Iron imbalance in cancer: Intersection of deficiency and overload.

Iron, an essential trace element, plays a complex role in tumour biology. While iron causes cancer clearance through toxic free radical generation, iron-induced free radical flux also acts as a cancer promoter. These fates majorly guided through cellular response towards pro-oxidant and antioxidant settings in a tumour microenvironment, designate iron-induced oxidative stress as a common yet paradoxical factor in pro-tumorigenesis as well as anti-tumorigenesis, posing a challenge to laying down iron thresholds favouring tumour clearance. Additionally, complexity of iron's association with carcinogenesis has been extended to iron-induced ROS's involvement in states of both iron deficiency and overload, conditions identified as comparable, inevitable and significant coexisting contributors as well as outcomes in chronic infections and tumorigenesis. Besides, iron overload may also develop as an unwanted outcome in certain cancer patients, as a result of symptomatic anaemia treatment owed to irrational iron-restoration therapies without a prior knowledge of body's iron status with both conditions synergistically acting towards tumour aggravation. The co-play of iron deficiency and overload along with iron's pro-tumour and antitumour roles with intersecting mechanisms, thus presents an unpredictable regulatory response loop in a state of malignancy. The relevance of iron's thresholds beyond which it proves to be beneficial against tumorigenesis hence becomes questionable. These factors pose a challenge, over establishing if iron chelation or iron flooding acts as a better approach towards antitumour therapies. This review presents a critical picture of multiple contrasting features of iron's behaviour in cancer, leading towards two conditions lying at opposite ends of a spectrum: iron deficiency and overload in chronic disease conditions including cancer, hence, validating the critical significance of diagnosis of patients' iron status prior to opting for subsequent therapies.

Pharmacogenomics and Personalized Medicine in Type 2 Diabetes Mellitus: Potential Implications for Clinical Practice.

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient's genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and "multiomics" studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.

Correction to: EpCAM aptamer mediated cancer cell specific delivery of EpCAM siRNA using polymeric nanocomplex.

An amendment to this paper has been published and can be accessed via the original article.

Gene expression profiling of tumor stroma interactions in retinoblastoma.

We aimed to identify the critical molecular pathways altered upon tumor stroma interactions in retinoblastoma (RB). In vitro 2 D cocultures of RB tumor cells (Weri-Rb-1 and NCC-RbC-51) with primary bone marrow stromal cells (BMSC) was established. Global gene expression patterns in coculture samples were assessed using Affymetrix Prime view human gene chip microarray and followed with bioinformatics analyses. Key upregulated genes from Weri-Rb-1 + BMSC and NCC-RbC-51 + BMSC coculture were validated using qRT-PCR to ascertain their role in RB progression. Whole genome microarray experiments identified significant (P ≤ 0.05, 1.1 log 2 FC) transcriptome level changes induced upon coculture of RB cells with BMSC. A total of 1155 genes were downregulated and 1083 upregulated in Weri-Rb-1 + BMSC coculture. Similarly, 1865 genes showed downregulation and 1644 genes were upregulation in NCC-RbC-51 + BMSC coculture. The upregulated genes were significantly associated with pathways of focal adhesion, PI3K-Akt signalling, ECM-receptor interaction, JAK-STAT, TGF-ß signalling thus contributing to RB progression. Validation of key genes by qRT-PCR revealed significant overexpression of IL8, IL6, MYC and SMAD3 in the case of Weri-Rb-1 + BMSC coculture and IL6 in the case of NCC-RbC-51 + BMSC coculture. The microarray expression study on in vitro RB coculture models revealed the pathways that could be involved in the progression of RB. The gene signature obtained in a stimulated model when a growing tumor interacts with its microenvironment may provide new horizons for potential targeted therapy in RB.

Author Correction: Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Evidence of Tumour Microenvironment and Stromal Cellular Components in Retinoblastoma.

BACKGROUND: The tumour microenvironment (TME) consisting of tumour cells and multiple stromal cell types regulate tumour growth, invasion and metastasis. While the concept of TME and presence of stromal cellular components is widely established in cancers, its significance in the paediatric intraocular malignancy, retinoblastoma (RB), remains unknown. METHODS: The study qualitatively identified the presence of multiple stromal cellular subtypes in RB TME by immunohistochemistry. RESULTS: Results of the study identified the presence of stromal cell types such as endothelial cells, tumour-associated macrophages, fibroblasts, cancer-associated fibroblasts, retinal astrocytes and glia in RB TME. The extent of stromal marker positivity, however, did not correlate with histopathological features of RB. CONCLUSIONS: The findings of the study convincingly suggest the presence of a stromal component in RB tumours. The interactions between stromal cells and tumour cells might be of profound importance in RB progression.

Correction to: Engineered atherosclerosis-specific zinc ferrite nanocomplex-based MRI contrast agents.

After publication of the original article [1], the authors found that Figure 2e (Hsp70-Ch-Lf-ZF in Jurkat cells, 2 h), Figure 5b (HSP70-Lf-ZF) and Figure 5c (control) contained incorrect images. This does not affect the figure legends, results and conclusions of the article.

Utility of nanomedicine targeting scar-forming myofibroblasts to attenuate corneal scarring and haze.

Corneal scarring refers to the loss of normal corneal tissue, replaced by fibrotic tissue (during wound repair) thereby affecting corneal transparency and vision quality. The corneal wound healing process involves a complex series of physiological events resulting in the transformation of transparent keratocytes into opaque myofibroblasts; the prominent cause of irregular extracellular matrix synthesis leading to the development of corneal opacity/hazy vision. Globally, corneal scarring/haze is one of the most prevalent causes of blindness. Ocular trauma (physical and chemical) and microbial infections induce corneal tissue damage. Although great progress has been made in the clinical management of ocular diseases, the global rates of corneal blindness remain high, nonetheless. The topical conventional modalities treating corneal wounds/injuries have inherent limitations/side effects such as low bioavailability of a therapeutic agent, upregulation of the intraocular pressure and the toxicity/allergy of the drug. These limitations/side effects rather than treating the wound, often negatively affect the healing process, especially, when applied frequently for longer periods. Recently, there has been an increasing evidence provided by the preclinical studies that nanotechnology-based drug-delivery systems can improve drug bioavailability, through controlled drug release and targeted delivery. After reviewing the epidemiology, risk factors of corneal scarring/haze and the conventional ocular medicines, we review here the different nanodrug-delivery systems and potential drug candidates including nanoherbal formulations investigated for their efficacy to heal the damaged cornea. Finally, we discuss the challenges of using these nanomedicinal platforms.

Correction to: Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer.

After publication of the original article [1], the authors found that Fig. 3 contained an incorrect version of Fig. 3c. This does not affect the Figure legend, results and conclusions of the article.

Correction: Survivin Mutant Protects Differentiated Dopaminergic SK-N-SH Cells Against Oxidative Stress.

[This corrects the article DOI: 10.1371/journal.pone.0015865.].

Corrigendum: Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze.

[This corrects the article DOI: 10.3389/fphar.2017.00223.].

Erratum: "Quick chip assay using locked nucleic acid modified epithelial cell adhesion molecule and nucleolin aptamers for the capture of circulating tumor cells" [Biomicrofluidics 9(5), 054110 (2015)].

[This corrects the article DOI: 10.1063/1.4930983.].

Aged macular degeneration: current therapeutics for management and promising new drug candidates.

In elderly aged related macular degeneration (AMD) is the common eye disease which impairs the vision and most of the time it creates permanent vision loss. Because elderly population constitute the larger percentage among society, visual loss due to AMD has become a growing problem. Despite the advances made in developing therapeutics, there is still no satisfactory treatment. The limitations of the available treatments are due to the absence of potent, non-invasive therapy. Furthermore, part of the available drugs targets angiogenesis and create a hypoxic environment that augment further angiogenesis. Therefore, it is reasonable to consider eye integrity and the correlation between hypoxia and angiogenesis before developing successful drugs. This review highlighted issues regarding the available therapeutic strategies and explored whether AMD can be managed by employing specific nanoformulations.

Neocarzinostatin, Aptamer Conjugates for Targeting EpCAM-positive Tumor Cells.

BACKGROUND/AIM: The aim of this study was to investigate the role of Neocarzinostatin (NCS) conjugated with epithelial cell adhesion molecule (EpCAM) aptamer in EpCAM-positive cancer cells. NCS is an antitumor antibiotic protein chromophore that has the ability to cleave double stranded DNA and can be used as a potential drug for the treatment of EpCAM-positive cancers. EpCAM aptamer is an oligonucleotide ligand that binds specifically to EpCAM, a protein overexpressed in tumor cells. MATERIALS AND METHODS: NCS was conjugated with EpCAM aptamer using Sulfo-Succinimidyl 6-(3-(2-pyridyldithio) - propionamide hexanoate) LC-(SPDP) cross-linker to deliver it to EpCAM-positive tumor cells. The conjugates were characterized using polyacrylamide gel electrophoresis (PAGE) and high-performance liquid chromatography (HPLC). Flow cytometry was used to study the binding efficiency of the aptamer and the conjugates in cancer cells. The effect of the conjugate on cancer cells was studied using propidium iodide (PI) to analyze the cell cycle phase changes. The apoptosis assay was performed using the IC50 concentration of NCS. Microarrays were performed to study the gene level changes in cancer cells upon treatment with NCS and the conjugate. RESULTS: Flow cytometry revealed significant binding of aptamer and conjugate in the MCF-7 and WERI-Rb1 cell lines. Briefly, 62% in MCF and 30% in WERI-Rb1 cells with conjugate treated cells (p<0.005). The cell-cycle analysis indicated G2 phase arrest in MCF-7 cells and S phase arrest in WERI-Rb1 cells (p<0.005). Microarray analysis showed differentially expressed genes involved in cell cycle, DNA damage, and apoptosis. The BrDU assay and the apoptosis assay showed that the expression of BrDU was reduced in conjugate-treated cells and the PARP levels were increased confirming the double stranded DNA breaks (p<0.005). In MCF-7 and WERI-Rb1 cells, most of the cells underwent necrosis (p<0.005). CONCLUSION: The EpCAM aptamer conjugated NCS showed specificity to EpCAM-positive cells. The effect of the conjugates on cancer cells were impressive as the conjugate arrested the cell cycle and promoted apoptosis and necrosis. The high levels of PARP expression confirmed the DNA breaks upon conjugate treatment. Our study demonstrates that the NCS conjugated with EpCAM can be targeted to cancer cells sparing normal cells.

Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze.

Alkali burn injury is a true ocular emergency of the conjunctiva and cornea that requires immediate precision. Lack of an immediate therapy can lead to a substantial damage in the ocular surface and anterior segment further causing visual impairment and disfigurement. We explored the regenerative capability of dominant negative survivin protein (SurR9-C84A) and histone deacetylase inhibitor trichostatin-A (TSA) in vivo, in a rat alkali burn model. A topical insult in rat eyes with NaOH led to degradation of the conjunctival and corneal epithelium. The integrity of the conjunctival and corneal tissue was increased by TSA and SurR9-C84A by improving the clathrin and claudin expressions. Wound healing was initiated by an increase in TGF-beta-1 and, increased endogenous survivin which inhibited apoptosis post-TSA and SurR9-C84A treatments. Protein expressions of fibronectin and alpha-integrin 5 were found to increase promoting corneal integrity. The cytokine analysis confirmed increased expressions of IL-1beta, IL-6, IL-12, IL-13, IFN-gamma, TNF-alpha, GMCSF, Rantes, and MMP-2 in injured cornea, which were found to be significantly downregulated by the combined treatment of SurR9-C84A and TSA. The ocular and systemic pharmacokinetic (PK) parameters were measured post-topical ocular administration of TSA and SurR9-C84A. The SurR9-C84A and TSA sustained relatively longer in the cornea, conjunctiva, and aqueous humor than in the tear fluid and plasma. Our results confirmed that a combination of TSA with SurR9-C8A worked in synergy and showed a promising healing and anti-inflammatory effect in a very short time against alkali burn. Therefore, a combination of TSA and SurR9-C84A can fulfill the need for an immediate response to wound healing in alkali burnt cornea. We also synthesized ultra-small chitosan nanoparticles (USC-NPs) targeted with alpha-SMA antibodies that can be used for delivery of TSA and SurR9-C84A specifically to the ocular burn site.

Progress on Azadirachta indica Based Biopesticides in Replacing Synthetic Toxic Pesticides.

Over the years, extensive use of commercially available synthetic pesticides against phytophagous insects has led to their bioaccumulation in the environment causing increased resistance and reduction in soil biodiversity. Further, 90% of the applied pesticides enter the various environmental resources as a result of run-off, exposing the farmers as well as consumers of the agricultural produce to severe health issues. Therefore, growing attention has been given toward the development of alternate environmentally friendly pesticides/insecticides that would aid an efficient pest management system and also prevent chronic exposures leading to diseases. One such strategy is, the use of neem plant's (Binomial name: Azadirachta indica) active ingredients which exhibit agro-medicinal properties conferring insecticidal as well as immunomodulatory and anti-cancer properties. The most prominent constituent of neem is azadirachtin, which has been established as a pivotal insecticidal ingredient. It acts as an antifeedant, repellent, and repugnant agent and induces sterility in insects by preventing oviposition and interrupting sperm production in males. This review discusses, key neem pesticidal components, their active functional ingredients along with recent strategies on employing nanocarriers, to provide controlled release of the active ingredients and to improve their stability and sustainability.