The sequence analysis of the SuSK revealed

homology to Ar

The sequence analysis of the SuSK revealed

homology to Arabidopsis thaliana shaggy-related protein kinase delta (E value, 1e(-108)), dzeta and iota. Alignment of the catalytic domain sequence of GSK-3/shaggy-like kinase with partial sequence of SuSK performed using ClustalW tool indicated kinase active-site signature sequence. Spatial and temporal transcript expression profiling of the SuSK gene based on Real-Time PCR revealed significant induction of transcript expression in response to short-term salt (NaCl 200 mM) or polyethylene glycol-8,000 (PEG; 20% w/v) induced osmotic stress in leaves and shoots of sugarcane plants. The transcript expression increased progressively under salt stress and reached to IWR-1 price 1.5-fold of the control up to 8 h treatment. In response to PEG stress, the transcript expression increased by 1.5-fold over the control in 2-h

treatment in leaf, whereas in shoots, the expression remained unchanged in response to the various treatments. Differences in growth parameters, relative water content, and membrane damage rate were statistically insignificant in the short-term salt or PEG-stressed plants as compared to the control, non-stressed plants. Expression analysis revealed the differential and temporal regulation of this gene under salt and PEG stress and that its early induction PLX-4720 mouse may indicate involvement in stress signaling.”
“The major capsid protein of norovirus GII.4 strains is evolving rapidly, resulting in epidemic strains with altered antigenicity. GII.4.2006 Minerva strains circulated at pandemic levels in 2006 and persisted at lower levels until 2009. In 2009, a new GII.4 variant, GII.4.2009 New Orleans, emerged and since then has become the predominant strain circulating in human populations. To determine whether changes in evolving blockade epitopes correlate

with the emergence of the GII.4.2009 New Orleans strains, we compared the antibody reactivity of a panel of mouse monoclonal antibodies (MAbs) against GII.4.2006 and GII.4.2009 virus-like particles (VLPs). Both anti-GII.4.2006 and GII.4.2009 MAbs effectively differentiated the two strains by VLP-carbohydrate ligand blockade assay. Most of the GII.4.2006 MAbs preferentially blocked GII.4.2006, while all of the GII.4.2009 AZD5363 MAbs preferentially blocked GII.4.2009, although 8 of 12 tested blockade MAbs blocked both VLPs. Using mutant VLPs designed to alter predicted antigenic epitopes, binding of seven of the blockade MAbs was impacted by alterations in epitope A, identifying residues 294, 296, 297, 298, 368, and 372 as important antigenic sites in these strains. Convalescent-phase serum collected from a GII.4.2009 outbreak confirmed the immunodominance of epitope A, since alterations of epitope A affected serum reactivity by 40%. These data indicate that the GII.4.

At 24 months, overall and cardiovascular mortality and thrombotic

At 24 months, overall and cardiovascular mortality and thrombotic events were all significantly higher in patients with high anti-beta- glycoprotein I antibodies. Multivariate analysis using Cox regression modeling found that age, hypoalbuminemia, use of dialysis catheters, and IgA beta-glycoprotein I antibodies were independent risk factors Vorinostat supplier for death. Thus, IgA antibodies to beta-glycoprotein I are detrimental to the clinical outcome of hemodialysis patients.”
“Site-directed spin labeling (SDSL) was used to investigate local structure and conformational exchange in two bacterial outer-membrane TonB-dependent transporters, BtuB and FecA. Protecting osmolytes,

such as polyethylene glycols (PEGs) are known to modulate a substrate-dependent conformational equilibrium in the energy coupling motif (Ton box) of BtuB. Here, we demonstrate that a segment that is N-terminal to the Ton box in BtuB, is in conformational exchange

between ordered and disordered states with or without substrate. Protecting osmolytes shift this equilibrium to favor the more ordered, folded state. However, a segment of BtuB that is C-terminal to the Ton box that is not solvent exposed is insensitive to PEGs. Protecting osmolytes also modulate a conformational equilibrium in the Ton box of FecA, with larger molecular weight PEGs producing the largest shifts in the conformational free energy. These data indicate that solvent-exposed regions of these transporters undergo conformational exchange and that regions of these transporters that are involved

in protein-protein interactions sample multiple conformational substates. The sensitivity THZ1 purchase to solute provides an explanation for differences seen between two high-resolution structures of BtuB, which each likely represent one conformation from a subset of states that are normally sampled by the protein. This work also illustrates how SDSL and osmolytes may be used to characterize and quantitate conformational equilibria in membrane proteins.”

Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase Selleck FHPI the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.


We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.

Low pH conditions lead to conformational changes associated with

Low pH conditions lead to conformational changes associated with increased alpha S fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary

chemical shifts, relaxation Pitavastatin datasheet parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of alpha S and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-beta component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a

role in the increased aggregation of alpha S at low pH, which we instead attribute to the increased hydrophobicity of the protein.”
“Purpose: We report on our initial experience in terms of efficacy and safety with a new, self-anchoring adjustable transobturator male system (A.M.I.(R) ATOMS System) for the treatment of male stress urinary incontinence after prostate surgery.

Materials and Methods: In this prospective, nonrandomized single center study conducted between March and December 2009, patients with stress urinary incontinence secondary else to prostatic surgery were treated with the ATOMS device. Urethroscopy, Mocetinostat mw filling and voiding cystometry were performed preoperatively for all patients. In addition, incontinence symptoms were assessed, and a physical examination, 24-hour pad test and 24-hour pad count were performed before and after surgery.

Results: A total of 38 patients were included in the study (36 after radical prostatectomy, 2 after benign

prostatic hyperplasia surgery). No intraoperative complications occurred. Mean number of adjustments during followup was 3.97 (range 0 to 9). At a mean followup of 16.9 months (range 13 to 21) the overall success rate was 84.2%. Of the successful cases 60.5% were considered dry (0 to 1 pad and less than 15 ml/24-hour pad test) and 23.7% improved (more than 1 pad per 24 hours but more than 50% decrease in pad use and less than 100 ml per 24-hour pad test). In 15.8% of the patients the treatment was considered to have failed (more than 2 pads daily and greater than 100 ml on 24-hour pad test).

Conclusions: The treatment of male stress urinary incontinence with the ATOMS is safe and effective. It is an excellent first or second line treatment for mild to moderate male stress urinary incontinence, even after external irradiation. The option of long-term, minimally invasive adjustment to respond to patient needs is a significant advantage of this new implant.

Control patients displayed a correlation between AQP1 and the alb

Control patients displayed a correlation between AQP1 and the albumin CSF/serum ratio (r = 0.390, p = 0.040).

This is the first study that detected AQP1 and AQP4 in CSF. Whether the significant elevation of AQP1 is due to a higher expression and

subsequent shedding into CSF or a BM-induced cell damage needs to be determined. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“The present study investigated the changes in several erythrocyte oxidative stress biomarkers in hypoxic elderly individuals to analyze the deleterious effects of low oxyhemoglobin saturation in an elderly population. We collected blood samples from one normoxic middle-aged group and two groups composed of individuals older learn more than 75 years of age: one normoxic group and one hypoxic group. Aging appeared to provoke a defective erythrocyte antioxidant defense associated with increased oxidative damage

in the elderly population. Acute hypoxia activated an insufficient antioxidant defense response as suggested by the oxidative damage observed. The oxidative imbalance presented in older participants and increased in hypoxia participants had a direct effect on glyceraldehyde-3-phosphate dehydrogenase cell distribution. Oxidative see more stress levels altered Band 3 protein and mediated caspase-3 activation in erythrocyte from the aged group although it was not extended to hypoxic individuals. Therefore, aged participants appeared to activate an insufficient antioxidant response against hypoxia-related oxidative stress.”
“Skin aging is an extremely important medical and social problem in the modern world. Therefore, a goal of the present work was to estimate changes in the numbers of fibroblast-like cells, proliferating cells nuclear antigen-positive cells, CD45-positive cells, mast cells, and eosinophils in human dermis at different ages. Skin specimens from human

fetuses that died antenatally from 20 to 40 weeks of pregnancy and humans who died from different causes from 1 day to 85 years of life were used for the study. Results showed a decrease in a total number and the number of proliferating cells nuclear antigen-positive about fibroblast-like cells in dermis with progression of age. The numbers of CD45-positive cells and mast cells are gradually increased with aging. Eosinophils are almost absent in dermis independently on age. Mast cells are probably a main factor that potentially can be involved in tissue damage and aging changes in skin. Mast cells should be regarded as an important target for anti-aging therapy.”
“The capacity to generate an efficient innate immune response is pivotal for survival. The objective of this study was to investigate innate immune function in relation to long-term survival in the oldest old. We measured ex vivo lipopolysaccharide-induced proinflammatory and antiinflammatory cytokine responses in 562 participants aged 85 years of the general population who were followed for mortality during 10 years.

The intraobserver variability of the measurements ranged from 3 4

The intraobserver variability of the measurements ranged from 3.4 to 4.1 % and the interobserver variability from 5.8 to 7.3 %. There were no significant differences in the variability between the techniques. The mean residual filling volume ranged from 16.3 +/- 19.0 mm(3) in TOF-MRA to 30.5 +/- 44.6 mm(3) in 3D-DSA (P < 0.04). Significant differences were found in the volumes measured with 3D-DSA and CE-MRA as compared to TOF-MRA and CE-TOF-MRA (P < 0.01). There was a moderate significant correlation between the

residual filling and the relative error of measurement in the case of TOF-MRA and CE-TOF-MRA.

TOF-MRA seems to underestimate the size of aneurysm remnants detected at follow-up and should not be used as a sole imaging method to decide on re-embolization.”
“Identification and characterization of recurrent supersecondary

structural elements is central to understanding the rules PF-4708671 governing protein tertiary structure. Here, we describe the GD box, a widespread noncontiguous supersecondary element, which we initially found in a group of topologically distinct but homologous beta-barrels-the cradle-loop barrels. The GD box is similar both in sequence and structure and comprises two short unpaired beta-strands connected by an orthogonal type-II beta-turn and a noncontiguous beta-strand forming hydrogen bonds with the beta-turn. Using structure-based ��-Nicotinamide in vivo analysis, we have detected 518 instances of the GD box in a nonredundant subset of the SCOP database comprising

3771 domains. Apart from the cradle-loop barrels, this, motif is also found in a diverse set of nonhomologous folds including other topologically related beta-barrels. Since nonlocal interactions are fundamental in the formation of protein structure, systematic identification and characterization of other noncontiguous supersecondary structural elements is likely to prove valuable to protein structure modeling, validation, and prediction.”
“Congenital infantile myofibromatosis (IM) is a rare mesenchymal disease, presenting with tumors in the skin, muscle, viscera, bone, and subcutaneous tissue. It can present as (a) a solitary form with subcutaneous, erythematous nodules, (b) a multicentric form with subcutaneous, muscle, and/or bony lesions, and (c) a multicentric form with visceral involvement. Cerebral or spinal involvement in myofibromatosis has been reported rarely.

We report seven cases of histology-proven infantile myofibromatosis with brain, spine, and/or head and neck involvement.

In three patients with multiple subcutaneous nodules, a multicentric form of IM with visceral involvement was diagnosed. In three patients, a multicentric form without visceral involvement was found. Two patients had brain involvement, and four patients had vertebral body involvement.

“Impulsivity and serotonergic neurotransmission have previ

“Impulsivity and serotonergic neurotransmission have previously been shown to be linked to the intensity dependence of auditory evoked potentials. The present study investigates whether impulsivity in normal healthy subjects has a similar influence on the neuronal correlates of the coding of sound intensity using functional magnetic resonance imaging (fMRI). Forty-four participants completed Cloninger’s Tridimensional Personality Questionnaire (TPQ). The dependence of fMRI activation on sound intensity was examined using continuous pink noise with varying intensity

as acoustic stimuli. Imaging data were analyzed for the volume of activation sensitive to sound intensity. Impulsivity has a significant effect on the volume of activation sensitive to sound intensity. Persons with Proteases inhibitor high impulsivity scores on the TPQ scale show approximately CH5183284 order twice the volume of activation when compared with persons with low impulsivity scores. The neuronal correlate of impulsivity as revealed by fMRI gives strong evidence of a link between impulsive behavior and neural activity

evoked by auditory stimulation. This link may prove useful for measuring central serotonergic neurotransmission in a clinical setting. (C) 2009 Elsevier Ireland Ltd. All rights reserved.”
“The replication of the hepatitis C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mechanistic understanding and structure-guided drug design efforts have been hampered by its propensity to crystallize in a closed, polymerization-incompetent state. The removal of an autoinhibitory beta-hairpin loop from genotype 2a HCV NS5B increases learn more de novo RNA synthesis by >100-fold, promotes RNA binding, and facilitated the determination of the first crystallographic

structures of HCV polymerase in complex with RNA primer-template pairs. These crystal structures demonstrate the structural realignment required for primer-template recognition and elongation, provide new insights into HCV RNA synthesis at the molecular level, and may prove useful in the structure-based design of novel antiviral compounds. Additionally, our approach for obtaining the RNA primer-template-bound structure of HCV polymerase may be generally applicable to solving RNA-bound complexes for other viral RdRps that contain similar regulatory beta-hairpin loops, including bovine viral diarrhea virus, dengue virus, and West Nile virus.”
“The abuse of psychoactive ‘bath salts’ containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices.

The sequencing of viral gene UL54 DNA, extracted from infected A1

The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.”
“Rationale Substance abuse is more prevalent among patients with schizophrenia than in the general population. The considerable overlap in neurobiological disruptions thought to underlie each condition suggests that addictive behavior may represent a primary Selleck SBC-115076 symptom of schizophrenia.

Objectives This study investigated drug-seeking in a neurodevelopmental animal

model of schizophrenia,

the neonatal ventral hippocampal lesion (NVHL) model.

Materials and methods At postnatal day 7, rats received an excitotoxic ventral hippocampus lesion or a sham procedure and were trained as adults to self-administer methamphetamine (0.1 mg/kg/infusion) or respond for natural reinforcement (water or food).

Results NVHL rats were faster than shams to acquire the operant response for either drug self-administration or water reinforcement, suggesting that simple instrumental GSK2879552 mw learning may be enhanced in these animals. NVHL and sham rats displayed no differences in fixed-ratio (FR) responding for either methamphetamine or food, Talazoparib manufacturer and both groups of animals were equally sensitive to methamphetamine dose changes (0.05, 0.1, or 0.2 mg/kg/infusion). However, under a progressive-ratio (PR) schedule, NVHL animals reached significantly higher break points (NVHL 18 infusions; sham 12 infusions) for methamphetamine but not food reinforcement, suggesting enhanced motivation to acquire drug and/or elevated incentive value of the drug that did not generalize to another form of reinforcement.

Conclusions These data indicate that developmental disruption of the hippocampus elevates rats’ vulnerability to drug-seeking behavior under PR conditions. Furthermore,

drug self-administration in the NVHL animal emulates addictive behavior in schizophrenia, making this model useful for investigating the mechanisms of dual diagnosis, including the neurobiological and behavioral similarities between addiction and schizophrenia.”
“T cell-mediated adaptive immune response is controlled by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. Coinhibition is exploited by prostate cancer as an immune evasion pathway. Overexpression of coinhibitory B7x and B7-H3 in prostate cancer correlates with poor disease outcome, whereas tumor-infiltrating immune cells have enhanced expression of PD-L1 and its receptor PD-1.

“Objectives: Two toxicologic studies of vigabatrin were c

“Objectives: Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1.

Methods: During Study 1, immature Sprague Dawley rats were orally Bindarit order administered deionized water (vehicle control), or vigabatrin at

5, 15, or 50 mg/kg/day for <= 9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50 mg/kg/day for <= 9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME.

Results: At

5-50 mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50 mg/kg/day, and were attenuated

during recovery. Vacuolar-change Urease morphology was characteristic of IME, Sonidegib datasheet with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4-15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4-46 and 4-65. Vacuolation was markedly attenuated in post-recovery-period rats.

Conclusions: The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages <50 mg/kg/day did not affect CNS, behavior, and reproductive development. However, at the greatest dosage, some retardation of physical growth, delay in sexual maturation, reduction in physical strength, and induction of CNS stimulation (handling-induced spasms) occurred. The key pathologic finding was vacuolar brain lesions in the white and gray matter, which generally reversed upon drug discontinuation. Vacuoles were confined to myelin sheaths, consistent with observations in adult rats. Vigabatrin delayed but did not eliminate myelination despite continued dosing, an effect greatest during active myelination. (C) 2011 Elsevier Inc. All rights reserved.

The 16-row scanner suffered from limited anatomic coverage that d

The 16-row scanner suffered from limited anatomic coverage that decreased the sensitivity to detect perfusion defects in the cranial parts of the middle cerebral artery region. The 16-row studies had poorer technical quality that was in part attributable to higher sampling frequency and smaller slice thickness making the imaging more sensitive to small-scale

movement of the patient.”
“Since its initial conceptualisation, metaplasticity has come to encompass a wide variety of phenomena and mechanisms, creating the important challenge of understanding how they contribute to network function and behaviour. Here, we Z-IETD-FMK supplier present a framework for considering potential roles of metaplasticity across three domains of see more function. First, metaplasticity appears ideally placed to prepare for subsequent learning by either

enhancing learning ability generally or by preparing neuronal networks to encode specific content. Second, metaplasticity can homeostatically regulate synaptic plasticity, and this likely has important behavioural consequences by stabilising synaptic weights while ensuring the ongoing availability of synaptic plasticity. Finally, we discuss emerging evidence that metaplasticity mechanisms may play a role in disease causally and may serve as a potential therapeutic target.”
“The popularity of smokeless tobacco (ST), or noncombusted no tobacco, usually placed within the mouth to be chewed, sucked, or swallowed, is growing rapidly and its prevalence of use is rising globally, due (in part) to greater convenience, as allowable cigarette smoking areas are rapidly decreasing, and increased social acceptability. Though data are limited, ST usage has been directly linked to a number of adverse health outcomes.

The potential role that immune dysfunction, including dysregulation of immune cells and their components, may play in the progression of these adverse health outcomes is only just beginning to emerge. Evidence suggesting reproductive outcomes, such as perinatal mortality, preterm birth, and reduced sperm viability, also exists in conjunction with ST use. Cardiovascular health may also be impacted by ST use, resulting in increased blood pressure and endothelial dysfunction, both of which may potentially lead to cardiovascular diseases. This review describes the toxicological implications associated with ST use, with emphasis on immune, reproductive, and cardiovascular outcomes. Epidemiological studies are discussed with respect to experimental studies to help develop the relationship between ST and disease pathology. This review also summarizes the gaps in ST knowledge and potential future directions that are needed to more fully delineate the complex systems driving the adverse health outcomes associated with its use.


numerous other strategies, both those invo


numerous other strategies, both those involving cellular transplantation and those examining neutralisation of inhibitory factors of the CNS, have achieved limited success. A combinational strategy, with olfactory ensheathing selleck kinase inhibitor cells at its centre, is arguably the best way forward in encouraging effective recovery following CNS injury.

This review examines the inhibitory environment of the CNS and the research to date on overcoming its effects on the regrowth of injured axons. The efficacy of therapies involving olfactory ensheathing cells, and the place of these therapies among the many other strategies being developed is examined. (c) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“Background Cabazitaxel

is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.

Methods We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously find more over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at, NCT00417079.

Findings 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the

intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15.1 months (95% CI 14.1-16.3) Blasticidin S ic50 in the cabazitaxel group and 12.7 months (11.6-13.7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0.70 (95% CI 0.59-0.83, p<0.0001). Median progression-free survival was 2.8 months (95% CI 2.4-3.0) in the cabazitaxel group and 1.4 months (1.4-1.7) in the mitoxantrone group (HR 0.74, 0.64-0.86, p<0.0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]).