In vitro anti-inflammatory, anti-arthritic and anti- proliferative activity of green synthesized silver nanoparticles - Phoenix dactylifera (Rothan dates)

Abstract Traditionally dates is consumed as a rich source of iron supplement and the current research discuss the synthesis of silver nanoparticles (AgNPs) using methanolic seed extract of Rothan date and its application over in vitro anti-arthritic, anti-inflammatory and antiproliferative activity against lung cancer cell line (A549). FTIR result of synthesised AgNPs reveals the presence of functional group OH as capping agent. XRD pattern confirms the crystalline nature of the AgNPs with peaks at 38º, 44º, 64º and 81º, indexed by (111), (200), (220) and (222) in the 2θ range of 10-90, indicating the face centered cubic (fcc) structure of metallic Ag. HR- TEM results confirm the morphology of AgNPs as almost spherical with high surface areas and average size of 42 ± 9nm. EDX spectra confirmed that Ag is only the major element present and the Dynamic light scattering (DLS) assisted that the Z-average size was 203nm and 1.0 of PdI value. Zeta potential showed − 26.5mv with a single peak. The results of the biological activities of AgNPs exhibited dose dependent activity with 68.44% for arthritic, antiinflammatory with 63.32% inhibition and anti-proliferative activity illustrated IC50 value of 59.66 µg/mL expressing the potential of AgNPs to combat cancer

A New Method for Syndrome Classification of Non-Small-Cell Lung Cancer Based on Data of Tongue and Pulse with Machine Learning.

OBJECTIVE: To explore the data characteristics of tongue and pulse of non-small-cell lung cancer with Qi deficiency syndrome and Yin deficiency syndrome, establish syndrome classification model based on data of tongue and pulse by using machine learning methods, and evaluate the feasibility of syndrome classification based on data of tongue and pulse. METHODS: We collected tongue and pulse of non-small-cell lung cancer patients with Qi deficiency syndrome (n = 163), patients with Yin deficiency syndrome (n = 174), and healthy controls (n = 185) using intelligent tongue diagnosis analysis instrument and pulse diagnosis analysis instrument, respectively. We described the characteristics and examined the correlation of data of tongue and pulse. Four machine learning methods, namely, random forest, logistic regression, support vector machine, and neural network, were used to establish the classification models based on symptom, tongue and pulse, and symptom and tongue and pulse, respectively. RESULTS: Significant difference indices of tongue diagnosis between Qi deficiency syndrome and Yin deficiency syndrome were TB-a, TB-S, TB-Cr, TC-a, TC-S, TC-Cr, perAll, and the tongue coating texture indices including TC-CON, TC-ASM, TC-MEAN, and TC-ENT. Significant difference indices of pulse diagnosis were t4 and t5. The classification performance of each model based on different datasets was as follows: tongue and pulse < symptom < symptom and tongue and pulse. The neural network model had a better classification performance for symptom and tongue and pulse datasets, with an area under the ROC curves and accuracy rate which were 0.9401 and 0.8806. CONCLUSIONS: It was feasible to use tongue data and pulse data as one of the objective diagnostic basis in Qi deficiency syndrome and Yin deficiency syndrome of non-small-cell lung cancer.

Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy.

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.

Neuroendocrine tumors of the lung: hystological classification, diagnosis, traditional and new therapeutic approaches.

Lung neuroendocrine tumors are neoplasms originating from bronchopulmonary neuroendocrine cells, usually Kulchitsky cells, loaded with argentaffin granules. They account for 20-25% of all primitive lung tumors, the most common being the small-cell undifferentiated carcinoma. They include different tumors, from tumors of low-grade malignancy, especially the typical carcinoids, with high survival rates after surgical therapy, to the high-grade malignancy tumors, especially small-cell undifferentiated carcinomas. The latter have very few indications for surgical treatment with a low survival rate, even after multimodal therapy. The aim of this review is to describe the present knowledge and discuss possible new developments in the management of pulmonary neuroendocrine tumors. The authors examine and discuss in particular the role that surgical techniques should have in the treatment of small-cell lung cancer in opposition to a nihilism position that has limited therapies to non-surgical approaches. The critical review of this attitude opens the door to a more aggressive approach. In the meantime the review shows that it might be possible to include the new minimally invasive percutaneous ablative techniques as cryosurgery, thermotherapy and irreversible electroporation within a modern and flexible framework. The authors also present the hypothesis that cancer stem cells (CSC) are at the basis of recurrences of small-cell lung cancer (SCLC) and therefore that the issue is of difficult solution with the conventional oncologic approach considering the chemo-resistance of CSC to drugs. For these reasons an epigenetic therapy based on differentiation factors is proposed alongside the usual surgical and chemo-radiation protocols.

NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.

BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

An algorithm for classifying tumors based on genomic aberrations and selecting representative tumor models.

BACKGROUND: Cancer is a heterogeneous disease caused by genomic aberrations and characterized by significant variability in clinical outcomes and response to therapies. Several subtypes of common cancers have been identified based on alterations of individual cancer genes, such as HER2, EGFR, and others. However, cancer is a complex disease driven by the interaction of multiple genes, so the copy number status of individual genes is not sufficient to define cancer subtypes and predict responses to treatments. A classification based on genome-wide copy number patterns would be better suited for this purpose. METHOD: To develop a more comprehensive cancer taxonomy based on genome-wide patterns of copy number abnormalities, we designed an unsupervised classification algorithm that identifies genomic subgroups of tumors. This algorithm is based on a modified genomic Non-negative Matrix Factorization (gNMF) algorithm and includes several additional components, namely a pilot hierarchical clustering procedure to determine the number of clusters, a multiple random initiation scheme, a new stop criterion for the core gNMF, as well as a 10-fold cross-validation stability test for quality assessment. RESULT: We applied our algorithm to identify genomic subgroups of three major cancer types: non-small cell lung carcinoma (NSCLC), colorectal cancer (CRC), and malignant melanoma. High-density SNP array datasets for patient tumors and established cell lines were used to define genomic subclasses of the diseases and identify cell lines representative of each genomic subtype. The algorithm was compared with several traditional clustering methods and showed improved performance. To validate our genomic taxonomy of NSCLC, we correlated the genomic classification with disease outcomes. Overall survival time and time to recurrence were shown to differ significantly between the genomic subtypes. CONCLUSIONS: We developed an algorithm for cancer classification based on genome-wide patterns of copy number aberrations and demonstrated its superiority to existing clustering methods. The algorithm was applied to define genomic subgroups of three cancer types and identify cell lines representative of these subgroups. Our data enabled the assembly of representative cell line panels for testing drug candidates.

The in vitro and in vivo apoptotic effects of Mahonia oiwakensis on human lung cancer cells.

Both the root and stem bark of Mahonia species were popular folk medicines. The plant has several proven biological activities including anti-bacterial, anti-fungal, and anti-inflammatory effects. However, Mahonia has not been studied for its anticancer effects. In the present study, we made extracts from Mahonia oiwakensis (MOE), a selected species in Taiwan, and investigated their effects on various human lung cells. We found that MOE-induced apoptotic death in human A549 non-small-cell lung carcinoma (NSCLC) cells in a dose- and time-dependent manner. Treatment with the extracts also caused an increase in the sub-G1 fraction of cells, chromosome condensation, and DNA fragmentation. The mitochondrial-mediated pathway was implicated in this MOE-induced apoptosis as evidenced by the activation of the caspase cascade, cleavage of poly (ADP-ribose) polymerase (PARP), disruption of mitochondrial membrane potential, and release of cytochrome C. A higher ratio of Bax/Bcl-2 proteins and cleavage of Bid were also observed in MOE-induced cell apoptosis. In A549 tumor-xenografted nude mice, MOE also retarded in vivo proliferation (P<0.05) and induced apoptosis in tumor cells, as shown by a decrease in Ki-67-positive staining (P<0.05) and increased transferase-mediated dUTP nick-end labeling (TUNEL)-positive staining (P<0.05). In conclusion, MOE inhibits the growth of human lung cancer cells in vitro and in vivo, suggesting that it may have therapeutic potential against human lung cancer.

Re-classification of pTNM staging for lung cancer: single-institution report at a Japanese comprehensive cancer hospital.

Among the major cancer sites, the lung has the most complicated pTNM description. Reclassification of International Union Against Cancer (UICC)-pTNM grading of 262 lung cancers resected at Shikoku Cancer Center was done using microscopy and audit of pathology reports. Of the 262 lung cancers, 222 were obtained at operation from 1999 to 2004 and 40 additional cases from 2006. Among 666 pTNM components of the former cases, 37 components (31T, 3N, 3M) in 35 cases were revised to different categories. The concordance rate (CR) of the original stage to the reclassified stage was 90% (210/222) in the five-group staging system (5GSS) without subdivisions and 84% (187/222) in the 8GSS with subdivisions such as IA and IB. It decreased in advanced cases. For example, the CR was higher in stage I (97%, 158/163) than in stage II-IV (88%, 51/59) in five-GSS (chi(2) test, P < 0.05). The CR in 8GSS of the additional 40 cases, which were diagnosed after the review of the former 222 cases, was 98% (39/40), indicating that the knowledge gained from the review improved the accuracy significantly (chi(2) test, P < 0.05). It is necessary to assess disparities in the accuracy of pTNM for lung cancer at each institution. This is also true for cancers at other sites.

Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.

Selective kinase inhibitors have had a substantial impact on the field of medical oncology. Whereas these agents can elicit dramatic clinical responses in some settings, their activity is generally limited to a subset of treated patients whose tumor cells harbor a specific genetic lesion. We have established an automated platform for examining the sensitivity to various molecularly targeted inhibitors across a large panel of human tumor-derived cell lines to identify additional genotype-correlated responses that may be clinically relevant. Among the inhibitors tested in a panel of 602 cell lines derived from a variety of human cancers, we found that a selective inhibitor of the anaplastic lymphoma kinase (ALK) potently suppressed growth of a small subset of tumor cells. This subset included lines derived from anaplastic large cell lymphomas, non-small-cell lung cancers, and neuroblastomas. ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of anaplastic large cell lymphoma patients, and has recently been implicated as an oncogene in a small fraction of non-small-cell lung cancers and neuroblastomas. Significantly, sensitivity in these cell lines was well correlated with specific ALK genomic rearrangements, including chromosomal translocations and gene amplification. Moreover, in such cell lines, ALK kinase inhibition can lead to potent suppression of downstream survival signaling and an apoptotic response. These findings suggest that a subset of lung cancers, lymphomas, and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition.

The influence of socio-economic and locational disadvantage on survival after a diagnosis of lung or breast cancer in Western Australia.

OBJECTIVE: The effects of demographic, locational and socio-economic disadvantage, and the influence of private health care on five-year mortality rates in patients with lung cancer or after breast cancer surgery in Western Australia were examined. METHODS: The Western Australian Record Linkage Project was used to extract all hospital morbidity, cancer and death records of all people with lung or breast cancer in Western Australia from 1982 to 1996. Mortality rate ratios after a diagnosis of lung cancer or breast cancer surgery were estimated using Cox regression. Two sets of analyses were carried out: demographically adjusted from 1982 to 1996; and demographically and disadvantage adjusted from 1992 to 1996. RESULTS: Overall, 87.7% of lung cancer and 17.8% of breast cancer patients were deceased by five years. Lung and breast cancer patients treated in rural hospitals had higher mortality rates (1992-1996: relative risk (RR) 1.24, 95% confidence interval (CI) 1.07-1.44, and RR 1.20, 95% CI 0.92-1.56, respectively; 1982-1996: RR 1.20, 95% CI 1.11-1.30, and RR 1.19, 95% CI 1.06-1.33, respectively), whereas location of residence had little effect. Lung and breast cancer patients treated in private hospitals had lower mortality (1992-1996: RR 0.85, 95% CI 0.76-0.95, and RR 0.90, 95% CI 0.77-1.05, respectively; 1982-1996: RR 0.91, 95% CI 0.84-0.97, and RR 0.92, 95% CI 0.85-0.99, respectively), although insurance status was not a factor. Women with breast cancer had significantly worse survival in the more socio-economically disadvantaged groups (1992-1996: RR 1.41 to 1.26; 1982-1996: RR 1.45 to 1.29). CONCLUSIONS: Survival was poorer in patients treated in the public hospital system, but the possession of private health insurance was not predictive of better outcomes. People treated in rural hospitals had worse survival, whereas location of residence was not an independent factor. Women in more socio-economically advantaged groups who underwent breast cancer surgery had improved survival.

Appraising the economic efficiency of cancer treatment: an exploratory analysis of lung cancer.

This paper tests whether the measured cost-effectiveness of treating different subgroups of an incident population of lung cancer patients differs significantly and, by implication, whether the provision of care to these patients is tolerably efficient in economic terms. Data from administrative records and Registry follow-up on 544 non-small cell lung cancer patients diagnosed at a single NCI-designated Comprehensive Cancer Center are used to conduct the empirical analysis. The main results show statistically significant differences in cumulative costs and patient outcomes across subgroups differing by disease stage and treatment modality. These findings imply that the delivery of lung cancer care is inefficient. Substantive and methodological implications are discussed.

A comparison between the localization of lung tumors in uranium miners and in nonminers from 1947 to 1991.

BACKGROUND: Lung cancer was noted to be increased in cigarette smoking miners and nonminers. Carcinogen particulates deposit differentially in the central, middle, and peripheral zones of the bronchial tree depending on the size of the particle. The object of this study was to evaluate the incidence of tumors; their cell types; and the relationship of particulate size to their position in the bronchial tree. METHODS: Tumor position in the bronchial tree was studied for a cohort of 467 uranium miners and 311 nonminers with lung cancer. RESULTS: An examination of all histologic subtypes showed that the proportion of lung cancers in the central zone was significantly greater in miners than in nonminers presumably due to the deposition of radon decay products attached to the silica dust particles. The higher percentage of central tumors in the miners was primarily due to the distribution of a greater proportion of squamous cell and small-cell tumors. The ratio of 0.75 for the central to middle and peripheral location for adenocarcinomas was much lower than for squamous cell and small-cell carcinomas with ratios of 1.4 and 7.3, respectively. In the mining cohort, there were ten times as many small-cell tumors in the central area as in the middle and peripheral regions, whereas, for the nonminers there were only five times as as many centrally located small-cell tumors as middle and peripheral (chi square is 7.0 degrees, P < 0.01). These data suggest that radon may be deposited preferentially to the central region of the lungs in uranium miners. CONCLUSIONS: Based on our observations of the differential positions of lung tumors in the bronchial tree for miners and nonminers and previous studies by others regarding size-dependent deposition of particulates in the bronchial tree, it is concluded that inhaled dust, radon, and cigarette smoke combine to form large particulates that deposit in the central bronchial tree. Filtered cigarette smoke or other small carcinogens from smaller particulates that deposit more peripherally.

Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors.

A binational panel of four Japanese and four American pathologists examined 208 pulmonary neoplasms, according to the World Health Organization (WHO) recommendations, second edition, for the histologic typing of lung tumors. The study design included independent evaluations by pathologists working alone, followed by group reviews. The individual evaluations, and their implications for reproducibility of the WHO recommendations, are reported. Consensus (agreement by six or more pathologists) with respect to major (ie, first digit) diagnosis was obtained for 76.4% of the cases. Consensus was obtained for 72.5% of the cases with any major diagnosis of small cell cancer; the comparable figures for adenocarcinoma and squamous cell carcinoma were 56% and 48%, respectively. American pathologists were twice as likely as Japanese pathologists to diagnose large-cell cancer, the only significant national difference. Consensus was far less frequent with the minor (ie, second digit) diagnosis categories. This study shows that lung cancers continue to be difficult to classify reproducibly.

[Probe into internal relation between classification of the differentiation-syndrome in traditional Chinese medicine and serum copper and zinc in lung cancer].

This article probed into the internal relations and significance between differentiation of syndrome of traditional Chinese medicine (TCM) and trace elements--copper and zinc in lung cancer patients. The serum copper and zinc of 95 patients with lung cancer and 82 healthy persons were measured. According to differentiation of syndrome of TCM types of 95 lung cancer patients were divided, and the relations with their levels of serum copper, zinc and the ratio of copper/zinc compared respectively. The authors found that there were some inner links among the differentiation syndromes and levels of serum copper, zinc and its ratio. The result showed that the level of Cu/Zn ratio could reflect increase and decrease of body resistance and pathogenic factors the level of Cu/Zn ratio was more significant than that of copper and zinc. The authors suggested that the ratio of Cu/Zn could be used as the criteria of differentiation of syndrome of TCM. It is clinically significant to combine the level of copper, zinc and its ratio with differentiation of syndrome of TCM to evaluate the severity and prognosis of the patients and to direct the treatment of them with TCM.