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Background: Human papillomavirus (HPV), one of the most frequently transmitted viruses, causes several malignancies, including cervical cancer. Aim: Owing to its unique pathogenicity, the HPV virus can persist in the host organism for a longer duration than other viruses to complete its lifecycle. During its association with the host, HPV causes various pathological conditions affecting the immune system by evading the host's immune mechanisms, thereby leading to the progression of various diseases, including cancer. Method: To date, ~ 150 serotypes have been identified, and certain high-risk HPV types are known to be associated with genital warts and cervical cancer. As of now, two prophylactic vaccines are in use for the treatment of HPV infection; however, no effective antiviral drug is available for HPVassociated disease/infections. Numerous clinical and laboratory studies have been conducted to formulate an effective and specific vaccine against HPV infections and associated diseases. Result: As the immunological basis of HPV infection and associated disease progress persist indistinctly, deeper insights into immune evasion mechanism and molecular biology of disease would aid in developing an effective vaccine. Conclusion: Thus, this systematic review focuses on the immunological aspects of HPV-associated cervical cancer by uncovering immune evasion strategies adapted by HPV.

Supplementary Figure Legends, Table Legends

Supplementary Tables S1 - S6. Supplementary Table S1. Patient clinical characteristics and summary of the observed molecular aberrations in the MTSCC cases studied. Supplementary Table S2. Sequencing quality metrics. Supplementary Table S3. Detailed list of somatic mutation calls in MTSCC cohort. Supplementary Table S4. Twenty three genes commonly regulated by PTPN14 siRNAs in the 3 cell lines identified by analysis of RNAseq data. (Supplementary Fig S4E). Supplementary Table S5. Geneset Enrichment analysis dataset details. Supplementary Table S6. Summary of immunohistochemistry staining results.

Supplementary Figures S1 - S8. Supplementary Figure S1. Intra-tumor mutational heterogeneity in MTSCC. Supplementary Figure S2. Copy number variation and Hippo pathway mutation in the MTSCC validation cohort and the TCGA KIRP outlier samples. Supplementary Figure S3. MTSCC Gene Expression Analyses. Supplementary Figure S4. PTPN14 function and Hippo pathway signature in kidney. Supplementary Figure S5. Gene set enrichment analysis. Supplementary Figure S6. HNF genes expression in normal human tissues, MTSCC and TCGA kidney cancer RNA-seq data. Supplementary Figure S7. Summary of YAP1 immunohistochemistry. Supplementary Figure S8. Gene expression correlation between MTSCC and nephron sections.

Breast cancer (BC) is the most serious and second leading cause of death in women worldwide. When breast cancer is diagnosed and treated early, the chance of long-term survival is up to 90%. On the other hand, 90% of BC patient deaths are due to metastasis and a lack of effective early diagnosis. The existing conventional chemotherapy provides negative feedback due to transportation barriers towards the action sites, multidrug resistance, poor bio-availability, non-specific delivery and systemic side effects on the healthy tissue. Syk protein Kinase has been reported in BC, as a tumor modulator, providing a pro-survival signal and also by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. In the present study, we explored the possibility of targeting BC by attenuating Syk protein Kinase. Hence, we have conjugated the hydrophobic Bendamustine (BEN) and hydrophilic Azacitidine (AZA) anticancer drugs to evaluate their efficacy against BC. The native drugs (BEN and AZA) and designed drug-drug conjugate (BEN-AZA) were docked with Syk protein. Then, the docked complex was performed for Binding Free Energy and Molecular Dynamics Simulations. Furthermore, DFT and ADME properties were carried out. The results revealed that the designed drug-drug conjugate has a better docking score, ΔGbind and admirable stability throughout the simulation when compared with native drugs. In DFT and ADME analyses, the designed drug-drug conjugate has shown good stereo electronic features and pharmaceutical relevant parameters than that of native drugs. The overall results suggested that the designed drug-drug conjugate may be a suitable candidate for BC treatment. Communicated by Ramaswamy H. Sarma

Silver nanoparticles synthesized from plant material have superior bioactivities. The purpose of this current study was to synthesis, characterize and to explore the bioactive efficacy of silver nanoparticles (Ag-NPs) using aqueous leaf extract of Tageteserecta. The biosynthesized Ag-NPs were characterized using ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction and Scanning electron microscopy. Ag-NPs were studied for in-vivo anti-inflammatory and wound healing activities performed in female Wistar albino rats. UV –Vis absorption spectrum of the T.erecta leaves extract was obtained at 428nm due to excitation of surface plasmon vibration in nanoparticles and confirms the synthesis of silver nanoparticles. The FTIR analysis showed the presence of sulfate, alkene and alcohol in the AgNP of T.erectaleaves. The average crystallite size of AgNP synthesized was found to be 27.2 nm. The spherical silver grain of 15.5 nm average size has been depicted with high-resolution scanning electron microscopy. Maximum activity (15mm) of T.erecta leaves silver nanoparticles was observed against Salmonella typhi (15mm) followed by Escherichia coli (12mm). Ag-NPs exhibited significant wound healing activity and anti-inflammatory activity in carrageenan-induced paw volume tests performed in female Wistar albino rats. Colloidal Ag-NPs can be synthesized by simple, nonhazardous methods, and biosynthesized Ag-NPs using T.erectaleaves extract have significant therapeutic properties.This work evidently confirmed that silver nanoparticles mediated T.erecta could be considered as a potential source for anti-inflammatory and wound healing drug.

Breast cancer (BC) is a heterogeneous disease distinct from major clinical hindrances, and microRNAs (miRNAs) have been accounted to partake in BC progression. Identifying potential miRNAs and their pathological significance in BC could pave the way for precisely targeted treatments. This study exploits transcriptomic BC miRNA, mRNA cohorts, and prognostic significance via an integrative functional approach. miRNA transcriptomic cohorts (GSE45666, GSE40267, and GSE19783) were utilized to disseminate differentially expressed miRNAs (DEmiRNAs) and their expression in the clinicopathological variables of BC. miR-182 was identified as a potent candidate, differentially expressed between each BC stage and its adjacent normal samples. The expression of miR-182 was significantly associated with estrogen receptor (ER) (p = 0.052), and closely related to progesterone receptor (PR) (p = 0.061) and human epidermal growth factor receptor 2 (Her2) (p = 0.077). miRNA-mRNA regulatory targets were predicted using six different databases, namely, TargetScan, miRDB, Diana, miRNet, TargetMiner, and miRWalk. Twenty-four promising mRNA regulatory targets were potentially identified for miR-182 and thus highly enriched with cellular metabolic processes, proteoglycans, and focal adhesion pathways in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms. Subsequently, the F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) gene was recognized as a hub with the highest connectivity score in the protein-protein interaction network. Furthermore, miR-182 and FBXW7 were associated with poor prognostic clinical outcomes in BC patients. Thus, our integrated functional analysis suggests that miR-182 might lead to a new therapeutic target in BC manifestation.

Cancer is a major health problem worldwide and one of the leading death-causing diseases. Mirk (Minibrain-related kinase is a member of the dual-specificity tyrosine-phosphorylation-regulated kinase (Dyrk) family that is highly upregulated in various solid tumors and mediates cell survival including lung cancer. Mirk effectively increases the expression of a series of antioxidant genes, which scavenge the reactive oxygen species and stabilize the p27kip1 that maintain the viability of the quiescent cancer cell and also mediates the cell cycle and survival of cancer cells by influencing the MAPK/ERK signaling pathway. Hence, Mirk acts as a novel therapeutic target for cancer prevention. Owing to the unavailability of the three-dimensional structure of Mirk, in the present study, we have modeled the 3D structure of Mirk, based on the crystal structure of Dyrk1a as a template, and subsequently used it as a target for virtual screening and molecular docking against a small molecule database. Based on the visual inspection, four best hits such as Chembridge_ID 7768949, 7771055, 7758866, and 7764195 have high binding affinity, good docking score, and pharmacokinetic properties were shortlisted. Further, the dynamic stability of lead molecules with modeled Mirk/Dyrk1B was evaluated using 10 ns molecular dynamics simulation approach. The four hit molecules exhibited good and stable binding complex in the binding pocket of the target protein. Collectively the finding of this study suggested that the identified molecules may serve as potential effective anti-cancer inhibitors for cancer prevention.

Enzymes exhibit a great catalytic activity for several physiological processes. Utilization of immobilized enzymes has a great potential in several food industries due to their excellent functional properties, simple processing and cost effectiveness during the past decades. Though they have several applications, they still exhibit some challenges. To overcome the challenges, nanoparticles with their unique physicochemical properties act as very attractive carriers for enzyme immobilization. The enzyme immobilization method is not only widely used in the food industry but is also a component methodology in the pharmaceutical industry. Compared to the free enzymes, immobilized forms are more robust and resistant to environmental changes. In this method, the mobility of enzymes is artificially restricted to changing their structure and properties. Due to their sensitive nature, the classical immobilization methods are still limited as a result of the reduction of enzyme activity. In order to improve the enzyme activity and their properties, nanomaterials are used as a carrier for enzyme immobilization. Recently, much attention has been directed towards the research on the potentiality of the immobilized enzymes in the food industry. Hence, the present review emphasizes the different types of immobilization methods that is presently used in the food industry and other applications. Various types of nanomaterials such as nanofibers, nanoflowers and magnetic nanoparticles are significantly used as a support material in the immobilization methods. However, several numbers of immobilized enzymes are used in the food industries to improve the processing methods which not only reduce the production cost but also the effluents from the industry.

Idiopathic dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. The aim of this study was to assess the role of mitochondrial DNA (mtDNA) variations and haplogroups in Indian DCM patients. Whole mtDNA analysis of 221 DCM patients revealed 48 novel, 42 disease-associated and 97 private variations. The frequency of reported variations associated with hearing impairment, DEAF, SNHL and LHON are significantly high in DCM patients than controls. Haplogroups H and HV were over represented in DCM than controls. Functional analysis of two private variations (m.8812A>G & m.10320G>A) showed decrease in mitochondrial functions, suggesting the role of mtDNA variations in DCM.

AbbreviationsADMEabsorption, distribution, metabolism, and excretionMMGB/SAmolecular mechanics generalized born surface areaIFDinduced fit dockingRTKreceptor tyrosine kinaseNSCLCnon-small-cell lung cancerATPadenosine triphosphateOPLSoptimized potential for liquid stimulationRMSDroot mean square deviationHTVShigh-throughput virtual screeningSPstandard precisionXPextra precisionOPLS-AAoptimized potential for liquid stimulation-all atomMDmolecular simulationMMEmolecular mechanics energiesSGBsurface generalized bornPOPC membrane1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membranePDBProtein Data BankDDR1discoidin domain receptor 1DDR2discoidin domain receptor 2DDRsdiscoidin domain receptorsECMextracellular matrixTIP4Ptransferable intermolecular potential 4 pointNPTconstant particle number, pressure and temperatureRMSFroot mean square fluctuationCommunicated by Ramaswamy H. Sarma.

Breast cancer (BC) is a common malignant tumor in females around the world. While multimodality therapies exist, the mortality rate remains high. The hypoxic condition was one of the potent determinants in BC progression. The molecular mechanisms underpinning hypoxia and their association with BC can contribute to a better understanding of tailored therapies. In this study, two hypoxic induced BC transcriptomic cohorts (GSE27813 and GSE47533) were assessed from the GEO database. The P4HA1 gene was identified as a putative candidate and significantly regulated in hypoxic BC cells compared to normal BC cells at different time intervals (6 h, 9 h, 16 h, 32 h, and 48 h). In patients with Luminal (p < 1E-12), triple-negative subclasses (p = 1.35059E-10), Stage 1 (p = 8.8817E-16), lymph node N1 (p = 1.62436E-12), and in the 40–80 age group (p = 1.62447E-12), the expression of P4HA1 was closely associated with the clinical subtypes of BC. Furthermore, at the 10q22.1 chromosomal band, the P4HA1 gene displayed a high copy number elevation and was associated with a poor clinical regimen with overall survival, relapse-free survival, and distant metastases-free survival in BC patients. In addition, using BioGRID, the protein–protein interaction (PPI) network was built and the cellular metabolic processes, and hedgehog pathways are functionally enriched with GO and KEGG terms. This tentative result provides insight into the molecular function of the P4HA1 gene, which is likely to promote hypoxic-mediated carcinogenesis, which may favor early detection of BC and therapeutic stratification.

Objective: To investigate the biogenic synthesis of silver nanoparticles (AgNPs) using partially purified ethyl acetate extract of Nannochloropsis sp. hexane (EAENH) fraction of microalga. Methods: The green synthesis of AgNPs was confirmed with UV-Vis spectrum which shows the surface plasmon resonance (SPR) at 421 nm. Fourier Transform Infrared Spectra (FTIR) presented the involvement of functional groups like carboxyl groups of fatty acids, tetraterpenoids of xanthophylls, hydroxyl groups of polyphenols, carbonyl and amide linkage of proteins in the AgNP synthesis. Gas Chromatography-Mass Spectrometry analysis (GCMS) revealed that phytochemicals like octadecanoic acid and hexadecanoic acid imply in capping, bioreduction, and stabilization of AgNps. Result: High-resolution Transmission electron microscope (HRTEM), Dynamic light scattering (DLS), X-ray diffraction (XRD) and EDX analysis showed the crystalline form of the AgNPs with Z-average size 57.25 nm. The zeta potential value of -25.7 mV demonstrated the negative surface charge and colloidal stability of AgNPs. The antimicrobial activity of AgNPs displayed effective inhibition zone against selected bacterial and fungal pathogens. In vitro, antioxidant effects were assessed by 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydrogen peroxide and reducing power assays which revealed excellent scavenging potential for AgNPs than the extracts. The anti-proliferative potential of biofabricated AgNPs and extracts on Human Non-small lung cancer cell line (A549) was assessed using 3–(4,5-dimethylthiazol-2-yl)-2,5- diphenyl-tetrazolium bromide (MTT) assay with IC50 values of 15 μgmL-1 and 175 μgmL-1 respectively. Conclusion: The study reveals that the microalgae-mediated AgNPs possesses potent antimicrobial and antioxidant activity along with the ability to stimulate apoptosis in A-549 cell line.

Theranostic nanoparticles with multifunctional ability have been emerging as a new platform for biomedical applications such as imaging, sensing and drug delivery. Despite gold nanorods (Au NRs) being an excellent nanosource with multifunctional versatility, they have certain limitations in biomedical applications, which include surfactant toxicity, biological stability and controlled drug release kinetics. Herein, we have developed Au NR–doxorubicin conjugates (DOX@PSS-Au NR) with improved drug loading efficiency (55 ± 6%) and minimum CTAB toxicity, by employing Au NRs (4.4 ± 0.5 aspect ratio) coated with poly(sodium 4-styrenesulfonate) (PSS). DOX@PSS-Au NR conjugates exhibited higher biological stability with sustained drug release kinetics at pH 5. The binding events of DOX molecules onto the PSS coated gold nanorods (PSS-Au NRs) were monitored through fluorescence quenching and the longitudinal surface plasmon resonance signals. Furthermore the anti-cancer potential and apoptosis inducing efficiency of DOX@PSS-Au NR conjugates in MCF-7 cells revealed higher therapeutic efficiency than free DOX, as corroborated through morphological assessment and in vitro cytotoxicity assay. In addition, DOX@PSS-Au NR conjugates showed efficient cellular entry and uniform intracellular distribution, suggesting the augmenting effect of chemotherapeutic drugs by Au NRs. Thus DOX@PSS-Au NR conjugates demonstrate significant therapeutic potential, suggesting their potential in anticancer therapy.

Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes—both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies. Patient summary Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients.

Despite, several lines of evidence suggesting the possible role of hypoxia in stem cell development and differentiation its significance in conferring the stemness and pluripotency remains elusive. In the present study we sought to delineate the candidate genes and molecular pathways imposed during hypoxic microenvironment and its physiological relevance in tipping the balance between the niche and cellular differentiation. Integrated meta-analysis was performed between the hypoxia exposed and normal human embryonic stem cells, employing three transcriptomic cohorts (GSE35819, GSE9510 and GSE37761) retrieved from Gene expression omnibus (GEO) database. Results reveal that a total number of 12 genes were consistently differentially expressed (6up regulated and 6 down regulated) with FDR0.05 and fold change1.5. The Gene Ontology (GO) functions and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis was performed using DAVID. The GO analysis showed DEG significantly enriched in terms of Cellular process (GO:0009987), protein binding (GO:0005515) and cell part (GO:0044464). KEGG analysis indicated participation of genes associated with circadian rthyum regulation and PPAR signalling pathway. Further, gene-set signature (MsigDB) enrichment analysis showed positive regulation with inflammatory signals and negative association with PPAR and p53 pathway. Protein-protein network of gene modules suggests significant hub proteins viz. CTTNB1 (Degree = 18), IL8 (Degree = 15), NFKB1 (Degree = 15) and RELA (Degree = 15) in the PPI network. MCODE algorithm was used for subnetworks of the PPI network. Our integrative analysis documents the potential candidate genes which serves distinct roles influencing metabolic shift and induce inflammatory effectors contributing to hypoxic mediated stem cell niche.

Recently, several attempts have been made to use the phytopharmaceuticals from plant extracts as reducing, capping and stabilizing agents for the biomimetic synthesis of various metal nanoparticles conjugated to the phytopharmaceuticals. These biogenic metal nanoparticles are non-toxic and can be used as contrast agents, drug delivery vehicles and photothermal agents for cancer therapy. Herein, we report the synthesis of both silver and gold nanoparticles using the pollen extract of Phoenix dactylifera (Date Palm), characterization using UV-visible spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy, quantitation of phytochemicals capping the nanoparticles using Folin - Ciocalteu's method, cytotoxicity studies on MCF-7 breast cancer cells, cancer cell death analysis using fluorescent microscopy, and modulation of expression of the pro-apoptotic p53 and anti-apoptotic Bcl-2 proteins. The biosynthesis resulted in stable and poly-dispersed silver nanoparticles and gold nanoparticles, exhibiting strong and broad surface plasmon absorption peaks. The elemental analysis confirmed the presence of gold and silver of high purity and also the organic moieties from the plant extract acting as capping and stabilizing agents. The biogenic nanoparticles also exhibited dose-dependent cytotoxicity on MCF-7 cells and showed signs of apoptotic cell death. Immunoassays revealed the upregulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2 after the nanoparticle treatment.

A sensitive and highly selective, fluorescent “turn–on” fluorescence sensor for Hg2+ and Fe3+ ions are reported by using an 3,3′–dihydroxybenzidine:α–cyclodextrin (DHB:α–CD) solid inclusion complex in an acetonitrile water system. Solid inclusion complex of DHB:α–CD was prepared by co-precipitation and kneading method and it was characterized by using FTIR, 1H NMR, XRD and SEM analysis. The investigation of fluorescence spectrum revealed that the host-guest system exhibited characteristic fluorescence behavior towards Hg2+ and Fe3+ ions in acetonitrile water system. With addition of Hg2+ and Fe3+, the host-guest system shows strong fluorescence enhancement, which resulted from the fluorophore of the coordination between DHB:α–CD and metal ions (Hg2+, Fe3+) with high binding constant (k = 3.1626 × 104 M−1, 1.8225 × 104 M−1). Moreover, high selectivity experiments revealed that the fluorescent sensor is specific to Hg2+ and Fe3+ ions even with interference from higher concentrations of other metal ions. Docked structure of DHB:α–CD (molecular docking studies) fully agree with experimental data. The molecular dynamic calculations show that there are structurally and energetically favourable association among the molecules, which are in good agreement with the experimental results. Further, bioimaging studies confirmed that the DHB:α–CD shows in vitro detection of Hg2+ and Fe3+ ions in HepG2 cells.

A novel fluorescent chemosensor based on a rhodamine derivative (RBD4) was designed, synthesized, and used as a selective Cd2+ ion sensor. The structure of the fluorescence sensor (RBD4) is confirmed through single crystal X-ray study. On the basis of the Forster resonance energy transfer mechanism between rhodamine and pyridine conjugated dyad, a new colorimetric as well as fluorescence probe was synthesized for the selective detection of Cd2+. This sensor shows high selectivity towards Cd2+ ions in the presence of other competing metal ions. On the basis of thorough experimental and theoretical findings, the additions of Cd2+ ions to the solution of RBD4 helps to generate a new fluorescence peak at 590 nm due to the selective binding of Cd2+ ions with RBD4 in a 1: 1 ratio with a binding constant (K) of 4.2524 × 104 M−1. The detection limit of RBD4 for Cd2+ was 1.025 × 10−8 M, which presented a pronounced sensitivity towards Cd2+. The in situ generated RBD4–Cd2+ complex is able to selectively sense S2− over other anions based on the displacement approach, given a remarkable recovery of fluorescence and UV–vis absorption spectra. The fluorescence sensor has also exhibited very good results in HeLa Cells imaging under physiological pH.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation. Significance: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258–66. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197

Surgical grade Ti-6Al-4V is considered to be the most attractive material in the medical field, but their low bioactivity, post-surgery infection, and poor osteointegration are a major drawback. Bioactive coating of the titanium alloy implant, increases the cell proliferation, biocorrosion, bioactivity, roughness with excellent antibacterial nature. In the present study, multi-minerals modified calcium silicate prepared by controlled substitution of Sr, Zn, Mg, Ce into calcium silicate. Additionally, a synergistic combination of the Hyatella cribriformis marine sponge, and mineral-calcium silicate electrolyte used for electrophoretic deposition on Ti-6Al-4V. Ceramic nanocomposite coating forms a homogenous layer with a higher distribution of mineral-sponge on the surface. Electron microscopy studies report-good structural stability of nanocomposites coating on the substrate surface due to functionalization and cross-linking. Coating form lower corrosion current density of 4.7× 10−7 A/cm−2 for sponge-mineral-CaSiO3 coating. Subsequently, the biological performances of the assemblies show drastic improvement in apatite formation in 15 days. The coating was biocompatible, and it displays a high cell proliferation rate at 10 μg/mL concentration. Coated hybrid surface enhances the osteoinductivity, mineralization of the extracellular matrix and filopodia formation. Improved antibacterial multifunctionality of sponge-ceramic coating exhibited the zone of inhibition of 16 mm, 13 mm for S. aureus, and E. coli at 50 μg/mL concentration. Therefore, the electrophoretic deposition of the sponge-Sr-Zn-Mg-Ce minerals incorporated calcium silicates coating, would successfully enhance the bone regeneration.

Hydroxychavicol (HC), a major phenolic derivative isolated from the leaves of

Drug delivery using synthetic mesoporous nanomaterials, including porous silicon, has been extensively used to ameliorate the constraints currently experienced with conventional chemotherapy. Owing to the amazing potential, the silica based nanomaterials have been used widely. Nevertheless, synthetic nanomaterial involves high cost, lack of scalability, and the use of toxic substances limits its utilization. These issues can be overcome by the use of nature generated nanoscale materials, such as diatoms would serve as a boon for pharmaceutical industries. In this study we investigate the use of a mesoporous, biodegradable nanomaterial obtained from the natural silica found in the diatom species Amphora subtropica (AMPS) for drug delivery applications. AMPS cultures cleaned and chemically treated to obtain Amphora frustules (exoskeleton) (AF), followed by surface functionalization with chitosan (Chi). Results of our experiments demonstrate high drug loading, strong luminescence, biodegradable and biocompatible nature of the doxorubicin tethered diatom. Further, toxicity studies employing immortalized lung cancer cell line (A549) indicates sustained drug delivery and less toxic compared to the free doxorubicin (DOX), suggesting AF could be an excellent substitute for synthetic nanomaterials used in drug delivery applications.

Prolonged cancer cell survival, acquiring drug resistance, and secondary cancer development despite chemotherapy are the major challenges during cancer treatment, whose underlying mechanism still remains elusive. In this study, low-doses of chemotherapeutic drugs (LDCD) - doxorubicin (DOX), etoposide (ETOP), and busulfan (BUS) were used to ascertain the effect of residual concentrations of drugs on breast cancer cells. Our results showed that exposure to LDCD caused significant induction of ROS, early signs of apoptosis and accumulation of cells in S and G2-M phases of the cell cycle in MCF-7 and MDA-MB-231 cell lines. Under drug-free recovery conditions, a decrease in the number of apoptotic cells and an increase in the number of colonies formed were observed. Analysis of the molecular mechanism showed lower expression of cleaved products of caspase 3, 9, PARP and occurrence of DNA strand breaks in recovered cells compared to LDCD-treated cells, suggesting incomplete cell death activation and survival of cells with genomic damage after therapeutic insult. Thus, LDCD induces defective apoptosis in cancer cells allowing a small population of cells to escape from cell cycle check points and survive with accumulated genetic damage that could eventually result in secondary cancers that warrants further studies for better therapeutic strategies.

The polymer-cobalt(III) complexes, [Co(bpy)(dien)BPEI]Cl3 · 4H2O (bpy = 2,2'-bipyridine, dien = diethylentriamine, BPEI = branched polyethyleneimine) were synthesized and characterized. The interaction of these complexes with human serum albumin (HSA) and bovine serum albumin (BSA) was investigated under physiological conditions using various physico-chemical techniques. The results reveal that the fluorescence quenching of serum albumins by polymer-cobalt(III) complexes took place through static quenching. The binding of these complexes changed the molecular conformation of the protein considerably. The polymer-cobalt(III) complex with x = 0.365 shows antimicrobial activity against several human pathogens. This complex also induces cytotoxicity against MCF-7 through apoptotic induction. However, further studies are needed to decipher the molecular mode of action of polymer-cobalt(III) complex and for its possible utilization in anticancer therapy.

The interaction of surfactant-cobalt(III) complexes [Co(bpy)(dien)TA](ClO4)3 · 3H2O (1) and [Co(dien)(phen)TA](ClO4)3 · 4H2O (2), where bpy = 2,2'-bipyridine, dien = diethylenetriamine, phen = 1,10-phenanthroline and TA = tetradecylamine with human serum albumin (HSA) under physiological conditions was analyzed using steady state, synchronous, 3D fluorescence, UV/visabsorption and circular dichroism spectroscopic techniques. The results show that these complexes cause the fluorescence quenching of HSA through a static mechanism. The binding constant (Kb ) and number of binding-sites (n) were obtained at different temperatures. The corresponding thermodynamic parameters (∆G°, ∆H° and ∆S°) and Ea were also obtained. According to Forster's non-radiation energy transfer theory, the binding distance (r) between the complexes and HSA were calculated. The results of synchronous and 3D fluorescence spectroscopy indicate that the binding process has changed considerably the polarity around the fluorophores, along with changes in the conformation of the protein. The antimicrobial and anticancer activities of the complexes were tested and the results show that the complexes have good activities against pathogenic microorganisms and cancer cells.

The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy.

Hydroxychavicol (HC), a major phenolic derivative isolated from the leaves of Piper betle L. is well known for its antibacterial, antifungal and antimutagenic properties. The present study evaluated the in vivo antitumor activity of HC against Ehrlich Ascites Carcinoma (EAC) cells in Swiss albino mice and in silico interaction of HC with the receptors involved in the cancer. Hydroxychavicol (200 and 400 mg/kg bw) was orally administered for 21 consecutive days and was effective in inhibiting the tumor growth in ascitic mouse model. HC consistently reduced the tumor volume, viable cell count, lipid peroxidation and elevated the life span of HC treated mice. Besides the hematological profiles, SGOT and SGPT levels reverted back to normal and oxidative stress markers GSH, SOD and CAT also increased in HC treated groups. In silico docking analysis revealed that HC possessed potent antagonist activity against all the cancer targets demonstrating its inhibitory activity.

Nanostructures of noble metals have been extensively studied recently because of their impressive physiochemical properties and wide range of applications in biology and medicine. In this study, the anticancer efficacy of green synthesized silver and gold nanoparticles (AgNPs and AuNPs) was assessed against human breast carcinoma cells (MCF-7). Treatment with different concentrations of NPs triggers the cellular toxicity in a dose and time dependent manner. Morphological features of apoptosis were measured using cell wall integrity, acridine orange/ethidium bromide and Hochest staining methods which clearly distinguishes the viable cells and the cells undergoing apoptosis. Flow cytometry and DNA fragmentation analysis were also used to substantiate that NPs induced cytotoxicity was primarily mediated by G2/M cell cycle arrest and apoptosis. NPs provoke intracellular reactive oxygen species that cause damage to various cellular components. Furthermore, the gene expression studies such as reverse transcription – polymerase chain reaction, quantitative polymerase chain reaction and western blot analysis shows the upregulation of Bax, Bcl2, caspases-6 and -9, PARP, p53 and downregulation of Bcl-2 depicts the induction of apoptosis upon exposure to NPs. The overall results clearly shows that green synthesized metal NPs can potentially inhibit the proliferation of MCF-7 cells and trigger apoptosis through Bax/Bcl2 and caspase–cascade mediated mitochondrial dysfunction. This research concludes that biogenic metal nano-drug formulations can be utilized for cancer chemotherapy.

Despite zinc oxide nanoparticles (ZnONPs) being increasingly used as carriers in biomedical fields due to their multifaceted properties and therapeutic importance, better understanding of the mechanisms and cellular consequences resulting from their interaction with cells and cellular components has been warranted. In the present study, we investigate the size-dependent interaction of ZnONPs on RBCs, and its impact on cell viability, DNA damage, ROS generation and morphological changes, employing cellular and analytical methods. Size, charge, stability and solubility were confirmed by DLS, zeta potential, ICP-AES and TEM analysis. Further ICP-AES, TEM, spectroscopic observations and cell based assays showed that ZnONPs exhibited a size dependent impact on RBCs and haemoglobin (Hb), particularly size

Recently, several attempts have been made to use the phytopharmaceuticals from plant extracts as reducing, capping and stabilizing agents for the biomimetic synthesis of various metal nanoparticles conjugated to the phytopharmaceuticals. These biogenic metal nanoparticles are non-toxic and can be used as contrast agents, drug delivery vehicles and photothermal agents for cancer therapy. Herein, we report the synthesis of both silver and gold nanoparticles using the pollen extract of Phoenix dactylifera (Date Palm), characterization using UV-visible spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy, quantitation of phytochemicals capping the nanoparticles using Folin - Ciocalteu's method, cytotoxicity studies on MCF-7 breast cancer cells, cancer cell death analysis using fluorescent microscopy, and modulation of expression of the pro-apoptotic p53 and anti-apoptotic Bcl-2 proteins. The biosynthesis resulted in stable and poly-dispersed silver nanoparticles and gold nanoparticles, exhibiting strong and broad surface plasmon absorption peaks. The elemental analysis confirmed the presence of gold and silver of high purity and also the organic moieties from the plant extract acting as capping and stabilizing agents. The biogenic nanoparticles also exhibited dose-dependent cytotoxicity on MCF-7 cells and showed signs of apoptotic cell death. Immunoassays revealed the upregulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2 after the nanoparticle treatment.

Renal cell carcinoma (RCC) subtypes with overlapping histomorphologic features pose diagnostic challenges. For instance, a unique category of sporadic renal tumors with eosinophilic cytoplasm and solid and cystic growth pattern (ESC RCC) may mimic a RCC subtype usually encountered in patients with germline aberrations of tuberous sclerosis complex (TSC) genes (TSC RCC). Here, we used next-generation sequencing (NGS) technology to interrogate the clinicopathologic and molecular profiles of ESC RCC tumors. Mutational and copy number analysis of NGS data from ESC RCC tumors revealed a somatic bi-allelic loss of TSC family genes, specifically TSC1 or TSC2, in six out of seven profiled cases. However, the corresponding background kidney showed only wild type alleles, thus excluding any germline involvement and differentiating ESC RCC from TSC RCC. Furthermore, bi-allelic loss of the TSC genes occurred in a mutually exclusively manner in this cohort. Our study clarifies the molecular identity of ESC RCC, and can thus guide future therapeutic strategies and provide a basis for the revision of current RCC classification. Citation Format: Nicole D. Lee, Pankaj Vats, Xuhong Cao, Fengyun Su, Robert Lonigro, Kumpati Premkumar, Kiril Trpkov, Jesse K. McKenney, Rohit Mehra, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. Somatic bi-allelic loss of TSC genes in eosinophilic solid and cystic renal cell carcinoma (ESC RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5342.

Nanoparticles mediated oral drug delivery system has attracted great attention in pharmacology to attain improved therapeutic index of chemotherapeutic drugs. In the present study, naringenin (NRG) - loaded gastroretentive mucoadhesive polymeric nanoparticles has been designed and investigated its application in oral drug delivery system. Naringenin loaded polymeric nanoparticles (NMPN) were prepared by thermal decomposition mediated nanoprecipitation method. Formulated NMPN were characterized and investigated for its mucoadhesive properties by swelling and in vitro mucoadhesion studies. The results indicated that the formulated NPMN were in the size of 66±7nm by dynamic light scattering analysis and the maximum drug loading efficiency was observed around 94.6±0.28%. Further the drug release studies showed that NMPN exhibited sustained drug release in stimulated gastric fluid (SGF; pH=1.2). Pharmacokinetic studies revealed that the formulated NMPN are highly biocompatible and showed enhanced therapeutic efficacy compared to free naringenin. The overall findings demonstrated that the gastroretentive mucoadhesive polymeric nanoparticles can act as a promising candidate with gastroprotective applications in biomedical research.

Chromosomal translocations as molecular signatures have been reported in various malignancies but, the mechanism behind which is largely unknown. Swapping of chromosomal fragments occurs by induction of double strand breaks (DSBs), most of which were initially assumed de novo. However, decoding of human genome proved that transposable elements (TE) might have profound influence on genome integrity. TEs are highly conserved mobile genetic elements that generate DSBs, subsequently resulting in large chromosomal rearrangements. Previously TE insertions were thought to be harmless, but recently gains attention due to the origin of spectrum of post-insertional genomic alterations and subsequent transcriptional alterations leading to development of deleterious effects mainly carcinogenesis. Though the existing knowledge on the cancer-associated TE dynamics is very primitive, exploration of underlying mechanism promises better therapeutic strategies for cancer. Thus, this review focuses on the prevalence of TE in the genome, associated genomic instability upon transposition activation and impact on tumorigenesis.