Respirable antisense oligonucleotides: a new drug class for respiratory disease

Respirable antisense oligonucleotides (RASONs), which attenuate specific disease-associated mRNAs, represent a new class of respiratory therapeutics with considerable potential. RASONs overcome previous obstacles that have impeded the development of antisense therapeutics targeting diseases in other organ systems. RASONs are delivered directly to the target tissue via inhalation; their uptake seems to be enhanced by cationic properties inherent in pulmonary surfactant, and, because of the markedly different target properties of mRNA and proteins, they can have very long durations of effect compared with traditional drugs targeting the protein of the same gene. RASONs contain chemical modifications that decrease their degradation by cellular nucleases. However, total insensitivity to nucleases is probably not an optimal design criterion for RASONs, because moderate nuclease sensitivity can prevent their systemic delivery, decreasing the potential for systemic toxicity. EPI-2010 is a 21-mer phosphorothioate RASON that attenuates bronchoconstriction, inflammation and surfactant depletion in preclinical models of human asthma, has a duration of effect of seven days, and seems to undergo minimal systemic delivery

Palpation Device for the Identification of Kidney and Bladder Cancer: A Pilot Study

PURPOSE: To determine the ability of a novel palpation device to differentiate between benign and malignant tissues of the kidney and bladder by measuring tissue elasticity. MATERIALS AND METHODS: A novel palpation device was developed, mainly composed of a micromotor, a linear position sensor, a force transducer, and a hemisphere tip and cylindrical body probe. Motion calibration as well as performance validation was done. The tissue elasticity of both benign and malignant tissues of the kidney and bladder was measured using this device. A single investigator performed the ex-vivo palpation experiment in twelve kidneys and four bladder specimens. Malignant tissues were made available from partial nephrectomy specimens and radical cystectomy specimens. Palpations for benign renal parenchyma tissue were carried out on nephroureterectomy specimens while non-involved areas in the radical cystectomy specimens were used for benign bladder samples. Elastic modulus (Young's modulus) of tissues was estimated using the Hertz-Sneddon equation from the experimental results. These were then compared using a t-test for independent samples. RESULTS: Renal cell carcinoma tissues appear to be softer than normal kidney tissues, whereas tissues from urothelial carcinoma of the bladder appear to be harder than normal bladder tissues. The results from renal cell carcinoma differed significantly from those of normal kidney tissues (p=0.002), as did urothelial carcinoma of the bladder from normal bladder tissues (p=0.003). CONCLUSION: Our novel palpation device can potentially differentiate between malignant and benign kidney and bladder tissues. Further studies are necessary to verify our results and define its true clinical utility.ope

Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition.</p> <p>Methods</p> <p>To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis.</p> <p>Results</p> <p>Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI₅₀values (<it>i.e</it>., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells.</p> <p>Conclusion</p> <p>Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.</p

DNA Methylation-Independent Reversion of Gemcitabine Resistance by Hydralazine in Cervical Cancer Cells

BACKGROUND: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase

The elite's collective subjectivities of the history of ethnic politics in Malaysia

Malaysia is one of the multi-ethnic, multi-cultural and multi-religious countries in Southeast Asia. Due to the pluralistic nature of Malaysia, it has a political structure based on ethnic politics. The ethnic preferential policies affected most domains of this country. The objective of this article is to examine the origin and background of ethnic politics in Malaysia. Findings of this study indicate that, ethnic politics originated during the British colonial period, it became a tool used by the Barisan Nasional for the legitimacy of regime. Moreover, ethnic politics in Malaysia today is intertwined with religion. Besides, there is the dilemma of the choice between the interest of certain ethnic group and national interests. However, with the opposition coalition Pakatan Harapan won the election in 9th May, UMNO-led BN lost power and interrupted its 61 years control, which leaves us an interesting topic to think about the future of Malaysian ethnic politics

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After ad'justing for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials. © 1999 Cancer Research Campaig