar tendency was observed for 90-day mortality. In the analysis of in-hospital mortality, the HR of fifth quintile (NLR 17.4) showed a slight decrease.Our analysis indicates that a higher level of NLR is associated with increased risk of 30-day and 90-day mortality in AKI patients. The similar upward trend is not detected in analysis of in-hospital mortality.

The total internal reflection effect in conventional electroluminescent devices causes a large amount of light energy to be trapped in devices and induces heat energy that adversely affects the performance of the device. To enhance the light outcoupling efficiency without sacrificing the electrical properties, a patterned inverted conical (PIC) structure fabricated by a focused femtosecond laser on a flexible substrate was demonstrated. Compared with the conventional flexible organic light-emitting diode (OLED), the OLED with the PIC structure exhibited a current efficiency increase of a factor of 2.6 with no emission spectrum altered. In addition, the flexible OLED with PIC substrate can avoid the mirror reflection effect under the strong ambient light for a better visual experience. This highly effective method is compatible with the current device fabrication process and is applicable for full-color OLED display and lighting.

// Yi-Jun Wang 1 , Yujian Huang 2 , Nagaraju Anreddy 1 , Guan-Nan Zhang 1 , Yun-Kai Zhang 1 , Meina Xie 1 , Derrick Lin 2 , Dong-Hua Yang 1 , Mingjun Zhang 2 , Zhe-Sheng Chen 1 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 2 Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210, USA Correspondence to: Zhe-Sheng Chen, e-mail: chenz@stjohns.edu Mingjun Zhang, e-mail: zhang.4882@osu.edu Keywords: tea nanoparticle, tumor xenograft, multidrug resistance, drug delivery, biocompatibility Received: September 02, 2015 Accepted: November 25, 2015 Published: December 21, 2015 ABSTRACT An infusion-dialysis based procedure has been developed as an approach to isolate organic nanoparticles from green tea. Tea nanoparticle (TNP) can effectively load doxorubicin (DOX) via electrostatic and hydrophobic interactions. We established an ABCB1 overexpressing tumor xenograft mouse model to investigate whether TNP can effectively deliver DOX into tumors and bypass the efflux function of the ABCB1 transporter, thereby increasing the intratumoral accumulation of DOX and potentiating the anticancer activity of DOX. MTT assays suggested that DOX-TNP showed higher cytotoxicity toward CCD-18Co, SW620 and SW620/Ad300 cells than DOX. Animal study revealed that DOX-TNP resulted in greater inhibitory effects on the growth of SW620 and SW620/Ad300 tumors than DOX. In pharmacokinetics study, DOX-TNP greatly increased the SW620 and SW620/Ad300 intratumoral concentrations of DOX. But DOX-TNP had no effect on the plasma concentrations of DOX. Furthermore, TNP is a safe nanocarrier with excellent biocompatibility and minimal toxicity. Ex vivo IHC analysis of SW620 and SW620/Ad300 tumor sections revealed evidence of prominent antitumor activity of DOX-TNP. In conclusion, our findings suggested that natural nanomaterials could be useful in combating multidrug resistance (MDR) in cancer cells and potentiating the anticancer activity of chemotherapeutic agents in cancer treatment.

Arabinoglactan protein (AGP)-rich nanoparticles obtained from the sticky exudates of Hedera helix (English ivy), have shown promising potential to be used in nanomedicine owing to their excellent aqueous solubility, low intrinsic viscosity, biocompatibility, and biodegradability. In this study, the feasibilities of utilizing ivy nanoparticles (INPs) as nano-carriers for delivering chemotherapeutic drugs in cancer therapy and as nano-fillers to develop novel scaffolds for tissue engineering in regenerative medicine are evaluated. Via electrostatic and hydrophobic interactions, pH-responsive nanoconjugates are formed between the INPs and the doxorubicin (DOX) with an entrapment ratio of 77.9 ± 3.9%. While the INPs show minimal cytotoxicity, the formed INP-DOX conjugates exhibit substantially stronger cytotoxic activity than free DOX against multiple cancer cell lines, suggesting a synergistic effect is established upon conjugation. The anti-cancer effects of the INP-DOX conjugates are further evaluated via in vivo xenograft assays by subcutaneously implanting DOX resistant cell line, SW620/Ad-300, into nude mice. The tumor volumes in mice treated with the INP-DOX conjugates are significantly less than those of the mice treated with free DOX. In addition, the INPs are further exploited as nano-fillers to develop fibrous scaffolds with collagen, via mimicking the porous matrix where the INPs are embedded under natural condition. Enhanced adhesion of smooth muscle cells (SMCs) and accelerated proliferation of mouse aortic SMCs are observed in this newly constructed scaffold. Overall, the results obtained from the present study suggest great potential of the INPs to be used as biocompatible nanomaterials in nanomedicine. The AGP-rich INP renders a glycoprotein architecture that is amenable for modification according to the functional designs, capable of being developed as versatile nanomaterials for extensive biomedical applications. Statement of Significance Naturally occurring organic nanomaterials have drawn increasing interest for their potential biomedical applications in recent years. In this study, a new type of naturally occurring nanoparticles obtained from the sticky exudates on the adventitious roots of English ivy ( H. helix ), was explored for its potential biomedical application. In particular, the feasibilities of utilizing ivy nanoparticles (INPs) as nano-carriers for delivering chemotherapeutic drugs in cancer therapy and as nano-fillers to develop novel scaffolds for tissue engineering in regenerative medicine were evaluated both in vitro and in vivo . Overall, the results obtained from the present study suggest the great potential of the INPs to be used as biocompatible nanomaterials in nanomedicine. This study may open a totally new frontier for exploring the biomedical application of naturally occurring nanomaterials.

ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of [(3)H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.

One glass single ITO layer solution has been demonstrated for large size projected-capacitive touch panels. Using simple touch sensors and algorithm, the proposed solution can effectively solve the issues of sensitivity reduction and large coordinate shifting existing in current large size touch panels. A touch system based on the proposed solution can achieve a coordinate shifting of less than 1.5%.

Background This study aimed to investigate the dosage, immunogenicity and safety profile of a novel human papillomavirus (HPV) types 16 and 18 bivalent vaccine produced by E. coli . Methods This randomized, double-blinded, controlled phase 2 trial enrolled women aged 18–25 years in China. Totally 1600 eligible participants were randomized to receive 90 μg, 60 μg, or 30 μg of the recombinant HPV 16/18 bivalent vaccine or the control hepatitis B vaccine on a 0, 1 and 6 month schedule. The designated doses are the combined micrograms of HPV16 and 18 VLPs with dose ratio of 2:1. The immunogenicity of the vaccines was assessed by measuring anti-HPV 16 and 18 neutralizing antibodies and total IgG antibodies. Safety of the vaccine was assessed. Results All but one of the seronegative participants who received 3 doses of the HPV vaccines seroconverted at month 7 for anti-HPV 16/18 neutralizing antibodies and IgG antibodies. For HPV 16, the geometric mean titers (GMTs) of the neutralizing antibodies were similar between the 60 μg (GMT = 10,548) and 90 μg (GMT = 12,505) HPV vaccine groups and were significantly higher than those in the 30 μg (GMT = 7596) group. For HPV 18, the GMTs of the neutralizing antibodies were similar among the 3 groups. The HPV vaccine was well tolerated. No vaccine-associated serious adverse events were identified. Conclusion The prokaryotic-expressed HPV vaccine is safe and immunogenic in women aged 18–25 years. The 60 μg dosage formulation was selected for further investigation for efficacy. Clinical trials registration : NCT01356823 .