Polymer-drug conjugates (PDCs) are drug delivery systems where one or more drug(s) are covalently attached to the functional groups of the polymer directly or through a spacer. Several anticancer drugs that have been used to synthesize PDCs are currently under clinical trials. PDCs have shown enhanced tumor accumulation, increased therapeutic index, and prolonged circulation, accompanied by a sustained release of the bound drug. Distinct cell uptake mechanisms make PDCs less sensitive to efflux pumps associated with the development of multi-drug resistance. However, the effectiveness of PDCs as a delivery system primarily depends on the drug, polymer, type of linkage, and presence of targeting groups. Due to the availability of different functional groups and spacers, it is possible to control drug release as well as multi-functionalize PDCs, thereby increasing their versatility as drug carriers. Furthermore, active tumor uptake may be achieved by using the concept of drug targeting. However, functionalization alters the in vivo behavior of the polymer, signifying the evaluation of safety and effectiveness of PDCs. Several PDCs are currently being tested in different phases of clinical trials. This review focuses on critical aspects in the design of PDCs when used in cancer drug delivery.

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Hyponatraemia (HN; serum sodium level < 135 mmol/l) is the most common electrolyte disturbance seen in clinical practice, and is associated with varying spectrum of symptoms. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common aetiology in hospitalised patients, and can be caused by several different underlying conditions.
The objectives of this study were to retrospectively examine the baseline characteristics, clinical outcomes and hospital resource utilisation of patients with HN and/or SIADH in Sweden over a 10-year period from 2001 to 2011. Additional analysis was performed on subpopulations of patients with hip fracture, pneumonia and small cell lung cancer (SCLC) to see if trends in outcomes were consistent across a broad range of aetiologies commonly associated with the condition.
Patient information was taken from the Swedish National Patient Registry, the Swedish Cancer Registry, the Swedish Cause of Death Register and the Swedish Prescribed Drug Register. A total of 34,537 patients (4.38%) were identified with HN and/or SIADH, with the incidence and prevalence rising over the 10-year study period.
Of the 34,537 patients identified, 841 had hip fracture, 2635 had pneumonia and 106 had SCLC. Compared with matched control patients, those with HN and/or SIADH had a longer length of hospital stay, a higher re-admission rate and a shorter time to re-admission.
This study showed that HN and/or SIADH negatively impact patient outcomes and healthcare resources related to hospital stay irrespective of the underlying cause. The impact of HN is not confined to the initial hospitalisation, as re-admission rates are also affected.
© 2016 John Wiley & Sons Ltd.

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Lysine deacetylases inhibitors (KDACIs) are used in basic research, and many are being investigated in clinical trials for treatment of cancer and other diseases. However, their specificities in cells are incompletely characterized. Here we used quantitative mass spectrometry (MS) to obtain acetylation signatures for 19 different KDACIs, covering all 18 human lysine deacetylases. Most KDACIs increased acetylation of a small, specific subset of the acetylome, including sites on histones and other chromatin-associated proteins. Inhibitor treatment combined with genetic deletion showed that the effects of the pan-sirtuin inhibitor nicotinamide are primarily mediated by SIRT1 inhibition. Furthermore, we confirmed that the effects of tubacin and bufexamac on cytoplasmic proteins result from inhibition of HDAC6. Bufexamac also triggered an HDAC6-independent, hypoxia-like response by stabilizing HIF1-α, providing a possible mechanistic explanation of its adverse, pro-inflammatory effects. Our results offer a systems view of KDACI specificities, providing a framework for studying function of acetylation and deacetylases.

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When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re-exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell-to-cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c-FLIP and Bcl-2), providing new insight into the control of cell fate by opposing pro-death and pro-survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.

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Monoclonal antibody (mAb) therapy has been successfully used for the treatment of B-cell lymphomas and is currently extended for the treatment of multiple myeloma (MM). New developments in MM therapeutics have achieved significant survival gains in patients but the disease still remains incurable. Elotuzumab (HuLuc63), an anti-CS1 monoclonal IgG1 antibody, is believed to induce anti-tumor activity and MM cytotoxicity through antibody dependent cellular cytotoxicity (ADCC) and inhibition of MM cell adhesion to bone marrow stromal cells (BMSCs). Modulations of the Fc glycan composition at the N297 site by selective mutations or afucosylation have been explored as strategies to develop bio-better therapeutics with enhanced ADCC activity. Afucosylated therapeutic antibodies with enhanced ADCC activity have been reported to possess greater efficacy in tumor growth inhibition at lower doses when compared to fucosylated therapeutic antibodies. The N-linked glycosylation pathway in Pichia pastoris has been engineered to produce human-like N-linked glycosylation with uniform afucosylated complex type glycans. The purpose of this study was to compare afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris with fucosylated anti-CS1 mAb expressed in mammalian HEK293 cells through in vitro ADCC and in vivo tumor inhibition models. Our results indicate that Fc glycosylation is critical for in vivo efficacy and afucosylated anti-CS1 mAb expressed in glycoengineered Pichia pastoris shows a better in vivo efficacy in tumor regression when compared to fucosylated anti-CS1 mAb expressed in HEK293 cells. Glycoengineered Pichia pastoris could provide an alternative platform for generating homogeneous afucosylated recombinant antibodies where Fc mediated immune effector function is important for efficacy.
Copyright © 2015 Elsevier B.V. All rights reserved.

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