Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science.

BACKGROUND: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL). METHODS: This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010. RESULTS: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population. CONCLUSIONS: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

The oxpA5 mutation of Aspergillus nidulans is an allele of adB, the gene encoding adenylosuccinate synthetase.

The oxpA5 mutation in Aspergillus nidulans results in a pleiotropic phenotype, including resistance to oxypurinol and partial constitutivity of the enzymes of purine catabolism. Here we show that the oxpA5 mutation is an allele of adB, the gene encoding adenylosuccinate synthetase (ASS). Cloning, sequencing and characterisation of the adB gene are reported in this paper. In vivo complementation tests indicate that the oxpA5 mutation is a partial loss-of-function mutation, and altered kinetic parameters of the ASS could account for the pleiotropic phenotype of the oxpA5 mutant. The transcriptional regulation of adB presents some interesting features, including increased gene expression in the presence of ammonium and of AMP, the final product of purine biosynthesis. The adB gene is located adjacent to helA, a newly identified gene coding for a putative RNA helicase.

Hip abductor weakness in distance runners with iliotibial band syndrome.

OBJECTIVE: To examine hip abductor strength in long-distance runners with iliotibial band syndrome (ITBS), comparing their injured-limb strength to their nonaffected limb and to the limbs of a control group of healthy long-distance runners; and to determine whether correction of strength deficits in the hip abductors of the affected runners through a rehabilitation program correlates with a successful return to running. DESIGN: Case series. SETTING: Stanford University Sports Medicine Clinics. PARTICIPANTS: 24 distance runners with ITBS (14 female, 10 male) were randomly selected from patients presenting to our Runners' Injury Clinic with history and physical examination findings typical for ITBS. The control group of 30 distance runners (14 females, 16 males) were randomly selected from the Stanford University Cross-Country and Track teams. MAIN OUTCOME MEASURES: Group differences in hip abductor strength, as measured by torque generated, were analyzed using separate two-tailed t-tests between the injured limb, non-injured limb, and the noninjured limbs of the control group. Prerehabilitation hip abductor torque for the injured runners was then compared with postrehabilitation torque after a 6-week rehabilitation program. RESULTS: Hip abductor torque was measured with the Nicholas Manual Muscle Tester (kg), and normalized for differences in height and weight among subjects to units of percent body weight times height (%BWh). Average prerehabilitation hip abductor torque of the injured females was 7.82%BWh versus 9.82%BWh for their noninjured limb and 10.19%BWh for the control group of female runners. Average prerehabilitation hip abductor torque of the injured males was 6.86%BWh versus 8.62%BWh for their noninjured limb and 9.73%BWh for the control group of male runners. All prerehabilitation group differences were statistically significant at the p < 0.05 level. The injured runners were then enrolled in a 6-week standardized rehabilitation protocol with special attention directed to strengthening the gluteus medius. After rehabilitation, the females demonstrated an average increase in hip abductor torque of 34.9% in the injured limb, and the males an average increase of 51.4%. After 6 weeks of rehabilitation, 22 of 24 athletes were pain free with all exercises and able to return to running, and at 6-months follow-up there were no reports of recurrence. CONCLUSIONS: Long distance runners with ITBS have weaker hip abduction strength in the affected leg compared with their unaffected leg and unaffected long-distance runners. Additionally, symptom improvement with a successful return to the preinjury training program parallels improvement in hip abductor strength.

Breast density as a predictor of mammographic detection: comparison of interval- and screen-detected cancers.

BACKGROUND: Screening mammography is the best method to reduce mortality from breast cancer, yet some breast cancers cannot be detected by mammography. Cancers diagnosed after a negative mammogram are known as interval cancers. This study investigated whether mammographic breast density is related to the risk of interval cancer. METHODS: Subjects were selected from women participating in mammographic screening from 1988 through 1993 in a large health maintenance organization based in Seattle, WA. Women were eligible for the study if they had been diagnosed with a first primary invasive breast cancer within 24 months of a screening mammogram and before a subsequent one. Interval cancer case subjects (n = 149) were women whose breast cancer occurred after a negative or benign mammographic assessment. Screen-detected control subjects (n = 388) were diagnosed after a positive screening mammogram. One radiologist, who was blinded to cancer status, assessed breast density by use of the American College of Radiology Breast Imaging Reporting and Data System. RESULTS: Mammographic sensitivity (i.e., the ability of mammography to detect a cancer) was 80% among women with predominantly fatty breasts but just 30% in women with extremely dense breasts. The odds ratio (OR) for interval cancer among women with extremely dense breasts was 6.14 (95% confidence interval [CI] = 1.95-19.4), compared with women with extremely fatty breasts, after adjustment for age at index mammogram, menopausal status, use of hormone replacement therapy, and body mass index. When only those interval cancer cases confirmed by retrospective review of index mammograms were considered, the OR increased to 9.47 (95% CI = 2.78-32.3). CONCLUSION: Mammographic breast density appears to be a major risk factor for interval cancer.

The Physical Activity for Total Health (PATH) Study: rationale and design.

PURPOSE: Physical activity has been associated with a decreased risk for breast cancer. Mechanisms for this association may involve hormonal pathways. The Physical Activity for Total Health study is testing the effect of a 1-yr moderate intensity physical activity intervention on the endogenous sex hormone profile of postmenopausal women in a randomized controlled study. METHODS: Women (N = 168) who are aged 55-75 yr, not using sex hormones, sedentary, nonsmokers, have no endocrine-related disease or cancer, and with body mass index of 25.0 or greater, are eligible. Women are recruited through mass mailings and media advertising and are randomized to either a 1-yr moderate intensity aerobic and strength training exercise program (monitored group exercise sessions plus home exercise) or a control program (stretching classes). RESULTS: Serum hormones to be assayed at baseline and at the end of the study include: total estrone, total estradiol, free estradiol, percent bioavailable estradiol, estrone sulfate, sex hormone binding globulin, albumin, testosterone, free testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, insulin, glucose, and triglycerides. Other outcome measures include: the ratio of urinary 2-hydroxyestrone: 16alpha-hydroxyestrone (an estrogen metabolite ratio that may be associated with risk for breast cancer), weight, body mass index, total fat mass, and body fat distribution (waist:hip circumference ratio, DEXA scan, and abdominal fat measured by computed tomography). CONCLUSION: This study is the first to examine the effect of change in physical activity level on sex hormones in postmenopausal women. It will provide insight into possible mechanisms through which physical activity might be associated with reduced risk of breast cancer.

Mutations in a dispensable region of the UaY transcription factor of Aspergillus nidulans differentially affect the expression of structural genes.

The uaY gene encodes a transcriptional activator mediating uric acid induction of at least nine genes of the purine-utilization pathway. In this article, we characterize a loss-of-function mutation, uaY205, as a 16 bp deletion that results in premature translation termination, and substitutes the C-terminal 63 amino acids for 13 amino acid residues. Reversion analysis demonstrates that the C-terminal 63 amino acid residues are unnecessary for UaY function, and that the loss-of-function phenotype resulting from the uaY205 mutation is caused by the new amino acid sequence present in the mutant protein. Revertants in two different frames (wild type and +1) restore function but show subtle differences in the expression of genes controlled by the UaY protein. Two strains showing elevated expression of genes under UaY control were shown to carry, in addition to a mutation leading to the recovery of the wild-type open reading frame, mutations in unlinked genes. Using crude extracts of Aspergillus nidulans, we have been able to detect, for the first time, in transcription factors of this class, specific retardation of a promoter probe. The binding activity is at least partially dependent on the presence of inducer. The gel shift experiments show that the novel inhibitory sequence present in the UaY205 protein can act either by affecting the stability of the protein, or via an inter- or intramolecular interaction impairing the specific DNA-binding activity.

A single amino acid change in a pathway-specific transcription factor results in differing degrees of constitutivity, hyperinducibility and derepression of several structural genes.

unYc462 is a gain-of-function mutation in the purine catabolism positive regulatory gene of Aspergillus nidulans. This allele leads to a constitutive, hyperinducible and derepressed expression of a least three genes controlled by uaY, and this occurs at different levels depending on the target gene. The uaYc462 allele was mapped physically in relation to known loss-of-function alleles and sequenced. uaYc462 is a one-base change in codon 222, resulting in a serine to leucine change. We propose that this mutation maps in a functional domain involved, directly or indirectly, in the interaction of UaY with other components of the transcriptional apparatus. A sequence similar to the motif surrounding serine 222 may play similar roles in the PPR1 and ADR1 proteins of Saccharomyces cerevisiae.

The sequence and binding specificity of UaY, the specific regulator of the purine utilization pathway in Aspergillus nidulans, suggest an evolutionary relationship with the PPR1 protein of Saccharomyces cerevisiae.

The uaY gene codes for a transcriptional activator mediating the induction of a number of unlinked genes involved in purine utilization in Aspergillus nidulans. Here we present the complete genomic and cDNA nucleotide sequence of this gene. The gene contains two introns. The derived polypeptide of 1060 residues contains a typical zinc binuclear cluster domain and shows a number of similarities with the PPR1 regulatory gene of Saccharomyces cerevisiae. These similarities are most striking in the putative linker and dimerization regions following the zinc cluster. Gel-shift and DNase I footprinting experiments have been carried out for three genes subject to UaY-mediated induction. The binding sequence is 5'-TCGG-6X-CCGA, which is identical to the proposed PPR1 binding sites. Nevertheless, the identity of the base immediately 3' of the 5'-TCGG sequence clearly affects the affinity of the site. The site upstream of the uapA gene has been shown to be active in vivo. Binding to this site has been analysed by a number of interference techniques. There is an interesting chemical similarity between the co-inducer of the purine utilization pathway (uric acid) and that of the genes of the pyrimidine biosynthetic pathway (dihydroorotic acid) and we show that dihydroorotic acid can act as a poor inducer of at least one activity under UaY control. These striking similarities, together with the unique pattern of regulation of pyrimidine biosynthesis in S. cerevisiae, suggest that PPR1 evolved through recruitment into the pyrimidine biosynthetic pathway of an ancestral gene related to uaY.

Sequence, regulation, and mutational analysis of the gene encoding urate oxidase in Aspergillus nidulans.

The uaZ gene of Aspergillus nidulans codes for a protein of 301 amino acids. The open reading frame is interrupted by two introns. A comparison with the open reading frames of 10 other urate oxidases reveals a number of scattered universally conserved residues and four clusters of high similarity. Two of these are of unknown function, and the other two are the putative sites for copper binding and the signal sequence for peroxisomal entry, respectively. This comparison also reveals that there are at 16 positions at which introns can be found in the gene coding for this enzyme in different species. The sequence of a number of mutations confirms the importance for enzyme activity of the carboxyl terminus of the protein. The most amino-terminal mutation (an ochre codon) results also in strikingly diminished steady-state levels of message. This agrees with results from other systems, suggesting that untranslated mRNA is preferentially degraded in eukaryotic cells. Northern blots show that specific induction, mediated by the UAY protein, and nitrogen metabolite repression, mediated by the AREA GATA factor, affect the steady-state levels of uaZ mRNA and thus act most probably at the level of transcription.

Characterisation, cloning and integrative properties of the gene encoding urate oxidase in Aspergillus nidulans.

A number of mutations have been obtained which define the structural gene (uaZ) coding for urate oxidase in linkage group I of Aspergillus nidulans. This gene has been cloned by transformation of a uaZ- null mutant. A chromosome I/VIII translocation which splits the gene has been defined both genetically and physically. All known mutations are contained in a 1-kb fragment, itself contained in the probe which recognizes a 1.2-kb inducible message. Plasmids carrying uaZ show a strict bias towards homologous recombination in transformation experiments.

The uaY positive control gene of Aspergillus nidulans: fine structure, isolation of constitutive mutants and reversion patterns.

The product of the uaY gene of Aspergillus nidulans is necessary for the expression of at least eight genes coding for enzymes and permeases of the purine utilisation pathway. A detailed fine structure map has been constructed of this gene involving 13 presumed point mutations and eight deletions. Gene conversion of these deletions was demonstrated. A technique was devised to select for constitutive mutations and two were obtained which map within the uaY gene. We have shown that the most centromere proximal allele reverts to a number of different phenotypes. The properties of this allele suggest that it may map in the open reading frame of the uaY gene, in a domain that could be altered in a way that would differentially affect the expression of genes under uaY control.

Molecular cloning of the uaY regulatory gene of Aspergillus nidulans reveals a favoured region for DNA insertions.

The cloning of the positive regulatory gene, uaY, which mediates uric acid induction of enzymes and permeases of the purine degradation pathway in the fungus Aspergillus nidulans is described here. The 4 kb uaY transcript is constitutively synthesised, it is not repressed by ammonia and its transcription does not require the AreA wide-domain transcription factor. We have determined that four deletions, which have been genetically characterised, are confined to a segment of 0.9 kb. Two other deletions are double events; each is a deletion of about 1 kb plus an insertion. The positions of the deletions confine 9 out of the 11 mapped putative point mutations within a 1 kb segment. Two other non-revertible alleles, which mapped as point mutations, are insertions of at least 11 and 18 kb respectively. The pattern of gene conversion within the uaY gene was described previously. The results reported here demonstrate that conversion of sequences of at least 18 kb can occur in A. nidulans.