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Sex is increasingly being reported as clinically important variable in the outcome of bladder cancer treatment. But the application of the Sex as a Biological Variable research design, analysis and reporting practices remains limited in biomedical research, dominated by the common use of sex-neutral language with regard to research participants. This study aimed to establish the prevalence of the Sex as a Biological Variable principles in bladder cancer research. Preclinical and clinical studies published in three urology journals were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis. A total of 489 articles were screened from which 133 met the inclusion criteria: 2 (2%) preclinical and 131 (98%) clinical studies. Three articles reported separate outcome data for male and female. Where sex of participants was stated 111/133 (83%); 3 manuscripts (97%) reported a larger number of male participants, compared to females. Only 47 (35%) used sex as a variable in data analysis from which 10 (21%) showed statistically significant difference between their male and female bladder cancer patient cohorts. The inclusion of sex as a biological variable is poorly practiced in bladder cancer research and should be more consistently requested.

Background: Preclinical and clinical research is largely inclusive of both the female and the male population, but the lack of specific separation of data according to patient sex prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as a biological variable in preclinical and clinical studies in kidney cancer. Methods: Preclinical and clinical studies pertaining to kidney cancer published in three leading urology journals over a two-year period were reviewed for the reporting of cells, animal or patient sex, and the inclusion of sex as a biological variable in both study design and data analysis. Results: 171 clinical studies and 5 preclinical studies were included. While the sex of the participants was disclosed in all but 10 of the 171 clinical studies reviewed, the patient populations were largely maledominated (male to female ratio > 1.5). Only 5 studies contained more female than male patients. Sexspecific reporting was performed in 3% of studies, and only 37% included sex as part of the statistical analysis. 26% of these identified a statistically significant difference in measured outcomes between male and female participants. Conclusion: Kidney cancer research is sex-inclusive, but the female patient population remains underrepresented. The consideration of sex in data analysis is low and could prevent the identification of key sex-specific optimization opportunities for the improved management of the disease.

Background: The sex-neutral language used in preclinical and clinical research intends to be inclusive of both the female and the male population, but the practice of data pooling prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as biological variable in the evaluation of radiation therapy in preclinical and clinical studies.Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis.Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clinical studies. Two articles reported separate outcome data for males and females. Where the sex of participants was stated (230/280 (82%), 81% reported a larger number of male participants, compared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex disparity was not dependent on study location but may be more prominent in certain cancer sites. In preclinical studies, sex was at best stated in those reporting on animals (48% of studies).Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of female and male data could introduce statistical biases and prevent the identification of key sex-specific biological subtilities that do affect radiation responses.

Prostate cancer is among the most prevalent life-threatening cancers diagnosed in the male population today. Various methods have been exploited in an attempt to treat this disease but these treatments, alongside preventative tactics, have been insufficient to control mortality rates and have usually resulted in detrimental adverse events. An opportunity to devise more-specific and potentially more-effective approaches for the eradication of prostate tumours can be found by targeting specific biological pathways. NUMB (protein numb homologue), a key regulator of cell fate, represents an attractive, actionable target in prostate cancer. NUMB participates in the observed deregulation of NOTCH (neurogenic locus notch homologue protein) signalling in prostate tumours, and the NUMB–NOTCH interaction regulates cell fate. NUMB has potential both as a target for control of prostate tumorigenesis and as a biomarker for identification of patients with prostate cancer who are likely to benefit from NOTCH inhibition.

Purpose: The comparison of cell lines with differing radiosensitivities and their molecular response to radiation exposure has been used in a number of human cancer models to study the molecular response to radiation. This review proposes to analyze and compare the protocols used by investigators for the development and validation of these isogenic models of radioresistance.Conclusion: There is large variability in the strategies used to generate and validate isogenic models of radioresistance. Further characterization of these models is required.

The risk of recurrence following radiation therapy remains high for a significant number of prostate cancer patients. The development of in vitro isogenic models of radioresistance through exposure to fractionated radiation is an increasingly used approach to investigate the mechanisms of radioresistance in cancer cells and help guide improvements in radiotherapy standards. We treated 22Rv1 prostate cancer cells with fractionated 2 Gy radiation to a cumulative total dose of 60 Gy. This process selected for 22Rv1-cells with increased clonogenic survival following subsequent radiation exposure but increased sensitivity to Docetaxel. This RR-22Rv1 cell line was enriched in S-phase cells, less susceptible to DNA damage, radiation-induced apoptosis and acquired enhanced migration potential, when compared to wild type and aged matched control 22Rv1 cells. The selection of radioresistant cancer cells during fractionated radiation therapy may have implications in the development and administration of future targeted therapy in conjunction with radiation therapy.

MicroRNAs (miRNAs) are an abundant class of noncoding RNAs that function to regulate post-transcriptional gene expression, predominantly by translational repression. In addition to their role in prostate cancer initiation and progression, recent evidence suggests that miRNAs might also participate in treatment response across a range of therapies including radiation treatment, chemotherapy and androgen suppression. The mechanism of this regulation is thought to be multifactorial and is currently poorly understood. To date, only a small number of studies have examined the functional role of miRNAs in response to prostate cancer treatment. Elucidating the role of miRNAs in treatment response following radiotherapy, chemotherapy and androgen suppression will provide new avenues of investigation for the development of novel therapies for the treatment of prostate cancer.

Summary In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93AE38%), and a combined use of both approaches allowed a multi timepoint evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0AE01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P =0 AE04), >0AE01% at the end of induction (P =0 AE02), >0AE01% at the end of consolidation (P =0 AE01), >0AE01% prior to the first delayed intensification (P =0 AE01), and >0AE1% prior to the second delayed intensification and continued maintenance (P =0 AE001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P =0 AE0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.

Introduction Radiotherapy (RT) has a prominent role when used as a single modality or in combination with androgen deprivation therapy (ADT) in the management of prostate cancer patients. However, even with currently available high-dose RT protocols, many patients develop recurrence or “biochemical failure” associated with a rise in PSA, and ultimately reduced overall survival. Key regulators of cancer cell behavior, dysregulation of miRNAs expression is associated with both prostate cancer pathogenesis and treatment resistance. This study aimed to identify a miRNAs signature of radioresistance in a prostate cancer model, as a prerequisite for the future development of a novel pre-treatment assay for the identification of radiotherapy prostate cancer patients at risk of biochemical failure. Methods Two models of radioresistance were used : (1) an isogenic radiation resistant model generated through weekly exposure to 2-Gy fractionated ionising radiation of 22Rv1 (primary) prostate cancer (CaP) cells to a cumulative dose of 60Gy. (2) chronically hypoxic 22Rv1 cells (48hrs). miRNA profiling of radioresistant and wild type cells was performed using the Exiqon miRCURY array and overlapping differentially expressed miRs were identified. Results The radiation survival curve of the resulting subline RR22Rv1 was associated with a significant increase in clonogenic survival (1.3 fold increase in survival after 2Gy and 2.2 fold increase after 10Gy), when compared to both parent 22Rv1 and aged-matched controls. The RR22Rv1 cell line is associated with decreased sensitivity to DNA damage (comet assay), enlargement of the S-phase cell population (PI staining) but no evidence for expansion of the senescent cell fraction (β-Gal assay). miRNA profiling identified 105 significantly differentially expressed miRNAs in RR22Rv1, when compared to the parent and age-matched control 22RV1 cells. A total of 12 miRNA were differentially expressed in chronically hypoxic compared to normoxic 22Rv1 cells. Three candidate miRNAs were associated with a radioresistant phenotype across the models: miR200a, miR210 and miR4284. Functional validation of these candidates is currently under way. Conclusion Available in tissues, serum and urine, miRNAs are ideal candidates for the development of novel biological tests. This study identifies a miRNAs signature of radioresistance in prostate cancer cells with potential for the development of a miRNA-based prognostic assay for radiotherapy prostate cancer patients. Citation Format: Niamh McDermott, Armelle Meunier, Christopher Hernandez, Karen J. Bowman, George D. Jones, Laure Marignol. Identification of a miRNAs signature of radioresistance in a prostate cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3444. doi:10.1158/1538-7445.AM2015-3444