Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) ...polymerase (PARP) inhibition in patients with prostate and other cancers.
We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in
,
, or
; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.
In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.
In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
The convergence of nano and biotechnology is enabling scientific and technical knowledge for improving human well being. Carbon nanotubes have become most fascinating material to be studied and ...unveil new avenues in the field of nanobiotechnology. The nanometer size and high aspect ratio of the CNTs are the two distinct features, which have contributed to diverse biomedical applications. They have captured the attention as nanoscale materials due to their nanometric structure and remarkable list of superlative and extravagant properties that encouraged their exploitation for promising applications. Significant progress has been made in order to overcome some of the major hurdles towards biomedical application of nanomaterials, especially on issues regarding the aqueous solubility/dispersion and safety of CNTs. Functionalized CNTs have been used in drug targeting, imaging, and in the efficient delivery of gene and nucleic acids. CNTs have also demonstrated great potential in diverse biomedical uses like drug targeting, imaging, cancer treatment, tissue regeneration, diagnostics, biosensing, genetic engineering and so forth. The present review highlights the possible potential of CNTs in diagnostics, imaging and targeted delivery of bioactives and also outlines the future opportunities for biomedical applications.
•Fetal liver conditioned medium (FLCM) was evaluated for the presence of 5 cytokines viz, GM-CSF, SCF, IL-6, Epo, and Flt-3 by ELISA.•IL-6 and FL-3 were found to be in maximum samples.•IL-6 and Flt-3 ...are present in considerable amounts in FLCM.•IL-6 and Flt-3 are major cytokines responsible for stimulating colonies in normal bone marrow samples.
Earlier research from our laboratory demonstrated the presence of stimulatory activity of different growth factors in the fetal liver (FL) extracts when collected in a medium known as fetal liver conditioned medium (FLCM) using Enzyme-linked Immunosorbent Assay (ELISA).
In the present study, we have assessed two other cytokines viz. IL-6 and FMS like tyrosine kinase-3 (Flt-3) with the help of bioneutralization assay. FLCM was prepared by incubating fetal liver cells with Iscove’s Modified Dulbecco’s Medium (IMDM) containing 10% fetal bovine serum (FBS) and 10% Phytohemagglutinin and collected after 24hrs, 48hrs, 72 hrs. and on the 7th day of incubation. Clonal cultures were established for 1 X 105 normal bone marrow (BM) mononuclear cells (NBM MNC) per plate with methylcellulose medium containing cytokines SCF and EPO. Mean Colony forming units-granulocytes, erythrocytes, macrophages, megakaryocytes (CFU-GEMM) were assessed with and without the addition of FLCM. It was found that FLCM enhanced the number of colonies made by NBM MNCs. Further, cytokines IL-6 and Flt-3, present in FLCM, were bioneutralized with respective anti-cytokine antibodies. Neutralized FLCM was evaluated for the colony-forming potential of CFU-GEMM colonies. The maximum reduction of 42% was seen with 20 ng/ml of anti-IL-6 antibody. Maximum suppression up to 20% was observed with 0.7 ng/ml of anti Flt-3 antibody for CFU-GEMM colonies. Presence of cytokines IL-6 and Flt-3 in FL extracts and their colony stimulatory activity suggests that fetal liver infusion (FLI) may be a valuable alternative for managing BM recovery in certain clinical conditions such as AA.
Abstract Carbon nanotubes (CNTs) have emerged as fascinating materials, exhibiting promising potential in receptor based targeting owing to their unique physicochemical properties (cell membrane ...penetration, high surface area and drug payload, biocompatibility, easy surface modification, photoluminescence property, and non-immunogenicity etc). The hydrophilicity, a major constrain associated with the first generation of CNTs i.e. pristine CNTs, could be overcome using functionalization techniques. In the last two decades variety of functionalized CNTs ( f -CNTs) i.e. oxidized, amidated, acylated, surfactant and biopolymer-assisted, and biomolecules modified have been developed and utilized as effective, safe, nano sized, and smart systems to deliver a wide range of bioactives in the biological system. The purpose of this review is to examine the various aspects of conjugation and associated conjugation chemistry of various targeting ligands to CNTs for their respective biomedical applications. The various biomolecules have been easily tethered to CNTs surfaces including proteins and amino acid, enzymes, nucleic acid (DNA and siRNA), aptamers, vitamins, monoclonal antibodies, peptides (NGR, RGD and Aniopep-2) and so on, for targeting purposes.
Abstract
Fetal liver hematopoietic stem and progenitor cells (HSPCs) have been considered appropriate for the management of aplastic anemia owing to their proliferative potential. Bone marrow ...recovery was possible in some cases; the engraftment potential of these cells, however was unsatisfactory, possibly due to the availability of a smaller number of these cells from a single fetus. The present study explores how we can expand fetal liver hematopoietic stem cells under in vitro conditions. We isolated mononuclear cells from fetal liver and hematopoietic stem cells were identified and analyzed by cell surface marker CD34. CD34
+
fetal liver HSPCs cells were separated by magnetic cell sorting positive selection method. HSPCs (CD34
+
) were cultured by using 5 cytokines, stem cell factor (SCF), granulocyte macrophages-colony stimulating factor (GM-CSF), interleukin-6 (IL-6), Fms-related tyrosine kinase 3 (FLT-3) and erythropoietin (EPO), in 4 different combinations along with supplements, in serum-free culture media for 21 days. Cell viability continued to be greater than 90% throughout 21 days of culture. The cells expanded best in a combination of media, supplements and 5 cytokines, namely SCF, FLT-3, IL6, EPO and GM-CSF to yield a large number of total (CD34
+
& CD34
-
) cells. Even though the total number of nucleated cells increased in culture significantly, levels of CD34 antigen expression declined steadily over this period.
ABSTRACT
Purpose
In the present investigation, we prepared and evaluated the paclitaxel loaded riboflavin and thiamine conjugated multi walled carbon nanotubes (PTX-Rf-MWCNTs and PTX-Tm-MWCNTs) for ...targeted delivery to cancer employing MCF-7 cancer cell lines.
Methods
The developed conjugates were characterized using FTIR, NMR spectroscopy, electron microscopy drug loading, release, stability, hemolytic,
ex vivo
and
in vivo
studies
etc.
Results
The percent entrapment efficiency was found to be 87.92 ± 0.48 and 82.75 ± 0.47% of PTX-Tm-MWCNTs, PTX-Rf-MWCNTs, respectively. The percent hemolysis of purified MWCNTs, PTX-MWCNTs, PTX-Tm-MWCNTs and PTX-Rf-MWCNTs was found to be 20.49 ± 0.97, 37.39 ± 0.78, 14.61 ± 0.84 and 11.17 ± 0.77% respectively. The PTX-Tm-MWCNTs and PTX-Rf-MWCNTs showed more cytotoxic effect as compared to PTX and PTX-MWCNTs with PTX-Rf-MWCNTs exhibiting the maximum cytotoxic potential.
Conclusion
Thus in final outcome, we concluded that the riboflavin and thiamine conjugated MWCNTs shown great promising potential in the treatment of cancer, but more exhaustive data is needed in future.
Dendrimers represents a novel class of macromolecules, which are derived from branches upon branches type structural design. Dendrimers are emerging as promising drug-delivery molecule because of ...their extraordinary properties including membrane interaction, monodispersity, well-defined size, shape and molecular weight, etc. Drugs interact with dendrimers in three ways; (a) physical encapsulation, (b) electrostatic interactions, and (c) covalent conjugations. Due to compact, globular structure and availability of interior cavity spaces and multiple surface functional groups, drug molecules can be encapsulated both in the interior of the dendrimers (physical encapsulation) as well as attached to the surface functional groups (covalent conjugations).
Summary
The two important issues affecting recipients of solid organ transplants and of importance to immunologists are (i) sensitization of the recipient to HLA antigens and the resultant humoral ...immune response leading to the development of anti‐HLA antibodies; and ii) development of robust assays for early detection of humoral rejection post‐transplant. Evidence from several studies clearly indicates that presence of circulating anti‐HLA antibodies especially donor specific leads to early graft loss and high titres of DSA may even lead to hyperacute or accelerated acute rejection. Long‐term graft survival too is adversely affected by the presence of either pre‐ or post‐transplant DSA. HLA matching status of the recipient – donor pair – is an important factor in the modulation of humoral response following transplantation and in a way affects de novo development of DSA. Data collected over the past decade clearly indicate significantly lower level of DSAs in optimally matched donor‐recipient pairs. HLA mismatches especially those on HLA‐DR and HLA‐C loci have wider implications on post‐transplant graft survival. The presence of circulating anti‐HLA antibodies leads to endothelial damage in the newly grafted organ through complement dependent or independent pathways. Although detection of C4d deposition in renal biopsies serves as an important indicator of humoral rejection, its absence does not preclude the presence of DSAs and humoral rejection, and hence, it cannot be relied upon in every case. The emergence of epitope‐based screening for anti‐HLA antibodies on Luminex platform with high degree of sensitivity has revolutionized the screening for anti‐HLA antibodies and DSAs. Studies indicate that humoral response to non‐HLA antigens might also have a detrimental effect on allograft survival. High titres of such circulating antibodies may even lead to hyperacute rejection. Pre‐emptive testing of solid organ recipients, especially kidney transplant recipients for anti‐HLA and non‐HLA antibodies and aggressive post‐transplant monitoring of allograft function to detect DSAs using Luminex‐based tests, is highly recommended.
In the present investigation, poly (propylene imine) dendrimers up to fifth generation (PPI G5.0) were synthesized using ethylene diamine and acrylonitrile. Lipoproteins (high-density lipoprotein; ...HDL and low-density lipoprotein; LDL) were isolated from human plasma by discontinuous density gradient ultracentrifugation, characterized and tethered to G5.0 PPI dendrimers to construct LDL- and HDL-conjugated dendrimeric nanoconstructs for tumor-specific delivery of docetaxel. Developed formulations showed sustained release characteristics in in vitro drug release and in vivo pharmacokinetic studies. The cancer targeting potential of lipoprotein coupled dendrimers was investigated by ex vivo cytotoxicity and cell uptake studies using human hepatocellular carcinoma cell lines (HepG2 cells) and biodistribution studies in albino rats of Sprague–Dawley strain. Lipoprotein anchored dendrimeric nanoconstructs showed significant uptake by cancer cells as well as higher biodistribution of docetaxel to liver and spleen. It is concluded that these precisely synthesized engineered dendrimeric nanoconstructs could serve as promising drug carrier for fighting with the fatal disease, i.e., cancer, attributed to their defined targeting and therapeutic potential.
In this study, we reported folate-conjugated polypropylene imine dendrimers (FA-PPI) as efficient carrier for model anticancer drug, methotrexate (MTX), for pH-sensitive drug release, selective ...targeting to cancer cells, and anticancer activity. In the in vitro drug release studies this nanoconjugate of MTX showed initial rapid release followed by gradual slow release, and the drug release was found to be pH sensitive with greater release at acidic pH. The ex vivo investigations with human breast cancer cell lines, MCF-7, showed enhanced cytotoxicity of MTX-FA-PPI with significantly enhanced intracellular uptake. The biofate of nanoconjugate was determined in Wistar rat where MTX-FA-PPI showed 37.79-fold increase in the concentration of MTX in liver after 24 h in comparison with free MTX formulation.
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