Scientists from North Carolina State University have developed a new drug delivery system in which a cocoon-like DNA nanocomposite is integrated with “caged worm” deoxyribonuclease(DNase) to achieve self-degradation for promoting drug release inside cells. The “worms” can be readily activated to degrade their cocoon to release encapsulated drugs in vivo anticancer efficacy and biocompatibility of this delivery system. This study was published in the Journal of the American Chemical Society.
Self-assembled DNA nanostructures have been developed with precisely controlled size and architecture. Because of DNA’s intrinsic biocompatibility and degradability, DNA nanostructures hold tremendous promise for drug delivery.
In this study, researchers have developed a bioinspired cocoon-like anticancer drug delivery system consisting of a deoxyribonuclease (ANase)-degradable DNA nanoclew(NCI) embedded with an acid-responsive DNaseⅠ nanocapsule(NCa) was developed for targeted cancer treatment. The NCI was assembled from a long-chain single-stranded DNA synthesized by rolling-circle amplification(RCA). Multiple GC-pair sequences were integrated into the NCI for enhanced loading capacity for the anticancer drug doxorubicin (DOX). Meanwhile, negatively charged DNaseⅠwas encapsulated in a positively charged acid-degradable polymeric nanogel to facilitate decoration of DNaseⅠinto the NCI by electrostatic interactions.
This study provides insights for the design of new prodrugs and can be further extended to engineer other programmes drug delievry systems.
Sun W, Jiang T, Lu Y, et al. Cocoon-Like Self-Degradable DNA Nanoclew for Anticancer Drug Delivery[J]. Journal of the American Chemical Society, 2014.
A study, published in Nature Medicine, reports that at least 2% of people over age 40 and 5% of people over 70 have mutations linked to leukemia and lymphoma in their blood cells.
As known to us, mutations in the body’s cells randomly accumulate as part of the aging process, and most are harmless. For some people, genetic changes in blood cells can develop in genes that play roles in initiating leukemia and lymphoma even though such people don’t have the blood cancers.
The researchers found that mutations in the blood would be associated with changes in stem cells that develop into blood cell, via zeroing in on such genetic mutations that were present in the blood but not in tumor samples from the same patients.
Many older people have mutations linked to leukemia. In 341 patients ages 40-49, fewer than 1% had mutations in 19 leukemia- or lymphoma-related genes. But among 475 people ages 70-79, over 5% did. And over 6% of the 132 people ages 80-89 had mutations in these genes.
The current study likely underestimates the percentage of people with mutations in leukemia and lymphoma genes because the researchers only were able to identify small mutations, not large structural variations or the insertions and deletions of chunks of genetic material.
Still, it would be premature for people to undergo genetic testing to see if they have mutations linked to leukemia and lymphoma as a means to predict their risk of blood cancers.
Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nature Medicine, 2014
Researchers at the Krummel’s Lab., UCSF, recently report that newly discovered population of immune cells in tumors is related to less severe cancer outcomes in humans, and may have therapeutic potential based on the study of 3,600 human tumors, as well as mouse experiments. The finding is published in the journal Cancer Cell.
They depleted the population of these already rare cells in mice and demonstrated that the immune system was then unable to control tumors, even when the mice were given immunotherapeutic treatments.
A rare cell type, present in most tumors, is found to confer immunity and thus assists in immune rejection of the tumor. The cells persist in trying to activate tumor-targeting T lymphocytes within the immune system, thereby strengthening anticancer effects.
Additionally, the researchers found specific molecules on the cells that serve as a signature for their identification, and molecules that might be targeted to boost the cells’ power to activate T lymphocytes.
As indicated from this study, patients who have antigen-presenting CD103+ dendritic cells live consistently longer than those with weak signatures. The association of the signature for such immune cells with better outcomes was especially strong in head and neck cancers and in breast cancers
Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen-Presenting Cells Critical for T Cell Immunity. Cancer Cell, 2014
Scientists from University Of California San Francisco have discovered a new type of immune cell which could have direct links with human cancer prognosis. This study was published in Cancer Cell.
It is well understood that antigen-presenting cells(APCs) within tumors typically do not maintain cytotoxic T cell(CTL) function, despite engaging them. Current cancer immunotherapies are based on enhancing the ability of host or introduced T cells to reject tumors. However efficient CTL function requires frequent repriming and abundant tumor macrophages, which capture CTL at the tumor margin, either fail to achieve this, and/or actively inhibit T cell responses.
In this study, researchers show that the abundant macrophages in tumors have a functional opposite, in the form of antigen-presenting CD103+DCs. These cells efficiently cross-present tumor antigens and are differentially distributed within the tumor microenvironment compared with tolerizing APCs. They also describe how intratumoral CD103+DCs are uniquely targetable, how their abundance is required for T cell therapy in mice, and how their transcript prevalence predicts outcome in human cancers.
This cell type discovered in this study presents opportunities for prognostic and therapeutic approaches across multiple cancer types.
Broz M L, Binnewies M, Boldajipour B, et al. Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen-Presenting Cells Critical for T Cell Immunity[J]. Cancer Cell, 2014.
Research from Zhaolong Chen, Dexin Yu, shows that Tunable SERS-Tags-Hidden Gold Nanorattles for Theranosis of Cancer Cells with Single Laser Beam.
In this study, STHGNRs for theranosis of cancer cells were produced by a galvanic replacement reaction between GMSSNs and HAuCl4. Their observed red-shift of SPR peak with increase of HAuCl4 is mainly due to reduction of the shell thickness (figure 1), which is consistent with our theoretical analysis. On one hand, increasing void size while fixing the inner core size and shell thickness constant, will contribute to the absorption band red-shift as the plasmon oscillation decreases in energy. This result is consist with the optical properties of hollow gold nanospheres. On the other hand, increasing shell thickness while fixing the inner core size and void size constant, will contribute to the SPR peak blue-shift. This result implies that STHGNRs takes on more solid-particle-like properties as inner cavity decreases and shell thickness increases. The SPR peak of 13 nm GNPs is approximately 520 nm. When it was trapped in hollow gold shell, the SPR peak would shift to lower energy, which can be explained with Halas’ Plasmon Hybridization Theory. The SPR peak of STHGNRs was readily tuned to NIR required for PTT and SERS detection by controlling the inner void sizes and shell thicknesses.
Zhaolong Chen, Dexin Yu, Tunable SERS-Tags-Hidden Gold Nanorattles for Theranosis of Cancer Cells with Single Laser Beam,Scientific Reports 4, Article number:6709, doi:10.1038/srep06709
Research from AIA Research Group shows that Increased N-glycosylation of Asn88 in serum pancreatic ribonuclease 1 is a novel diagnostic marker for pancreatic cancer.
The study shows that N-glycosylation at Asn88 in serum RNase1 was significantly increased in patients with PaCa. This finding was established using an immunoassay that was developed to determine the level of total RNase1 compared with that of RNase1 that was not N-glycosylated on Asn88 (Asn88-free). The increase levels of RNase1 with N-glycosylated Asn88 in the sera of patients suspected of having PaCa thus shows promise as a novel diagnostic marker for screening and detection of PaCa. The immunoassay and Western blot-base analysis were developed for detecting this change in N-glycosylation of RNase1 using RrhRN0723 mAb and RN3F34 mAb, respectively. Both antibodies directed against human RNase1 recognize the peptide region surrounding the Asn88N-glycosylation site containing unglycosylated Asn88, but not when its Asn88 is N-glycosylated. The EIA analysis using RrhRN0723 which allows the high-throughput and quantitative detection of the levels of Asn88-free RNase1 is suitable for clinical purpose. In contrast, the Western blot analysis using RN3F34 which allows the qualitative detection of the changes in N-glycosylation at Asn88 is good for research tool rather than clinical purpose.
AIA Research Group , Increased N-glycosylation of Asn88 in serum pancreatic ribonuclease 1 is a novel diagnostic marker for pancreatic cancer, Scientific Reports 4,Article number:6715, doi:10.1038/srep06715
Scientists from University of Luxembourg have identified a new effective biomarker which could be used to detect colorectal cancer. The study was published in British Journal of Cancer.
Despite progress made during the past decades, Colorectal Cancer(CRC) is still one of the most frequent and deadly cancers world-wide in both women and men. The primary cause of death is the development of distant metastases in organs such as liver and lungs. Strikingly, diagnosed in time, CRC can be cured in 9 out of 10 cases. Thus, it is highly important to identify more sensitive and specific CRC markers to strengthen the efficiency of early diagnosis as well as to improve therapeutic strategies.
Over the past years , some members of the family of suppressor of cytokine signaling(SOCS) proteins have emerged as potential tumor suppressors. In this study, researchers have examined the expression as well as the methylation status of SOCS proteins in primary colon tumors, its precursor lesions and distant normal tissue. They used laser microdissection (LMD) to select for a highly pure population of epithelial cells in primary CRC tumors as well as in normal colon tissue.
The results point towards the involvement of SOCS2 and SOCS6 in the carcinogenesis of CRC and demonstrate their potential use as biomarkers.
Letellier E, Schmitz M, Baig K, et al. Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer[J]. British journal of cancer, 2014, 111(4): 726-735.
A study, published in Science, reports that UK Investigators have discovered that lung cancer can stay hidden for over 20 years before suddenly turning into an aggressive form of the disease. The findings help improve early detection of the disease.
It is a great discovery that after the first genetic mistakes that cause the cancer, it can exist undetected for many years until new, additional faults trigger rapid growth of the disease. During its expansion, there is a surge of different genetic faults appearing in Separate areas of tumors, along with each distinct section evolving down different paths.
As an involved researcher said, “Lung cancer is the world’s deadliest cancer, killing an estimated 4,300 people a day. Many new targeted treatments make a limited impact on the disease, resulting in survival rate remaining significant low. By understanding how it develops we’ve opened up the disease’s evolutionary rule book in the hope that we can start to predict its next steps.”
The study also highlighted the role of smoking in the development of lung cancer. Many of the early genetic faults are caused by smoking. But as the disease evolved these became less important with the majority of faults now caused by a new process generating mutations within the tumour controlled by a protein called APOBEC.
The wide variety of faults found within lung cancers explains why targeted treatments have had limited success. Attacking a particular genetic mistake identified by a biopsy in lung cancer will only be effective against those parts of the tumour with that fault, leaving other areas to thrive and take over.
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science, 2014; 346 (6206): 251
Research from Xuefeng Gu and Maoying Fu showed that High expression of MAGE-A9 correlates with unfavorable survival in HCC. They concluded for the first time that MAGE-A9 can be recognized as a prognostic factor in HCC and that targeting MAGE-A9 may provide apromising therapeutic strategy for HCC treatment. Further studies that included more clinical samples of HCC are necessary to confirm our findings and to elucidate the possible mechanisms of MAGE-A9 characteristics in HCC.
In this study, they first investigated MAGE-A9mRNA expression in cell lines by RT-PCR. The results showed elevated MAGE-A9 expression in four HCC cell lines compared to non-cancerous cell lines. Subsequently, the expression of MAGE-A9 mRNA in fresh
HCC tissues and matched non-cancerous tissues was evaluated by qPCR.
For survival analysis, Cox proportional hazards regression models,in which the effect of covariates is to multiply the hazard function by a function of the explanatory covariates, have achieved widespread application in the analysis of time-to-event data, with censoring and covariates. Their research team also constructed an anti-MAGE-A1 immunotoxin and verified its anti-tumor effectiveness. Considering the oncogenic role of MAGE-A9 in cancer, the application of treatment targeting MAGE-A9 is anticipated, and a fully human anti-MAGE-A9 antibody is currently being generated by their research group.
Xuefeng Gu, Maoying Fu and Zhijun Ge,etc. High expression of MAGE-A9 correlates with unfavorable survival in hepatocellular carcinoma, Scientific Reports4, Article number:6625 doi:10.1038/srep06625
Results of researches from C S Monast and M J Lazzara highlight numerous other considerations that determine biochemical efficacy beyond those reflected by equilibrium affinities. By integrating these considerations, their model also predicts minimum therapeutic combination concentrations to maximally reduce receptor phosphorylation.
Their finding that the abilities of cetuximab and gefitinib to antagonize EGFR phosphorylation are determined by processes beyond those describing equilibrium drug binding motivates new consideration of optimal design strategies for EGFR-targeted therapeutics. To the extent that EGFR phosphorylation level correlates with clinical efficacy, these results also identify possible factors that could underlie the differential effectiveness of the therapeutics among patients.
The identification of EGFR dephosphorylation kinetics as a key determinant of therapeutic biochemical efficacy is intriguing given that the activities of protein tyrosine phosphatases that regulate EGFR are altered in certain cancer settings.
Their results also predict IC50 dependence on the rates of drug and ligand association and dissociation, even for constant affinities. Their prediction that slowing EGFR gefitinib binding and dissociation cycling decreases IC50 is consistent with the observation that slower erlotinib cycling promotes growth inhibition of lung and brain cancer cells.
Identifying Determinants of EGFR-Targeted Therapeutic Biochemical Efficacy Using Computational Modeling, CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e141; doi:10.1038/psp.2014.39