Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator.

Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity.

Communication dysfunction, body image, and symptom severity in postoperative head and neck cancer patients: factors associated with the amount of speaking after treatment.

PURPOSE: The purpose of this study was to determine the relationships of communication dysfunction, body image, and amount of speaking in patients who were treated for head and neck cancers (HNCs). METHODS: This was a cross-sectional study of postoperative HNC patients at the otolaryngology outpatient departments of two leading medical centers in northern Taiwan. Data were collected using questionnaires to assess perceived communication dysfunction, body image, symptom severity, and amount of speaking after treatment. RESULTS: A total of 130 HNC patients were included in the analysis, and 70.8 % of patients reported speaking less after surgery as compared to the period before having HNC surgery. Overall, patients perceived a moderate level of communication dysfunction. Those with higher distress over their body image, higher symptom severity, and with hypopharyngeal and laryngeal cancer reported speaking less. Patients with advanced stage cancer and a tumor in a facial area and those that received reconstructive surgery were more likely to have a negative body image. CONCLUSIONS: Dissatisfaction with body image, greater symptom severity, and hypopharyngeal and laryngeal cancer are predictive of the amount HNC patients speak, as compared with the amount they spoke before having HNC. Clinicians should be aware of and systematically assess communication problems of HNC patients to promote their social function. Further research on interventions that facilitate the development of a positive body image and communication is strongly suggested.

Return to work in head and neck cancer survivors: its relationship with functional, psychological, and disease-treatment factors.

PURPOSE: Return to work (RTW) is important for survivors of head and neck cancer (HNC). The purposes of the study were to investigate the RTW ratio among HNC survivors and identify factors significantly affecting RTW in this population. METHODS: A cross-sectional study with consecutive sampling was conducted in a medical center in Taiwan, with 111 patients with HNC who had completed major treatments within 5 years and were employed before their cancer diagnosis enrolled as participants. Cervical range of motion (CROM) functionality, handgrip and hip flexor strength, maximal mouth opening (MMO), selected symptoms, depression, and disease/treatment-related factors were assessed. All of the factors were analyzed using t-test, chi-square test, and multiple logistic regression. RESULTS: Less than half (44.1%, n = 49) of the participants had returned to work. The t-test/chi-square test results showed the RTW group to be younger in age and better educated; have better handgrip/hip flexor strength, MMO, and CROM; have less speech difficulty and pain; and have less-advanced cancer than the non-RTW group. Further analysis of the above significant variables by logistic regression revealed early cancer stage, dominant handgrip strength, and less speech difficulty were the robust factors related to RTW. CONCLUSIONS: The RTW ratio is low in HNC survivors. RTW in HNC survivors is a multifactorial and complicated issue and needs to be further examined. IMPLICATIONS FOR CANCER SURVIVORS: Assessing the factors related to RTW systematically and developing comprehensive interventions and rehabilitation programs to reduce related dysfunctions are necessary to enhance RTW ability in HNC survivors.

Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation.

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

Hydrogel Transformed from Nanoparticles for Prevention of Tissue Injury and Treatment of Inflammatory Diseases.

Functional hydrogels responsive to physiological and pathological signals have extensive biomedical applications owing to their multiple advanced attributes. Herein, engineering of functional hydrogels is reported via transformable nanoparticles in response to the physiologically and pathologically acidic microenvironment. These nanoparticles are assembled by a multivalent hydrophobic, pH-responsive cyclodextrin host material and a multivalent hydrophilic guest macromolecule. Driven by protons, the pH-responsive host-guest nanoparticles can be transformed into hydrogel, resulting from proton-triggered hydrolysis of the host material, generation of a hydrophilic multivalent host compound, and simultaneously enhanced inclusion interactions between host and guest molecules. By in situ forming a hydrogel barrier, the orally delivered transformable nanoparticles protect mice from ethanol- or drug-induced gastric injury. In addition, this type of nanoparticles can serve as responsive and transformable nanovehicles for therapeutic agents to achieve triggerable and sustained drug delivery, thereby effectively treating typical inflammatory diseases, including periodontitis and arthritis in rats. With combined advantages of nanoparticles and hydrogels, together with their good in vivo safety, the engineered transformable nanoparticles hold great promise in tissue injury protection and site-specific/local delivery of molecular and cellular therapeutic agents.

Identifying Epstein-Barr virus peptide sequences associated with differential IgG antibody response.

BACKGROUND: Epstein-Barr virus (EBV) infection contributes to cancers in a fraction of seropositive individuals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults. METHODS: A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity. RESULTS: Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A); and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1). CONCLUSION: This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans.

The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis.

Ubiquitin C-terminal hydrolase L1 (UCHL1), which is a deubiquitinating enzyme, is known to play a role in chemoresistance in cancers. However, its potential roles and mechanisms in the chemoresistance of breast cancer (BC) remain unclear. In this study, we examined its expression in patients with BC and employed Kaplan-Meier analysis and the log-rank test for survival analyses. It was found that up-regulated UCHL1 expression was positively associated with both chemoresistance and poor prognosis, especially in patients with HER2+ BC. Moreover, UCHL1 expression was elevated in HER2+ BC cells (SK-BR-3 and BT474). Similarly, doxorubicin (DOX)-resistant BC cells (MCF-7/DOX) had higher UCHL1 levels than MCF-7 cells. CCK-8 assay showed that BC cells with higher UCHL1 levels were more resistant to DOX. Furthermore, by inhibiting UCHL1 in BC cells with elevated UCHL1 expression, we demonstrated that UCHL1 promoted DOX-resistance in BC. Mechanistically, UCHL1 probably promoted DOX-resistance of BC by up-regulating free fatty acid (FFA) synthesis, as exhibited by reduced FFA synthase expression and resurrected DOX-sensitivity upon UCHL1 inhibition. Overall, UCHL1 up-regulation is associated with DOX-resistance and poor prognosis in patients with HER2+ BC. UCHL1 induces DOX-resistance by up-regulating FFA synthesis in HER2+ BC cells. Thus, UCHL1 might be a potential clinical target for overcoming DOX resistance in patients with HER2+ BC.

Facile Engineering of Indomethacin-Induced Paclitaxel Nanocrystal Aggregates as Carrier-Free Nanomedicine with Improved Synergetic Antitumor Activity.

Carrier-free nanomedicines mainly composed of drug nanocrystals are considered as promising candidates for next-generation nanodrug formulations. However, such nanomedicines still need to be stabilized by additive surfactants, synthetic polymers, or biologically based macromolecules. Based on the strong intermolecular interactions between indomethacin (IDM, a COX-2 inhibitor) and paclitaxel (PTX, a chemotherapy drug), we herein successfully engineered a novel kind of carrier-free nanomedicines that organized as IDM-induced PTX nanocrystal aggregates via one-pot self-assembly without any nonactive excipients. In the assemblies of IDM and PTX (IDM/PTX assemblies), PTX nanocrystals were casted with amorphous IDM molecules, like a "brick-cement" architecture. In serum, these nanoassemblies could rapidly collapse into a great number of smaller nanoparticles, thus targeting the tumor site through the EPR effect. Under the assistance of IDM on immunotherapy, the IDM/PTX assemblies showed obviously improved synergetic antitumor effects of immunotherapy and chemotherapy. The self-assembly of two synergistic active substances into nanomedicines without any nonactive excipients might open an alternative avenue and give inspiration to fabricate novel carrier-free nanomedicines in many fields.

A new prognostic histopathologic classification of nasopharyngeal carcinoma.

BACKGROUND: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response. METHODS: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS). RESULTS: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28). CONCLUSIONS: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Precancerous esophageal epithelia are associated with significantly increased scattering coefficients.

The progression of epithelial precancers into cancer is accompanied by changes of tissue and cellular structures in the epithelium. Correlations between the structural changes and scattering coefficients of esophageal epithelia were investigated using quantitative phase images and the scattering-phase theorem. An ex vivo study of 14 patients demonstrated that the average scattering coefficient of precancerous epithelia was 37.8% higher than that of normal epithelia from the same patient. The scattering coefficients were highly correlated with morphological features including the cell density and the nuclear-to-cytoplasmic ratio. A high interpatient variability in scattering coefficients was observed and suggests identifying precancerous lesions based on the relative change in scattering coefficients.

FNC, a novel nucleoside analogue, blocks invasion of aggressive non-Hodgkin lymphoma cell lines via inhibition of the Wnt/ß-catenin signaling pathway.

Chemotherapy is the primary therapy for malignant lymphoma (ML). However, the clinical outcome is still far from satisfactory. Consequently, an understanding of the mechanism of modulating cancer cell invasion, migration and metastasis is important for the development of more effective chemotherapeutic agents. FNC, 2'- deoxy- 2' -ß- fluoro -4'- azidocytidine, a novel cytidine analogue, has demonstrated significantly inhibitory effects on proliferation of several non-Hodgkin lymphoma (NHL) cell lines. A previous study indicated that FNC effectively inhibited the growth of Raji and JeKo-1 cells in dose-time dependent effects with IC50 values of 0.2µM and 0.097µM, respectively. This study was focused on investigating the anti-invasive properties of FNC on NHL cells and its potential mechanisms of action. Cell adhesion and transwell chamber assays were utilized to investigate the anti-invasive effects of FNC on Raji and JeKo-1 cells. Real-time PCR and Western blotting were employed to qualify the expression of ß-catenin, the glycogen synthase kinase-3 beta (GSK-3ß), E-cadherin vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The results revealed that FNC remarkably inhibited the adhesion, migration and invasion of two human aggressive non-Hodgkin lymphoma cell lines in a dose dependent manner. Furthermore, ß-catenin, MMP-2, MMP-9, VEGF mRNA and protein levels were decreased after FNC treatment, while GSK-3ß and E-cadherin increased. Our studies thus provide evidence and a rationale that FNC may offer an effective chemotherapeutic agent by regulating the invasion and metastasis of aggressive non-Hodgkin lymphoma via inhibition of the Wnt/ß-catenin signaling pathway.

Nanostructured poly(L-lactide) matrix as novel platform for drug delivery.

With the aim to establish new strategies for fabricating bioactive nanostructured matrices for controlled drug delivery or potential tissue engineering, a facile and one-pot protocol was developed in this study to produce drug-loaded poly(l-lactide) (PLLA) nanostructures by thermally induced phase separation. Using both steroidal and nonsteroidal anti-inflammatory drugs, we demonstrated that lipophilic drugs can be efficiently incorporated in either nanosheet-like or nanofibrous PLLA matrices. Thus entrapped drug was randomly distributed in the interconnected nanostructures in the form of nanoscaled crystals. In vitro release study revealed that drug release kinetics may be modulated, on the one hand, by the nanostructure of matrices, while on the other hand by the polymer concentration utilized for fabrication. As for hydrophilic compounds, they could be conveniently loaded into nanofibrous structure by post-fabrication absorption. In addition to the conceptual proof of potential applications of nanostructured PLLA matrices for controlled drug delivery, the strategy employed herein offers a new way to construct bioactive scaffolds, such as antibacterial or anti-inflammatory scaffolds, which may find broad applications for tissue regeneration and stem cells-based biotherapy.

Accuracy of faecal occult blood test and Helicobacter pylori stool antigen test for detection of upper gastrointestinal lesions.

OBJECTIVE: Highly sensitive guaiac-based faecal occult blood (Hemoccult SENSA) and Helicobacter pylori stool antigen testing might help detect upper gastrointestinal lesions when appended to a colorectal cancer screening programme with faecal immunochemical testing. We evaluated the diagnostic accuracies of two stool tests in detecting upper gastrointestinal lesions. DESIGN: Cross-sectional design. SETTING: Hospital-based and community-based screening settings. PARTICIPANTS: A hospital-based deviation cohort of 3172 participants to evaluate test performance and a community-based validation cohort of 3621 to verify the findings. INTERVENTIONS: Three types of stool tests with bidirectional endoscopy as the reference standard. OUTCOMES: Sensitivity, specificity and positive and negative likelihood ratios. RESULTS: For detecting upper gastrointestinal lesions in cases with negative immunochemical tests, the sensitivity, specificity, and positive and negative likelihood ratios of the guaiac-based and H pylori antigen tests were 16.3% (95% CI 13.3% to 19.8%), 90.1% (88.9% to 91.2%), 1.64 (1.31 to 2.07), and 0.93 (0.89 to 0.97), respectively, and 52.5% (48.1% to 56.9%), 80.6% (79.0% to 82.1%), 2.71 (2.41 to 3.04) and 0.59 (0.54 to 0.65), respectively. For detecting upper gastrointestinal lesions in cases with normal colonoscopy, the results of the guaiac-based and H pylori antigen tests were 17.9% (14.8% to 21.5%), 90.1% (88.9% to 91.2%), 1.81 (1.45 to 2.26) and 0.91 (0.87 to 0.95), respectively, and 53.1% (48.6% to 57.4%), 80.7% (79.1% to 82.2%), 2.75 (2.45 to 3.08) and 0.58 (0.53 to 0.64), respectively. Within the community, positive predictive values of the immunochemical and H pylori antigen tests were 36.0% (26.0% to 46.0%) and 31.9% (28.3% to 35.5%), respectively, for detecting lower and upper gastrointestinal lesions, which were similar to expected values. CONCLUSIONS: The H pylori stool antigen test is more accurate than the guaiac-based test in the screening of upper gastrointestinal lesions in a population with high prevalence of H pylori infection and upper gastrointestinal lesions. It is applicable to add the H pylori antigen test to the immunochemical test for pan detection. TRIAL REGISTRATION: NCT01341197 (ClinicalTrial.gov).