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The present article introduced an natural enzyme-covered/amino-modified Pd-Pt bimetallic-doped zeolitic imidazolate framework (NAPPZ) for ultrasensitive and specific detection of glucose. The dodecahedral nanomaterial zeolitic imidazolate framework (ZIF-8)-loaded Pd-Pt bimetallic nanoparticles endowed the composite with peroxidase-like activity. The modification with glucose oxidase (GOx) facilitated the rapid access of H 2 O 2 produced through glucose oxidation to the Pd-Pt nanoparticles vicinity reducing diffusion. GOx specifically catalyzes the transformation of glucose into H 2 O 2 , which then H 2 O 2 rapidly migrates to the Pd-Pt nanoparticles, catalyzing the oxidation of colorless o-phenylenediamine into the orange-yellow product 2,3-diaminophenazine. Based on the aforementioned cascade reaction, the NAPPZ and NAPPZ based on ChOx were utilized for detecting glucose in human urine samples and cholesterol in milk, respectively. The NAPPZ strategy presented a broad detection range (20-1100 μmol L -1 ) and a low detection limit (15.9 μmol L -1 ) for glucose, and the NAPPZ based on ChOx strategy approach offered a broad detection range (10-500 μmol L -1 ) and low detection limit (6.4 μmol L -1 ) for cholesterol. Therefore, this novel method holds significant potential in the areas of clinical diagnostics and food safety., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Ethnopharmacological Relevance: The anti-tumor related diseases of Coptidis Rhizoma (Huanglian) were correlated with its traditional use of removing damp-heat, clearing internal fire, and counteracting toxicity. In the recent years, Coptidis Rhizoma and its components have drawn extensive attention toward their anti-tumor related diseases. Besides, Coptidis Rhizoma is traditionally used as an anti-inflammatory herb. Epiberberine (EPI) is a significant alkaloid isolated from Coptidis Rhizoma, and exhibits multiple pharmacological activities including anti-inflammatory. However, the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis has not been demonstrated clearly., Aim of the Study: Bone metastatic breast cancer can lead to osteolysis via inflammatory factors-induced osteoclast differentiation and function. In this study, we try to analyze the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis., Methods: To evaluate whether epiberberine could suppress bone metastatic breast cancer-induced osteolytic damage, healthy female Balb/c mice were intratibially injected with murine triple-negative breast cancer 4T1 cells. Then, we examined the inhibitory effect and underlying mechanism of epiberberine on breast cancer-induced osteoclastogenesis in vitro. Xenograft assay was used to study the effect of epiberberine on breast cancer cells in vivo. Moreover, we also studied the inhibitory effects and underlying mechanisms of epiberberine on RANKL-induced osteoclast differentiation and function in vitro., Results: The results show that epiberberine displayed potential therapeutic effects on breast cancer-induced osteolytic damage. Besides, our results show that epiberberine inhibited breast cancer cells-induced osteoclast differentiation and function by inhibiting secreted inflammatory cytokines such as IL-8. Importantly, we found that epiberberine directly inhibited RANKL-induced differentiation and function of osteoclast without cytotoxicity. Mechanistically, epiberberine inhibited RANKL-induced osteoclastogensis via Akt/c-Fos signaling pathway. Furthermore, epiberberine combined with docetaxel effectively protected against bone loss induced by metastatic breast cancer cells., Conclusions: Our findings suggested that epiberberine may be a promising natural compound for treating bone metastatic breast cancer-induced osteolytic damage by inhibiting IL-8 and is worthy of further exploration in preclinical and clinical trials., Competing Interests: Declaration of competing Interest The authors confirm that this article content has no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanozyme, with enzyme-mimicking activity and excellent stability, has attracted extensive attention. However, some inherent disadvantages, including poor dispersion, low selectivity, and insufficient peroxidase-like activity, still limit its further development. Therefore, an innovative bioconjugation of a nanozyme and natural enzyme was conducted. In the presence of graphene oxide (GO), histidine magnetic nanoparticles (H-Fe 3 O 4 ) were first synthesized by a solvothermal method. The GO-supported H-Fe 3 O 4 (GO@H-Fe 3 O 4 ) exhibited superior dispersity and biocompatibility because GO was the carrier and possessed outstanding peroxidase-like activity because of the introduction of histidine. Furthermore, the mechanism of the peroxidase-like activity of GO@H-Fe 3 O 4 was the generation of •OH. Uric acid oxidase (UAO) was selected as the model natural enzyme and covalently linked to GO@H-Fe 3 O 4 with hydrophilic poly(ethylene glycol) as a linker. UAO could specifically catalyze the oxidation of uric acid (UA) to generate H 2 O 2 , and subsequently, the newly produced H 2 O 2 oxidized the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue ox-TMB under the catalysis of GO@H-Fe 3 O 4 . Based on the above cascade reaction, the GO@H-Fe 3 O 4 -linked UAO (GHFU) and GO@H-Fe 3 O 4 -linked ChOx (GHFC) were used for the detection of UA in serum samples and cholesterol (CS) in milk, respectively. The method based on GHFU exhibited a wide detection range (5-800 μM) and a low detection limit (1.5 μM) for UA, and the method based on GHFC exhibited a wide detection range (4-400 μM) and a low detection limit (1.13 μM) for CS. These results demonstrated that the proposed strategy had great potential in the field of clinical detection and food safety., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

When nanozymes are used in biological analysis, higher activity can improve the detection sensitivity, and better selectivity can eliminate other interference. To improve the specificity and sensitivity, we fabricated an innovative bioconjugated nanozyme with natural enzyme (BNNZ), in which natural ChOx was immobilized onto histidine-modified Fe 3 O 4 (His-Fe 3 O 4 ) with hydrophilic poly(ethylene glycol) (PEG) as a linker. ChOx could specifically catalyze the oxidation of cholesterol to generate H 2 O 2 molecule, and then the newly formed H 2 O 2 oxidized the colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue ox-TMB by peroxidase-like His-Fe 3 O 4 . According to the above cascade reaction, the BNNZ-based colorimetric strategy was proposed for the detection of cholesterol. Wherein, natural enzymes specifically catalyzed substrates, which endowed BNNZ with excellent specificity for target molecules; meanwhile, the introduction of histidine on His-Fe 3 O 4 effectively increased the peroxidase-like activity of BNNZ, which provided a guarantee for sensitivity. Furthermore, BNNZ after reaction could be rapidly separated by an external magnetic field without interfering with colorimetric quantitative detection. The proposed strategy exhibited excellent sensitivity with limit of detection of 0.446 μM and was successfully used for the detection of cholesterol in spiked human serum sample with recovery and relative standard deviation in the range of 97.9-103.5% and 2.5-4.0%, respectively. This work indicates that the bioconjugation of nanozyme and natural enzyme may be a universal strategy for synthesis of high-performance enzyme-nanozyme systems, and the new-type BNNZ will be widely used in biological detection and disease treatment., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here, we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib-activated STING/TBK1-dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome-scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next-generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier-generation PARPi., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Molecularly imprinted polymers (MIPs) can exhibit antibody-level affinity for target molecules. However, the nonspecific adsorption of non-imprinted regions for non-target molecules limits the application range of MIPs. Herein, we fabricated PEGylated boronate-affinity-oriented ellagic acid-imprinting magnetic nanoparticles (PBEMN), which first integrated boronate-affinity-oriented surface imprinting and sequential PEGylation for small molecule-imprinted MIPs. The resultant PBEMN possess higher adsorption capacity and faster adsorption rate for template ellagic acid (EA) molecules than the non-PEGylated control. To prove the excellent performance, the PBEMN were linked with hydrophilic boronic acid-modified/fluorescein isothiocyanate-loaded graphene oxide (BFGO), because BFGO could selectively label cis-diol-containing substances by boronate-affinity and output ultrasensitive fluorescent signals. Based on a dual boronate-affinity synergy, the PBEMN first selectively captured EA molecules by boronate-affinity-oriented molecular imprinted recognition, and then the EA molecules were further labeled with BFGO through boronate-affinity. The PBEMN linked BFGO (PBPF) strategy provided ultrahigh sensitivity for EA molecules with a limit of detection of 39.1 fg mL -1 , resulting from the low nonspecific adsorption of PBEMN and the ultrasensitive fluorescence signal of BFGO. Lastly, the PBPF strategy was successfully employed in the determination of EA concentration in a spiked beverage sample with recovery and relative standard deviation in the range of 96.5 to 104.2% and 3.8 to 5.1%, respectively. This work demonstrates that the integration of boronate-affinity-oriented surface imprinting and sequential PEGylation may be a universal tool for improving the performance of MIPs., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Molecularly imprinted polymers (MIPs) as artificial receptors have been widely applied in various fields. However, construction of MIPs for precise recognition of glycoprotein still remains a rather challenging task. To overcome this problem, we first fabricated boronate-affinity-oriented and sequential-surface imprinting magnetic nanoparticles (BSIMN) through integrating the boronate-affinity-oriented and sequential surface imprinting. The boronate-affinity-oriented immobilization of glycoprotein template endowed the BSIMN with homogeneous imprinted cavities. In addition, the polydopamine (PDA) imprinted layer was introduced by self-polymerization of dopamine in the first imprinting process, and then the phenylboronic acid (PBA) imprinted layer was introduced by boronate-affinity interaction in the second imprinting process. Surprisingly, the PBA imprinted layer possessed self-healing property due to the presence of pH-dependent boronate-affinity interaction between two imprinted layers. Therefore, the fabricated BSIMN exhibited excellent selectivity toward glycoprotein templates. To quantitatively detect glycoproteins in biological samples, the BSIMN was linked with hydrophilic rhodamine B-loaded/boronic acid-modified graphene oxide (HRBGO), which could selectively label glycoprotein and output amplified signal. In quantitative analysis, target glycoproteins were firstly captured by BSIMN and then specifically labeled by HRBGO; subsequently, the releasing agent was added to release numerous rhodamine B from HRBGO, and the corresponding fluorescence signal was used for further quantitative analysis. The proposed strategy showed ultrahigh sensitivity for ovalbumin, carcinoembryonic antigen and alpha fetoprotein with limit of detection of 4.5 fg mL -1 , 3.6 fg mL -1 and 4.2 fg mL -1 , respectively, and was successfully applied in determination of these glycoproteins in serum samples., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi-disciplinary team comprising of experts from all sub-specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence-based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow-up of NPC, which aim to improve the management of NPC., (© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Inflammatory bowel disease (IBD) is a prevalent worldwide health problem featured by relapsing, chronic gastrointestinal inflammation. Enhancer of zeste homolog 2 (EZH2) is a critical epigenetic regulator in different pathological models, such as cancer and inflammation. However, the role of EZH2 in the IBD development is still obscure., Aim: To explore the effect of EZH2 on IBD progression and the underlying mechanism., Methods: The IBD mouse model was conducted by adding dextran sodium sulfate (DSS), and the effect of EZH2 on DSS-induced colitis was assessed in the model. The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit, transepithelial electrical resistance analysis, and Western blot analysis of related markers, including Zona occludens 1, claudin-5, and occludin, in NCM460 and fetal human colon (FHC) cells. The mechanical investigation was performed by quantitative reverse transcription - polymerase chain reaction, Western blot analysis, and chromatin immunoprecipitation assays., Results: The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system. DSS treatment caused a decreased histological score in the mice, which was reversed by EZH2 depletion. The inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, were induced in the DSS-treated mice, in which the depletion of EZH2 could reverse this effect. Moreover, the tumor necrosis factor-α treatment induced the apoptosis of NCM460 and FHC cells, in which EZH2 depletion could reverse this effect in the cells. Moreover, the depletion of EZH2 attenuated permeability of colonic epithelial cells. Mechanically, the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2 (JK2) and signal transducer and activator of transcription in the NCM460 and FHC cells. Specifically, EZH2 inactivated JAK2 expression by regulating histone H3K27me3. JAK2 inhibitor TG101348 was able to reverse EZH2 knockdown-mediated colonic epithelial cell permeability and apoptosis., Conclusion: Thus, we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/ signal transducer and activator of transcription signaling in IBD. EZH2 may be applied as a potential target for IBD therapy., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined., Materials and Methods: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model., Results: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate., Conclusion: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC., Implications for Practice: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer., (© 2021 AlphaMed Press.)

Purpose: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC)., Methods: The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations., Results: The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options., Recommendations: Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Background: Transforming growth factor beta-induced (TGFBI) protein has been found expressed in several cancer types, and expression levels of TGFBI can affect the cancer patients' outcomes, but the role of TGFBI in glioblastoma multiforme (GBM) remains obscure., Methods: The TGFBI expression levels in GBM were performed via Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN databases. Further, the mutations types of TGFBI were analyzed by using the cBioportal dataset. LinkedOmics selected correlated genes, kinases, and microRNA (miRNA) targets of TGFBI. GEPIA conducted the prognostic value of TGFBI and correlated genes. Then, the relationship between TGFBI and immune infiltrates was performed by Tumor Immune Estimation Resource (Timer). We compared the TGFBI protein expression levels in GBM and control samples through the Human Protein Atlas (HPA). Finally, the GSCAlite was used to achieve the drugs, and molecules target the TGFBI and significantly correlated genes., Results: TGFBI is significantly overexpressed in GBM, but the clinical features do not have considerable influence on TGFBI expression levels. Overexpression of TGFBI acts as an adverse biomarker of GBM. The enrichment function of TGFBI showed that the main biological functions, including extracellular matrix (ECM) organization, angiogenesis, leukocyte migration, T cell activation, cell cycle G2/M phase transition, and growth factor binding. About the significant correlated genes, overexpression of mitogen-activated protein kinase 13 (MAPK13) [Log-rank P=0.08 HR (high) =1.4], myosin IG (MYO1G) [Log-rank P=0.06 HR (high) =1.4], plasminogen activator urokinase receptor (PLAUR) [Log-rank P=0.03 HR (high) =1.5], thrombomodulin (THBD) [Log-rank P=0.028 HR (high) =1.5] indicated the poor prognosis of GBM. Further, TGFBI had a significant association with dendritic cell (DC) infiltrates (cor =0.516, P=9.00e-30). The higher the DC infiltration, the shorter survival of GBM. TGFBI protein expression levels were not significantly different in GBM and normal tissue. Finally, TGFBI is associated with resistance to belinostat, LAQ824, CAY10603, CUDC-101, methotrexate, 5-fluorouracil, and navitoclax., Conclusions: In the present study, we showed TGFBI was overexpressed in GBM, and TGFBI is associated with DC cell infiltrates. Overexpression of TGFBI and high DC infiltration might be an adverse biomarker of GBM. Finally, TGFBI is associated with tumor multi-drug resistance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-2906). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C.

There were no systematic researches about autophagy-related long noncoding RNA (lncRNA) signatures to predict the survival of patients with colon adenocarcinoma. It was necessary to set up corresponding autophagy-related lncRNA signatures. The expression profiles of lncRNAs which contained 480 colon adenocarcinoma samples were obtained from The Cancer Genome Atlas (TCGA) database. The coexpression network of lncRNAs and autophagy-related genes was utilized to select autophagy-related lncRNAs. The lncRNAs were further screened using univariate Cox regression. In addition, Lasso regression and multivariate Cox regression were used to develop an autophagy-related lncRNA signature. A risk score based on the signature was established, and Cox regression was used to test whether it was an independent prognostic factor. The functional enrichment of autophagy-related lncRNAs was visualized using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Ten prognostic autophagy-related lncRNAs (AC027307.2, AC068580.3, AL138756.1, CD27-AS1, EIF3J-DT, LINC01011, LINC01063, LINC02381, AC073896.3, and SNHG16) were identified to be significantly different, which made up an autophagy-related lncRNA signature. The signature divided patients with colon adenocarcinoma into the low-risk group and the high-risk group. A risk score based on the signature was a significantly independent factor for the patients with colon adenocarcinoma (HR = 1.088, 95%CI = 1.057 - 1.120; P < 0.001). Additionally, the ten lncRNAs were significantly enriched in autophagy process, metabolism, and tumor classical pathways. In conclusion, the ten autophagy-related lncRNAs and their signature might be molecular biomarkers and therapeutic targets for the patients with colon adenocarcinoma., Competing Interests: The authors declare there are no competing interests., (Copyright © 2020 Weige Zhou et al.)

Systemic inflammatory response markers are associated with poor survival in many types of malignances. This study aimed to evaluate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP) in patients with non-small cell lung cancer (NSCLC).We retrospectively evaluated 254 NSCLC patients who underwent radical surgery between January 2012 and April 2014 in the Sichuan Provincial Cancer Hospital. The cut-off values of NLR, PLR, LMR, and CRP were determined according to the receiver operating characteristic curve, and the correlation of NLR, PLR, LMR, and CRP with prognosis was analyzed based on the cut-off value.The cut-off value for NLR, PLR, LMR, and CRP were 3.18, 122, 4.04, and 8.8, respectively. Univariate analysis showed that age (P = .022), tumor-node-metastasis (TNM) stage (P < .001), T stage (P = .001), and N stage (P < .001) were significantly correlated with disease-free survival (DFS), while age (P = .011), TNM stage (P < .001), T stage (P = .008), N stage (P < .001), and PLR (P = .001) were significantly correlated with overall survival (OS). In multivariate analysis, age (hazard ratio [HR]: 1.564, 95% confidence interval [CI]: 1.087-2.252, P = .016) and TNM stage (HR: 1.704, 95% CI: 1.061-2.735, P = .027) remained independent risk factors affecting DFS, while age (HR: 1.721, 95% CI: 1.153-2.567, P = .008), TNM stage (HR: 2.198, 95% CI: 1.263-3.824, P = .005), and PLR (HR: 1.850, 95% CI: 1.246-2.746, P = .002) were independent risk factors affecting OS.The preoperative PLR is superior to NLR, LMR, and CRP as a biomarker for evaluating the prognosis of patients undergoing curative surgery for NSCLC.

Tumor complexity makes the development of highly sensitive tumor imaging probes an arduous task. Here, we construct a peptide-based near-infrared probe that is responsive to fibroblast activation protein-α (FAP-α), and specifically forms nanofibers on the surface of cancer-associated fibroblasts (CAFs) in situ. The assembly/aggregation-induced retention (AIR) effect results in enhanced accumulation and retention of the probe around the tumor, resulting in a 5.5-fold signal enhancement in the tumor 48 h after administration compared to that of a control molecule that does not aggregate. The probe provides a prolonged detectable window of 48 h for tumor diagnosis. The selective assembly of the probe results in a signal intensity over four- and fivefold higher in tumor than in the liver and kidney, respectively. With enhanced tumor imaging capability, this probe can visualize small tumors around 2 mm in diameter., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors., Methods: Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates TYMS transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated in vitro and in vivo., Findings: TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating TYMS transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC., Interpretation: Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic., Funding: This work was financially supported by grants of NKRDP (2016YFC1302400), STCSM (16JC1406200), NSFC (81872890, 81322034, 81372346) and CAS (QYZDB-SSW-SMC034, XDA12020210)., (Copyright © 2019. Published by Elsevier B.V.)

ZIP4 is a zinc transporter involved in epithelial cell morphology and migration in various cancers. In the epithelial-to-mesenchymal transition (EMT), epithelial cells transition into mesenchymal cells. The EMT plays a crucial role in invasiveness and metastasis during tumorigenesis. The aim of this study was to investigate the role of ZIP4 in the invasiveness and radiosensitivity of human nasopharyngeal carcinoma (NPC). In this study, results from 99 human patients with NPC showed that ZIP4 expression levels significantly correlated with a higher TN (tumor, lymph node) classification, as well as shorter overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Forced overexpression of ZIP4 promoted the migration and invasion of C666-1 cells through regulation of the EMT process. In contrast, ZIP4 silencing by lentivirus-mediated shRNA inhibited the EMT and metastasis of C666-1 cells in vitro and in vivo. Importantly, protein microarray analyses showed that downregulation of ZIP4 in C666-1 cells resulted in the decreased abundance of phosphoinositide 3-kinase (PI3K) p85 (Tyr607), phosphorylated (p)-Akt (Ser473), phosphorylated (p)-Akt (Thr308), and phosphorylated glycogen synthase kinase 3β (pGSK3β; Ser9). These data suggest that ZIP4 induces the EMT and promotes migration and invasion via the PI3K/Akt signaling pathway in NPC. Moreover, ZIP4 silencing significantly enhanced radiation-induced apoptosis and growth inhibition of human C666-1 cells in vitro and enhanced the antitumor activity of ionizing radiation (IR), leading to tumor growth inhibition in vivo. These results demonstrate that ZIP4 is a novel prognostic factor for malignant NPC progression. More importantly, targeting ZIP4, along with radiotherapy, may be an effective new treatment for NPC.

To explore famous veteran traditional Chinese medicine( TCM) doctors' medication rules in treating spermatorrhea based on the medical cases about spermatorrhea collected from Hundred TCM Clinical Doctors of Hundred Years in China and Proven Cases and National Medical Master Test Case. Researchers extracted such data as medicinal and therapies from these cases according to the inclusion and exclusion criteria. Then,Excle 2010,SPSS Clementine 12. 0 and SPSS 22. 0 were adopted respectively for frequency analysis,association rules analysis,cluster analysis and factor analysis. Cluster analysis was carried out by Ochiai algorithm of binary variable data,one of the systematic clustering methods. And principal component analysis was used for factor analysis. Finally,27 medical cases and 41 prescriptions were included in total. The frequency analysis showed that the most common therapy was the astringent therapy( n = 28),which was followed by the tonifying method,tranquilizing method,heat-clearing method,damp-dispelling method and Qiregulating method. The top three kinds of high-frequency traditional Chinese medicines were Poria,Ostreae Concha and Dioscoreae Rhizoma. The association rules analysis found out 11 association rules of medicine pairs,23 association rules of medicine combinations of the three kinds of herbs and 6 association rules of medicine combinations of five kinds of herbs. Among them,the representatives were Rubi Fructus→Fossilia Ossis Mastodi,Rehmanniae Radix Praeparata + Corni Fructus→Dioscoreae Rhizoma,and Pinelliae Rhizoma→Citri Reticulatae Pericarpium,which showed the therapeutic characteristics of astringing,tonifying the kidney and replenishing essence,fortifying the spleen and dispelling dampness. Moreover,7 medicine groups with relevance were extracted from the tree map generated by cluster analysis,including " Phellodendri Chinensis Cortex and Anemarrhenae Rhizoma" and " Angelicae Sinensis Radix,Rehmanniae Radix,Bupleuri Radix and Glycyrrhizae Radix et Rhizoma",which demonstrated the effects of nourishing Yin and purging fire,tonifying and soothing the liver. Besides,totally 12 common factors were obtained according to factor analysis,including 14 drug combinations,like " Amomi Fructus,Anemarrhenae Rhizoma and Phellodendri Chinensis Cortex" and " Nelumbinis Stamen,Moutan Cortex,Poria and Scrophulariae Radix",which indicated the compatibility characteristics of tonifying the spleen and purging fire,dispelling dampness and clearing heat. In conclusion,data mining techniques( including frequency analysis,association rules analysis,cluster analysis and factor analysis) were used to comprehensively analyze the famous veteran TCM doctors' medication rules in treating spermatorrhea,which was helpful for guiding the clinical practice of treating spermatorrhea in TCM.

Rationale: Primary undifferentiated pleomorphic sarcoma is extremely rare in the thyroid, and can be easily misdiagnosed as anaplastic thyroid cancer., Patient Concerns: We present a case of a 71-year-old woman who presented with a rapidly growing painless mass in the neck., Diagnoses-Interventions-Outcomes: Computed tomography showed a large hypointense mass with hyperdense areas involving whole of the right lobe of thyroid gland and fine-needle aspiration cytology found a few atypical cells. Surgical exploration was performed subsequently and frozen section showed malignant tumor. Therefore, a total thyroidectomy, central, and bilateral lateral neck dissection were performed and adjuvant radiotherapy of 60 Gy was administered. The patient was alive and had no recurrence at 6-month follow-up., Lessons: Although primary undifferentiated pleomorphic sarcoma in the thyroid is extremely rare, patients who presented with a rapidly growing painless mass in the neck should be considered and it is essential to excise the tumor completely as soon as possible.

Objective: B lymphoma is a type of malignant tumor originating from the lymphatic hematopoietic system. The pathogenesis and treatment methods are not clear. The change of oxidative stress is closely related to the cell DNA damage and cell apoptosis, which may be served as a target for cancer treatment. This study aims to illustrate the role of oxidative stress in the regulation of B lymphocytoma., Patients and Methods: The tumor tissue was collected from patients with B lymphocytoma. The p66shc level was detected by Western blot. Hydrogen peroxide (H2O2) was assessed by the kit. The oxidative stress model of B lymphoma cell was established by H2O2 treatment. ROS inhibitor or RNAi was used to regulate ROS level. ROS level was determined by flow cytometry. 8-OHdG level (DNA damage product) was tested by the kit. Cell apoptosis was evaluated by annexin V-PI., Results: P66shc expression was significantly reduced, while H2O2 production was significantly decreased in the tumor tissue of B lymphoma compared with adjacent normal control. H2O2 stimulation markedly elevated ROS level and p66shc expression (p < 0.05), accompanied by the aggravation of DNA damage and increase of apoptosis. ROS inhibitor or p66shc RNAi treatment significantly attenuated DNA damage and declined cell apoptosis (p < 0.05)., Conclusions: ROS production promoted p66shc expression, induced DNA damage, and facilitated cell apoptosis. Upregulation of p66shc by oxidative stress could be treated as a new therapeutic target for B lymphoma.

Background: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) for nasopharyngeal carcinoma (NPC) remains controversial. This study was designed to provide a more accurate assessment of the prognostic value, based on a meta-analysis., Methods: A comprehensive search for relevant studies published before June 2016 was performed using the PubMed, Cochrane Library, and Web of Science databases. The correlations of NLR with overall survival (OS) and progression-free survival (PFS) were evaluated for NPC. Hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated to estimate the effects., Results: Six studies with a total of 4359 NPC patients were included in this meta-analysis. The pooled results showed that, among patients with NPC, elevated pretreatment NLR was associated with poorer OS (HR = 1.74, 95% CI = 1.45-2.10) and PFS (HR = 1.48, 95% CI = 1.30-1.69). Subgroup analyses indicated that the use of different cut-off values for NLR (<3 or ≥3) did not affect the consistent prognostic value of NLR for OS or PFS. No significant heterogeneity or publication bias was observed among the included studies for OS or PFS (P > .05)., Conclusions: This meta-analysis indicates that elevated pretreatment NLR might be a valuable predicative biomarker of poor prognosis for patients with NPC.

Portal vein tumor thrombosis (PVTT) is an intractable condition but common phenomenon in hepatocellular carcinoma (HCC). HCC patients with PVTT may have worse liver function, a higher chance of comorbidity related to portal hypertension, lower tolerance to treatment and poorer prognoses. In Western guidelines, patients are offered palliative treatment with sorafenib or other systemic agents because HCC with PVTT is grouped together with metastatic HCC during the planning of its management. In recent years, various treatment options have become available for patients with HCC and PVTT. Therapy has also shifted toward evidence-based treatment. However, policies for the management of HCC with PVTT have not been established. This comprehensive literature review aims to present current and available management options for patients with HCC and PVTT. Evidence is mainly based on studies published after 2010., Competing Interests: The authors have no conflict of interests related to this publication.

Although radiation therapy is the primary treatment for nasopharyngeal carcinoma, radioresistance remains a major obstacle to successful treatment in many cases, and the exact underlying molecular mechanisms are still ill-defined. EMP2, epithelial membrane protein-2, was a recently identified potential oncogene involved in multiple biological processes including cell migration and cell proliferation. This study was to explore the potential relationship between EMP2 expression, nasopharyngeal carcinoma genesis, and radioresistance. EMP2 expression status in 98 nasopharyngeal carcinoma clinical samples was examined by immunohistochemical staining. As a result, most of the nasopharyngeal carcinoma tumor samples were weakly or negatively stained, while paired adjacent normal tissues were moderately or strongly stained. Moreover, patients with higher expression of EMP2 had significant longer survival times. EMP2 re-expression suppresses cell growth, induces S-phase cell cycle arrest, and promotes radiosensitivity and apoptosis in nasopharyngeal carcinoma cells. These results support that loss of EMP2 is common, and its re-expression may serve as an approach to enhance radiation sensitivity in nasopharyngeal carcinoma.

Histone demethylases have emerged as key regulators of biological processes. The H3K9me2 demethylase plant homeo domain finger protein 8(PHF8), for example, is involved in neuronal differentiation, but its potential function in the differentiation of embryonic stem cells (ESCs) to cardiomyocytes is poorly understood. Here, we explored the role of PHF8 during mesodermal and cardiac lineage commitment of mouse ESCs (mESCs). Using a phf8 knockout (ph8(-/Y) ) model, we found that deletion of phf8 in ESCs did not affect self-renewal, proliferation or early ectodermal/endodermal differentiation, but it did promote the mesodermal lineage commitment with the enhanced cardiomyocyte differentiation. The effects were accompanied by a reduction in apoptosis through a caspase 3-independent pathway during early ESC differentiation, without significant differences between differentiating wide-type (ph8(+/Y) ) and ph8(-/Y) ESCs in cell cycle progression or proliferation. Functionally, PHF8 promoted the loss of a repressive mark H3K9me2 from the transcription start site of a proapoptotic gene pmaip1 and activated its transcription. Furthermore, knockdown of pmaip1 mimicked the phenotype of ph8(-/Y) by showing the decreased apoptosis during early differentiation of ESCs and promoted mesodermal and cardiac commitment, while overexpression of pmaip1 or phf8 rescued the phenotype of ph8(-/Y) ESCs by increasing the apoptosis and weakening the mesodermal and cardiac differentiation. These results reveal that the histone demethylase PHF8 regulates mesodermal lineage and cell fate decisions in differentiating mESCs through epigenetic control of the gene critical to programmed cell death pathways. Stem Cells 2016;34:1527-1540., (© 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Pilomatrix carcinoma (PC) is a rare neoplasm, particularly in the parotid region. Thus, it is easily misdiagnosed and an optimal treatment regimen has not yet been established. The present study reports the case of a 43-year-old female who presented with a PC of the parotid region and reviews the associated published literature. The patient underwent three surgical excisions prior to the tumor being completely removed, and was misdiagnosed four times prior to the correct diagnosis. Once the tumor was completely removed, the patient received radiation therapy (RT). At the 2-year follow-up, the patient remained free of local recurrence and metastasis. To the best of our knowledge, only 3 cases of PC on the parotid region have been reported. Although an optimal treatment regimen has not been established, surgery with wide margins is recommended, with RT and chemotherapy producing mixed results.

In the present study, the expression of p53, mouse double minute 2 homolog (MDM2), eukaryotic translation initiation factor 4E (eIF4E), and epidermal growth factor receptor (EGFR) were investigated in nasopharyngeal carcinoma (NPC), and the correlation between their expression and clinicopathological characteristics and prognosis was analyzed. The medical records of 96 NPC patients who had undergone biopsy prior to radical radiotherapy and chemotherapy between 2005 and 2009 were reviewed, retrospectively. All patients received intensity-modulated radiotherapy with concurrent platinum-based chemotherapy. Patients were followed-up for three years. Streptavidin-peroxidase immunohistochemistry was used to evaluate the expression of p53, MDM2, eIF4E and EGFR in NPC biopsy specimens, and the association between their expression and clinical parameters and survival was analyzed. The p53, MDM2, eIF4E and EGFR expression rates were 65.6% (63/96), 79.16% (76/96), 77.08% (74/96) and 89.5% (86/96), respectively. p53 (χ 2 ,20.322; P=0.001) and EGFR (χ 2 ,8.337; P=0.005) expression were found to correlate with T stage, whereas MDM2 (χ 2 ,16.361; P=0.001) expression was found to correlate with lymph node metastasis. p53 expression was found to inversely correlate with MDM2 expression (r, -3.24; P<0.05). Three-year survival rates were lower in p53-positive (76.2%) patients when compared with p53-negative (93.9%) patients. In addition, three-year survival rates were lower in EGFR-positive (75.8%) patients than in EGFR-negative patients (91.2%). The Cox proportional-hazards regression model revealed that p53 (β,-0.455; χ 2 ,5.491; P=0.019) and EGFR (β, 3.93; χ 2 , 11.95; P=0.001) expression were independent prognostic factors. Thus, it was hypothesized that p53 and EGFR expression present potential unfavorable prognostic markers for patients with NPC.

Pemetrexed is an antifolate agent which has been used for treating malignant pleural mesothelioma and non small lung cancer in the clinic as a chemotherapeutic agent. In this study, pemetrexed inhibited cell growth and induced G1 phase arrest in the A549 cell line. To explore the molecular mechanisms of pemetrexed involved in cell growth, we used a two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics approach to analyze proteins changed in A549 cells treated with pemetrexed. As a result, twenty differentially expressed proteins were identified by ESI-Q-TOF MS/MS analysis in A549 cells incubated with pemetrexed compared with non-treated A549 cells. Three key proteins (GAPDH, HSPB1 and EIF4E) changed in pemetrexed treated A549 cells were validated by Western blotting. Accumulation of GAPDH and decrease of HSPB1 and EIF4E which induce apoptosis through inhibiting phosphorylation of Akt were noted. Expression of p-Akt in A549 cells treated with pemetrexed was reduced. Thus, pemetrexed induced apoptosis in A549 cells through inhibiting the Akt pathway.

Objective: To compare the clinical efficacy in the treatment of post-stroke shoulder-hand syndrome between floating-needle therapy and conventional acupuncture on the basis of rehabilitation training., Methods: One hundred cases of post-stroke shoulder-hand syndrome were randomized into a floating-needle group and an acupuncture group, 50 cases in each one. The passive and positive rehabilitation training was adopted in the two groups. Additionally, in the floating-needle group, the floating-needle therapy was used. The needle was inserted at the site 5 to 10 cm away from myofasical trigger point (MTrP), manipulated and scattered subcutaneously, for 2 min continuously. In the acupuncture group, the conventional acupuncture was applied at Jianqian (EX-UE), Jianyu (LI 15), Jianliao (TE 14), etc. The treatment was given once every two days, 3 times a week, and 14 days of treatment were required. The shoulder hand syndrome scale (SHSS), the short form McGill pain scale (SF-MPQ) and the modified Fugl-Meyer motor function scale (FMA) were used to evaluate the damage severity, pain and motor function of the upper limbs before and after treatment in the two groups. The clinical efficacy was compared between the two groups., Results: SHSS score, SF-MPQ score and FMA score were improved significantly after treatment in the two groups (all P < 0.01), and the improvements in the floating-needle group were superior to those in the acupuncture group (all P < 0.05). The total effective rate was 94.0% (47/50) in the floating-needle group, which was better than 90.0% (45/50) in the acupuncture group (P < 0.05)., Conclusion: The floating-needle therapy combined with rehabilitation training achieves a satisfactory efficacy on post-stroke shoulder-hand syndrome, which is better than the combined therapy of conventional acupuncture and rehabilitation training.

The aim of this study was to evaluate the oxygen partial pressure of the rabbit model of the VX2 tumor using a 64-slice perfusion CT and to compare the results with that obtained using the oxygen microelectrode method. Perfusion CT was performed for 45 successfully constructed rabbit models of a VX2 brain tumor. The perfusion values of the brain tumor region of interest, the blood volume (BV), the time to peak (TTP) and the peak enhancement intensity (PEI) were measured. The results were compared with the partial pressure of oxygen (PO2) of that region of interest obtained using the oxygen microelectrode method. The perfusion values of the brain tumor region of interest in 45 successfully constructed rabbit models of a VX2 brain tumor ranged from 1.3-127.0 (average, 21.1 ± 26.7 ml/min/ml); BV ranged from 1.2-53.5 ml/100g (average, 22.2 ± 13.7 ml/100g); PEI ranged from 8.7-124.6 HU (average, 43.5 ± 28.7 HU); and TTP ranged from 8.2-62.3 s (average, 38.8 ± 14.8 s). The PO2 in the corresponding region ranged from 0.14-47 mmHg (average, 16 ± 14.8 mmHg). The perfusion CT positively correlated with the tumor PO2, which can be used for evaluating the tumor hypoxia in clinical practice.

Epidermal growth factor receptor (EGFR) initiates a signaling cascade that leads to DNA synthesis and cell proliferation, but its role in regulating DNA replication licensing is unclear. Here, we show that activated EGFR phosphorylates the p56 isoform of Lyn, p56(Lyn), at Y32, which then phosphorylates MCM7, a licensing factor critical for DNA replication, at Y600 to increase its association with other minichromosome maintenance complex proteins, thereby promoting DNA synthesis complex assembly and cell proliferation. Both p56(Lyn) Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cells and correlated with poor survival of breast cancer patients. These results establish a signaling cascade in which EGFR enhances MCM7 phosphorylation and DNA replication through Lyn phosphorylation in human cancer cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Reprogramming healthy somatic cells into induced pluripotent stem cells (iPSCs) with four defined factors (Oct4, Sox2, c-Myc and Klf4) has been intensively investigated. However, reprogramming diseased cells such as cancer cells has fallen much behind. In this issue of Oncogene, Zhang et al. demonstrated that reprogrammed sarcoma cells with defined factors, as well as Nanog and Lin28, lost their tumorigenicity and dedifferentiated to mesenchymal stem cells (MSC) and hematopoietic stem cell (HSC)-like cells that can be terminally differentiated into mature connective tissues and red blood cells, suggesting sarcoma cells may be reversed back to a stage of common ancestor iPSC bifurcating for HSC and MSC ontogeny. It may, therefore, provide a novel strategy for cancer treatment via ancestor pluripotency induction.

Purpose: This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT)., Methods: Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood-vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated., Results: Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium., Conclusion: This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Esophageal adenocarcinoma (EAC) is the most prevalent esophageal cancer type in the United States. The TNF-α/mTOR pathway is known to mediate the development of EAC. Additionally, aberrant activation of Gli1, downstream effector of the Hedgehog (HH) pathway, has been observed in EAC. In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu. Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

CT perfusion imaging is a promising technique for delineating the target volume for three-dimensional conformal radiotherapy, but it is difficult in humans to obtain gross pathological samples at the same level of the brain tumor to evaluate this technique. The aim of this study was to use the BV map of CT perfusion imaging to assess the target volume in the rabbit VX2 brain tumor model, which has similar characteristics to human brain tumor, and compare the results to those of CECT. New Zealand white rabbits were used for the animal model. After tumor cell implantation 21 rabbits underwent 64-slice CT scanning. The target slice was selected and the maximum major axis length and minimum minor axis length of the tumor in the target slice on BV maps and contrast-enhanced CT images were measured. Pathological specimens were obtained from the rabbit brains which were removed intact. The GTV and CTV of the imaging methods were compared. Scanning was successful in 20 rabbits. The CECT images showed the target area for the VX2 tumor in 16 rabbits. The BV maps showed the target area for the tumor in 20 rabbits. The probability was 95% that the GTV determined by pathology can be covered completely when BV maps are used. CT perfusion imaging appears to be a promising technique for delineating the GTV of brain tumors in clinical practice.

The aim of this study was to determine the relationship between nuclear factor κB and the prognosis of patients with nasopharyngeal carcinoma. We used immunohistochemical studies to examine nuclear factor κB expression in 42 patients with nasopharyngeal carcinoma. The results showed that tumors positive for nuclear factor κB were associated with an increased relapse potential, poor disease-free survival, and reduced overall survival in nasopharyngeal carcinoma. Our study indicates that nuclear factor κB could be an independent molecular marker for predicting poor prognosis among patients with nasopharyngeal carcinoma. Understanding the biology of nuclear factor κB-mediated pathways may lead to the development of novel therapeutic strategies for nasopharyngeal carcinoma.

Breast cancer initiating cells (BCICs), which can fully recapitulate the tumor origin and are often resistant to chemo- and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. Here, we show that BIKDD, a constitutively active mutant form of proapoptotic gene, BIK, effectively induces apoptosis of breast cancer cells and synergizes with lapatinib. Most importantly, BikDD significantly reduces BCICs through co-antagonism of its binding partners Bcl-2, Bcl-xL, and Mcl-1, suggesting a potential therapeutic strategy targeting BCICs. Furthermore, we developed a cancer-specific targeting approach for breast cancer that selectively expresses BikDD in breast cancer cells including BCICs, and demonstrated its potent antitumor activity and synergism with lapatinib in vitro and in vivo., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Up-regulation of the dolichol pathway, a "hallmark" of asparagine-linked protein glycosylation, enhances angiogenesis in vitro. The dynamic relationship between these two processes is now evaluated with tunicamycin. Capillary endothelial cells treated with tunicamycin were growth inhibited and could not be reversed with exogenous VEGF(165). Inhibition of angiogenesis is supported by down-regulation of (i) phosphorylated VEGFR1 and VEGFR2 receptors; (ii) VEGF(165)-specific phosphotyrosine kinase activity; and (iii) Matrigel(TM) invasion and chemotaxis. In vivo, tunicamycin prevented the vessel development in Matrigel(TM) implants in athymic Balb/c (nu/nu) mice. Immunohistochemical analysis of CD34 (p < 0.001) and CD144 (p < 0.001) exhibited reduced vascularization. A 3.8-fold increased expression of TSP-1, an endogenous angiogenesis inhibitor in Matrigel(TM) implants correlated with that in tunicamycin (32 h)-treated capillary endothelial cells. Intravenous injection of tunicamycin (0.5 mg/kg to 1.0 mg/kg) per week slowed down a double negative (MDA-MB-435) grade III breast adenocarcinoma growth by ∼50-60% in 3 weeks. Histopathological analysis of the paraffin sections indicated significant reduction in vessel size, the microvascular density and tumor mitotic index. Ki-67 and VEGF expression in tumor tissue were also reduced. A significant reduction of N-glycan expression in tumor microvessel was also observed. High expression of GRP-78 in CD144-positive cells supported unfolded protein response-mediated ER stress in tumor microvasculature. ∼65% reduction of a triple negative (MDA-MB-231) breast tumor xenograft in 1 week with tunicamycin (0.25 mg/kg) given orally and the absence of systemic and/or organ failure strongly supported tunicamycin's potential for a powerful glycotherapeutic treatment of breast cancer in the clinic.

Amplification or overexpression of murine double minute 2 (MDM2) promotes a variety of human tumors by degrading tumor suppressor proteins such as p53. Phosphorylation of MDM2 on Ser(166) and Ser(186) by the survival kinase Akt inhibits p53-mediated apoptosis. However, it is unclear whether this pathway contributes to normal or malignant pathophysiology in vivo. To address these questions, we generated transgenic mice expressing the Akt-phosphorylated form of MDM2 (MDM2DDS166D/S186D) in the mammary epithelium. Activation of MDM2 delayed mammary gland involution and accelerated tumor progression in mouse mammary tumor virus/neu transgenic mice by inhibiting apoptosis in a manner associated with decreased p53 expression. Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis., (© 2010 AACR.)

A new quassinoid, designated 2'-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2-8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre]. The structure of 1 was determined by spectroscopic analysis and by semisynthesis from glaucarubolone. Complete (1)H and (13)C NMR assignments of compounds 1-8 were also established from detailed analysis of two-dimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor or progesterone receptor. When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.

Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.

Background and Objective: Combined hypoxic cytotoxic drugs and chemoradiotherapy is an important mean of oncotherapy, and Tirapazamine (TPZ) is one of the most remarkable drugs. It has been shown that TPZ has a synergistic effect with radiotherapy on tumor cells, but whether TPZ would down-regulate the expression of the hypoxia-induced genes has not been reported. This study was to investigate the hypoxia-induced mRNA expressions of hypoxia inducible factor-1alpha (HIF-1alpha) and osteopontin (OPN) in human nasopharyngeal carcinoma HNE-1 and CNE-1 cells and the radiosensitization of TPZ, a hypoxia-specific drug, on HNE-1 and CNE-1 cells in vitro., Methods: The IC50 values of TPZ for HNE-1 and CNE-1 cells were measured using MTT assay, and the mRNA expressions of HIF-1alpha and OPN in HNE-1 and CNE-1 cells was determined using RT-PCR under aerobic and hypoxic conditions, respectively. The survival rates of HNE-1 and CNE-1 cells treated with or without TPZ at IC10 in the presence or absence of oxygen for 6 h were determined using colony formation assay following exposure to 1-6 Gy of 60Co radiation. The dose-survival curves were plotted and the values of D0, Dq and SER were calculated as a single-hit multitarget model., Results: The IC50 values of TPZ were 34.81 μmol/L and 35.02 μmol/L in HNE-1 and CNE-1 cells under aerobic condition, and 30.20 μmol/L and 28.48 μmol/L under hypoxic condition, respectively. The expressions of HIF-1alpha and OPN mRNA were reduced by TPZ in HNE-1 cells, but not in CNE-1 cells under hypoxic condition. For the HNE-1 cells, the respective values of D0 and Dq were 0.89 Gy and 0.28 Gy following normoxic irradiation versus 1.47 Gy and 0.44 Gy following hypoxic irradiation. For the CNE-1 cells, the respective values of D0 and Dq were 0.72 Gy and 0.68 Gy following normoxic irradiation versus 0.95 Gy and 0.56 Gy following hypoxic irradiation. The values of D0 and Dq for HNE-1 and CNE-1 cells treated with TPZ under hypoxic condition following irradiation were 0.66 Gy, 0.21 Gy and 0.85 Gy, 0.79 Gy, respectively., Conclusion: TPZ can down-regulate hypoxia-induced expression of HIF-1alpha and OPN mRNA of HNE-1 cells and radiosensitize the HNE-1 cells but not CNE-1 cells, and act as a hypoxia modifier.

6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100-250-fold more potent against SK-BR-3 (ED(50) 0.28 and 0.44microM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The purpose of this research was to evaluate the clinical outcome and factors influencing postoperative intracavity brachytherapy in treating oral squamous cell carcinoma. As a part of their primary treatment, 108 patients received postoperative intracavity brachytherapy only and 85 patients received postoperative intracavity brachytherapy with external radiotherapy. 78 patients were given surgical treatment alone as a control. The survival rates and local tumor control rates were calculated and the therapeutic effects of various treatment methods compared. Overall 5- and 10-year survival rates for patients receiving surgical treatment alone, postoperative intracavity brachytherapy with or without external radiotherapy were 59% and 17%, 73% and 47%, 78% and 57%, respectively. The corresponding local tumor control rates were 53% and 51%, 73% and 71%, 75% and 73%, respectively. Surgical treatment with postoperative intracavity brachytherapy controlled tumor recurrence effectively (p<0.01) and improved survival rates (p<0.01). UICC stages, grading and tumor site had an important influence on overall survival and local tumor control rates. Local tumor excision followed by postoperative intracavity brachytherapy achieved good local tumor control and survival rate, and may be considered as a new and routine treatment for oral cancer.

Objective: To observe the therapeutic effect of acupuncture ("Jin's Sanzhen") treatment for autism patients with different severity., Methods: A total of 202 autism children were divided into treatment group (n=118) and control group (n=84) according to their parents' will. Autism children in the treatment group were treated with "Jin's Sanzhen" therapy [for example, Niesanzhen: the point 2 cun superior to the ear tip, and those at the same level 1 cun apart on the left and right sides; Naosanzhen: Naohu (GV 17), bilateral Naokong (GB 19), etc.], while those of control group accepted special training: behavior education (cognition, speech, communication ability, life self-care ability, etc.) and sensory integration training. The treatment was given to the patients in both groups once per day, six times a week for 4 months., Results: Of the 78 and 58 severe patients in the treatment and control groups, 63 (80.8%) and4 (6.9%) experienced marked improvement, 9 (11.5%) and 33 (56.9%) experienced improvement, 6 (7.7%) and 21 (36.2%) failed, with the effective rates being 92.3% and 63.8% respectively. Of the 118 and 84 patients in the treatment and control groups, after the treatment, the no symptoms, mild, moderate and severe cases were 12 (10.2%) and 3 (3.6%), 56 (47.5%) and 25 (29.8%), 45 (38.1%) and 23 (27.4%), 5 (4.2%) and 33 (39.3%), respectively. The total score of Childhood Autism Rating Scale of treatment group was significantly lower than that of control group after the treatment in severe cases (P < 0.01), showing a better therapeutic effect of the treatment group., Conclusion: "Jin's Sanzhen" therapy has a better therapeutic effect for improving the autism patients symptoms at different severity.

Cytokine interferon-alpha (IFN-alpha) is an immunomodulator and neuromodulator, which modulates central nervous system function partially by activating opioid receptors. However, the role that IFN-alpha plays in relapse to drug abuse is still largely unknown. Thus, we studied whether human recombinant INF-alpha (rIFN-alpha) would reinstate morphine-conditioned place preference (CPP) in rats. In Experiment 1, rats were trained for morphine-CPP with 8-day alternate subcutaneous (s.c.) injections of morphine and saline, and the effect of human rIFN-alpha (20 000 IU/5 microl, intracerebroventricularly) on CPP reinstatement was examined after extinction. In Experiment 2, rats underwent morphine (5 mg/kg, s.c.) unconditioned training with 8 daily alternate injections of morphine (5 mg/kg, s.c.) and saline. Then, the effect of human rIFN-alpha (20 000 IU/5 microl, intracerebroventricularly) on reinstatement of CPP was examined after extinction. In Experiment 3, the effect of opioid receptor antagonist naloxone (1 mg/kg, intraperitoneally) on human rIFN-alpha-induced reinstatement of morphine-CPP was investigated. We found that human rIFN-alpha reinstated morphine-CPP in rats trained under morphine conditioning after extinction, but did not affect CPP in rats that underwent unconditioned training. Naloxone significantly inhibited human rIFN-alpha-induced reinstatement of morphine-CPP. These results indicate that IFN-alpha is a stimulus for reinstatement of morphine-CPP by activation of opioid receptors, which extends our understanding on the high comorbidity of heroin relapse and viral infection.

Objective: To study the clinicopathologic features and immunophenotype of renal cell carcinomas, and to discuss their diagnostic value., Methods: The clinicopathologic features of 114 cases of renal cell carcinoma were reviewed and categorized on the basis of 2004 WHO classification. Immunohistochemical study for a panel of antibodies (including CK, CD10, vimentin, CD117, AMACR, CK7 and TFE3) was carried out. The follow-up data, if available, were also analyzed., Results: The cases were reclassified into 5 subtypes, including 77 cases (67.5%) of clear cell carcinoma (CCRCC), 11 cases (9.6%) of papillary renal cell carcinoma (PRCC), 14 cases (12.3%) of chromophobe renal cell carcinoma (chrRCC), 10 cases (8.8%) of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions (Xp11.2RCC) and 2 cases (1.8%) of unclassified renal cell carcinoma (unRCC). Immunohistochemical study showed that the expression rates of CK, CD10 and vimentin in CCRCC were 93.5% (72/77), 93.5% (72/77) and 75.3% (58/77), respectively. On the other hand, all the 11 cases of PRCC studied were positive for AMACR. The expression rate of CD117 in chrRCC was 78.5% (11/14). In the 10 cases of Xp11.2 RCC studied, the expression rates of TFE3, AMACR, CD10 and CK were 100% (10/10), 100% (10/10), 90% (9/10) and 70% (7/10), respectively., Conclusions: The various subtypes of renal cell carcinomas are heterogeneous in histologic appearance and demonstrate distinctive immunophenotype. The expressions of CD10, vimentin, CD117, AMACR, CK7 and TFE3 are helpful in the differential diagnosis.