Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
111
result(s) for
"Bullock, Nicholas"
Sort by:
The movement for housing reform in Germany and France, 1840-1914
During the 1920s and 1930s, a series of housing developments were built in Europe. This study sets out to discover how these developments came to being by looking into the evolution of the movement for housing reform in Germany and France, from the middle of the 19th century until the First World War.
Book
The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.
Journal Article
Pathological upgrading in prostate cancer treated with surgery in the United Kingdom: trends and risk factors from the British Association of Urological Surgeons Radical Prostatectomy Registry
Background
Accurate grading at the time of diagnosis if fundamental to risk stratification and treatment decision making in patients with prostate cancer. Whilst previous studies have demonstrated significant pathological upgrading and downgrading following radical prostatectomy (RP), these were based on historical cohorts and do not reflect contemporary patient selection and management practices. The aim of this national, multicentre observational study was to characterise contemporary rates and risk factors for pathological upgrading after RP in the United Kingdom (UK).
Methods
All RP entries on the British Association of Urological Surgeons (BAUS) Radical Prostatectomy Registry database of prospectively entered cases undertaken between January 2011 and December 2016 were extracted. Those patients with full preoperative PSA, clinical stage, needle biopsy and subsequent RP pathological grade information were included. Upgrade was defined as any increase in Gleason grade from initial needle biopsy to pathological assessment of the entire surgical specimen. Statistical analysis and multivariate logistic regression were undertaken using R version 3.5 (R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 17,598 patients met full inclusion criteria. Absolute concordance between initial biopsy and pathological grade was 58.9% (
n
= 10,364), whilst upgrade and downgrade rates were 25.5% (
n
= 4489) and 15.6% (
n
= 2745) respectively. Upgrade rate was highest in those with D’Amico low risk compared with intermediate and high-risk disease (55.7% versus 19.1 and 24.3% respectively,
P
< 0.001). Although rates varied between year of surgery and geographical regions, these differences were not significant after adjusting for other preoperative diagnostic variables using multivariate logistic regression.
Conclusions
Pathological upgrading after RP in the UK is lower than expected when compared with other large contemporary series, despite operating on a generally higher risk patient cohort. As new diagnostic techniques that may reduce rates of pathological upgrading become more widely utilised, this study provides an important benchmark against which to measure future performance.
Journal Article
Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer
As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient’s treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.
Journal Article
Establishing a national high fidelity cadaveric emergency urology simulation course to increase trainee preparedness for independent on-call practice: a prospective observational study
Background
Whilst competence in the management of a wide range of urological emergencies is a requirement for certification in urology, many conditions are uncommon and exposure during training may be limited. This prospective observational study sought to evaluate the feasibility and effectiveness of a standardised cadaveric emergency urology simulation course aimed at improving operative confidence and competence prior to independent on-call practice in the United Kingdom.
Methods
A two-day cadaveric emergency urology simulation course supported by the British Association of Urological Surgeons (BAUS) was implemented at two pilot centres. All delegates that undertook one of the initial series of courses were invited to complete online pre- and post-course questionnaires relating to prior operative experience, documented competence and perceived confidence in being able to perform specific emergency procedures independently. Primary outcome was a self-reported ‘confidence score’ selected from a linear numeric scale ranging from 1 (not at all confident to perform a given procedure independently) to 10 (fully confident). Statistical analysis was undertaken using SPSS Statistics for Mac Version 25 and the paired student’s t-test used to compare mean pre- and post-course scores.
Results
One hundred and four delegates undertook the course during the study period. Of these, 85 (81.7%) completed the pre-course survey and 67 (64.4%) completed the post-course survey, with 61 (58.7%) completing both. The greatest proportion of respondents were Speciality Trainees in Urology of ST5 level or higher (equivalent of Resident/Fellows with 4 or more years of surgical training;
n
= 31, 36.5%). Delegates reported variable pre-course exposure, with most experience reported in loin approach to the kidney (median 10) and least in exploration and packing of a transurethral resection cavity and emergency nephrectomy (median 0). Following course completion, a statistically significant increase in confidence score was observed for each procedure, with the greatest increases seen for shunt for priapism (4.87 to 8.80,
p
< 0.001), ureteric reimplantation (3.52 to 7.33,
p
< 0.001) and primary ureteric anastomosis (3.90 to 7.49,
p
< 0.001).
Conclusions
A standardised high fidelity cadaveric simulation course is feasible and significantly improves the confidence of trainees in performing a wide range of emergency procedures to which exposure is currently limited.
Journal Article
Perception of urinary biomarker tests among patients referred with suspected urological malignancy
Objective To determine the acceptability of a non‐invasive urinary biomarker test in place of conventional flexible cystoscopy for the diagnosis of bladder cancer in patients referred to a Rapid Access Haematuria Clinic (RAHC) with suspected urological malignancy. Patients and methods Patients attending a RAHC were recruited to a prospective observational study evaluating a novel urinary biomarker (URO17™) for the detection of bladder cancer and invited to complete a two‐part structured questionnaire. Questions related to demographics, attitudes towards conventional cystoscopy and the minimal acceptable sensitivity (MAS) at which a urinary biomarker would be considered an alternative to flexible cystoscopy both before and after undergoing the procedure. Results A total of 250 patients completed the survey; the majority of whom were referred with visible haematuria (75.2%). One hundred seventy‐one (68.4%) would be willing to accept a urinary biomarker in place of cystoscopy, with 59 (23.6%) expressing preference for the biomarker with a MAS as low as 85%. Conversely, 74 patients (29.6%) would not be willing to accept a urinary biomarker, regardless of its sensitivity. A significant number of patients reported a change in MAS after undergoing cystoscopy, with 80 (32.0%) and 16 (6.4%) increasing and decreasing the required value respectively (P = 0.001). The greatest increase was seen in the proportion of patients unwilling to accept a urinary biomarker regardless of its sensitivity, rising from 29.6% to 38.4%. Conclusions Although many patients attending a RAHC would be willing to accept a urinary biomarker test in place of conventional flexible cystoscopy for the detection of bladder cancer, effective patient, public and clinician engagement will be necessary at all stages of implementation if it is to become an established component of the diagnostic pathway.
Journal Article
Enhancing the Therapeutic Efficacy of Poly(Adp-Ribose) Polymerase (Parp) Inhibitors in Prostate Cancer
Despite developments in recent years, outcomes remain poor for men with castrate resistant prostate cancer (CRPC). Inhibitors of poly(ADP-ribose) polymerase (PARPi), which plays a key role in the DNA damage response (DDR), are effective in men with CRPC and pre-existing aberrations in genes encoding proteins involved in homologous recombination (HR) repair of double strand DNA breaks (DSBs). However, responses are limited in patients that lack such aberrations, indicating a need to improve the efficacy of PARPi in this cohort. Experiments in this thesis show that whilst HR-proficient CRPC cells are insensitive to PARPi, treatment leads to DNA damage and activation of CHK1, the downstream effector of another key DDR protein, ataxia telangiectasia and Rad-3 related (ATR). ATR inhibition (ATRi) reverses CHK1 activation and is synergistic with PARPi in vitro in HR-proficient CRPC cells. Furthermore, combined PARPi and ATRi significantly reduces growth and vascularity of PC-3 subcutaneous xenograft tumours compared with vehicle or monotherapy, as well as the prevalence of invasive carcinoma in a genetically modified mouse model (GEMM) of p53 and PTEN deficient localised prostate cancer. Likewise, combination therapy also reduces proliferation of tumour cells within a novel ex vivo model of neuroendocrine CRPC. The role of PARP1, the predominant PARP isoform, was also explored through use of transgenic mouse models. Genetic depletion of PARP1 within prostatic epithelial cells did not alter the phenotype of glands within the normal adult mouse prostate or tumours in the aforementioned GEMM of p53 and PTEN deficient localised prostate cancer. On the contrary, siRNA mediated depletion of PARP1 reduces proliferation of CRPC cells in vitro, with simultaneous PARP2 depletion having no additional benefit, suggesting selective PARP1 inhibition may reduce off target toxicity whilst maintaining efficacy. Collectively, these results demonstrate that combined PARP and ATR inhibition is effective against HR-proficient prostate cancer and support its ongoing investigation in this setting.
Dissertation
Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion
Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from radical prostatectomy specimens of 110 patients. SRPK1 expression was significantly higher in tumour compared with benign tissue (p<0.00001) and correlated with higher pT stage (p=0.004), extracapsular extension (p=0.003) and extracapsular perineural invasion (p=0.008). Interestingly, the expression did not correlate with Gleason grade (p=0.21), suggesting that SRPK1 facilitates the development of a tumour microenvironment that favours growth and invasion (possibly through stimulating angiogenesis) while having little bearing on the morphology or function of the tumour cells themselves.
Journal Article
The 100 most influential manuscripts in andrology: a bibliometric analysis
Background
As the specialty of Andrology expands it is important to establish the most important studies that have shaped, and continue to shape, current research and clinical practice. Bibliometric analysis involving a citation rank list is an established means by which to identify the published material within a given field that has greatest intellectual influence. This bibliometric analysis sought to identify the 100 most influential manuscripts in Andrology, as well as the key research themes that have shaped contemporary understanding and management of andrological conditions.
Methods
The Thompson Reuters Web of Science citation indexing database was interrogated using a number of search terms chosen to reflect the full spectrum of andrological practice. Results were ranked according to citation number and further analysed according to subject, first and senior author, journal, year of publication, institution and country of origin.
Results
The Web of Science search returned a total of 24,128 manuscripts. Citation number of the top 100 articles ranged from 2819 to 218 (median 320). The most cited manuscript (by Feldman et al., The Journal of Urology 1994; 2819 citations) reported the prevalence and risk factors for erectile dysfunction (ED) in the Massachusetts Male Ageing Study. The Journal of Urology published the highest number of manuscripts (
n
= 11), followed by the New England Journal of Medicine (
n
= 10). The most common theme represented within the top 100 manuscripts was erectile dysfunction (
n
= 46), followed jointly by hypogonadism and male factor infertility (
n
= 24 respectively).
Conclusion
Erectile dysfunction should be considered the most widely researched, published and cited field within andrological practice. This study provides a list of the most influential manuscripts in andrology and serves as a reference of what comprises a ‘highly citable’ paper for both researchers and clinicians.
Journal Article
Implementation of medication-related indicators of potentially preventable hospitalizations in a national chronic disease management program for older patients with multimorbidity
Abstract
Initial assessment
Older people are at increased risk of medication-related potentially preventable hospitalizations (MR-PPH) due to the presence of multiple chronic conditions (multimorbidity) and subsequent polypharmacy.
Choice of solution
A pilot study was conducted, using evidence-based indicators to detect older patients in a chronic disease management program (CDMP) at risk of hospitalization due to sub-optimal medication use.
Implementation
Previously validated indicators for MR-PPH were applied to patients with multimorbidity, aged 65 years or older and who were enrolled in a national community-based CDMP. Nurse-led telephone interviews and case note abstraction were used as data sources.
Evaluation
Nineteen patients triggered the MR-PPH indicators 85 times with a median of four per patient. Sub-optimal medication management was identified 34 times (40%) with a median of two per patient. The most common reasons for sub-optimal medication management were exposure to medications associated with falls, underuse of angiotensin-converting enzyme inhibitor/angiotensin-2 receptor blocker medications for cardiovascular disease and low rates of hemoglobin A1c and renal monitoring in patients with diabetes.
Lessons learned
This study has shown the utility of MR-PPH indicators within a CDMP to identify and monitor sub-optimal medication-related care. Implementation and ongoing monitoring of these types of indicators can support the development of targeted programs to reduce the ongoing risk of adverse events in the older population and improve the overall quality of life.
Journal Article