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Biomedical subjects

Tim O'Brien

Publications and source records attributed to Tim O'Brien.

8 recordsLinked to original sources
PubMed2025

Tracking Nongenetic Evolution from Primary to Metastatic ccRCC: TRACERx Renal.

While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.

Journal Article↗
PubMed2005

Defining the learning curve for percutaneous nephrolithotomy.

PURPOSE: To define the learning curve for percutaneous nephrolithotomy (PCNL) using three potential surrogate markers of surgical expertise. MATERIALS AND METHODS: The learning curve of an endourologist with no previous experience at performing solo PCNL was studied. Three putative parameters of expertise were reviewed, namely, operating time, fluoroscopic screening time, and radiation dose. Operations were analyzed in cohorts of 15 to determine when a plateau was reached for all three variables. Comparison was then made with the results of a surgeon who had performed more than 1600 PCNLs. Stone type and stone clearance rate were also noted. RESULTS: The mean operating time of the novice surgeon fell to a plateau of 92 minutes after 60 cases, but screening time and radiation dose did not plateau until case 115, when values of 231 seconds and 406 cGy/cm2 were recorded, respectively. The senior surgeon had a mean operating time of 98 minutes and screening parameters equivalent to those of the novice surgeon after 115 cases. The complexity of the stones tackled grew with increasing experience, although stone-free rates remained constant. CONCLUSIONS: This study of the learning curve of a single surgeon suggests that competence at performing PCNL is reached after 60 cases and excellence after 115. Radiation parameters are a valuable tool in the assessment of operative competence.

Clinical Competence↗
PubMed2004

Laparoscopic nephroureterectomy for adult incontinence caused by functioning ectopic pelvic kidney draining into vagina.

A 29-year-old woman had been continent of the majority of her urine for her entire life but had constant, uncontrollable dribbling. A contrast CT scan showed a solitary functioning left kidney and a dysplastic right pelvic kidney with a tortuous dilated ureter running close to the vaginal vault. The kidney was removed whole at transperitoneal laparoscopy, rendering the patient continent. This is the first such case reported in an adult.

Abnormalities, Multiple↗
PubMed2004

The two-week-wait cancer initiative in urology: useful modernization?

The two-week-wait cancer initiative in the UK was designed to speed referral of patients suspected of having cancer and, by so doing, improve their outcome. We reviewed the case notes of all patients referred under this scheme to a single urology department over twelve months. In the department, nearly one-third of new outpatient appointments came under this scheme. 124 patients were referred and all but 7 were seen within the 14-day deadline. In 62 the reason for referral was haematuria, which was macroscopic in 42. Of those with macroscopic haematuria 6 proved to have cancer, newly diagnosed in 4 (2 bladder, 2 renal); no patient with microscopic haematuria had cancer. Of 35 referred with a raised prostate-specific antigen 11 had prostate cancer, in most cases beyond cure. Cancer was found in 1 of 19 patients referred with a testicular mass. In patients referred under the two-week-wait scheme with macroscopic haematuria, cancer is common. Microscopic haematuria is seldom significant. Carcinoma of the prostate is usually advanced and beyond cure at presentation. Among patients referred with scrotal lumps, cancer of the testis is not common. The scheme as a whole is unlikely to improve cancer outcomes. Patients with macroscopic haematuria might be better served by one-stop clinics. For those with testicular lumps, most of which will be benign, the best answer might be direct general practitioner access to scrotal ultrasonography.

Adult↗
PubMed2002

The induced sector Arabidopsis apical embryonic fate map.

Creation of an embryonic fate map may provide insight into the patterns of cell division and specification contributing to the apical region of the early Arabidopsis embryo. A fate map has been constructed by inducing genetic chimerism during the two-apical-cell stage of embryogenesis to determine if the orientation of the first anticlinal cell division correlates with later developmental axes. Chimeras were also used to map the relative locations of precursors of the cotyledon and leaf primordia. Genetic chimeras were induced in embryos doubly heterozygous for a heat shock regulated Cre recombinase and a constitutively expressed beta-glucuronidase (GUS) gene flanked by the loxP binding sites for Cre. Individual cells in the two-apical-cell stage embryo responding to heat shock produce GUS-negative daughter cells. Mature plants grown from seed derived from treated embryos were scored for GUS-negative sector extent in the cotyledons and leaves. The GUS-negative daughters of apical cells had a strong tendency to contribute primarily to one cotyledon or the other and to physically adjacent true leaf margins. This result indicated that patterns of early cell division correlate with later axes of symmetry in the embryo and that these patterns partially limit the fates available for adoption by daughter cells. However, GUS-negative sectors were shared between all regions of the mature plant, suggesting that there is no strict fate restriction imposed on the daughters of the first apical cells.

Arabidopsis↗
PubMedDate not supplied

Factors associated with internal hip rotation gait in patients with cerebral palsy.

Internal rotation gait is common in children with cerebral palsy. Factors thought to contribute include femoral anteversion, hip flexor tightness, imbalance of hip rotators, and hamstring and adductor tightness. The exact cause of internal rotation must be defined before contemplating surgery. We investigated the prevalence of internal hip rotation and associated factors, which are considered to influence this walking pattern, in patients with cerebral palsy. Gait laboratory data of 222 patients with cerebral palsy were studied retrospectively. Two groups were selected; those with maximum dynamic hip internal rotation of more than 27 degrees and those with less than 20 degrees. Of 222 patients, 27.0% (diplegia, 61.7%; hemiplegia, 38.3%) had at least one hip with dynamic internal rotation of more than 27 degrees. This study suggests that dynamic hip internal rotation is multifactorial in origin. The most significant differences in clinical measures were found in values of passive hip external rotation range, femoral anteversion and hip flexor contracture. We discuss the role of early treatment of hip flexion contracture.

Adolescent↗