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Julie George

Publications and source records attributed to Julie George.

9 recordsLinked to original sources
PubMed2026

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Humans↗
PubMed2025

Functional synapses between neurons and small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1-3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.

Animals↗
PubMed2006

Gene-associated single nucleotide polymorphism discovery in perennial ryegrass (Lolium perenne L.).

Molecular genetic marker development in perennial ryegrass has largely been dependent on anonymous sequence variation. The availability of a large-scale EST resource permits the development of functionally-associated genetic markers based on SNP variation in candidate genes. Genic SNP loci and associated haplotypes are suitable for implementation in molecular breeding of outbreeding forage species. Strategies for in vitro SNP discovery through amplicon cloning and sequencing have been designed and implemented. Putative SNPs were identified within and between the parents of the F(1)(NA(6) x AU(6)) genetic mapping family and were validated among progeny individuals. Proof-of-concept for the process was obtained using the drought tolerance-associated LpASRa2 gene. SNP haplotype structures were determined and correlated with predicted amino acid changes. Gene-length LD was evaluated across diverse germplasm collections. A survey of SNP variation across 100 candidate genes revealed a high frequency of SNP incidence (c. 1 per 54 bp), with similar proportions in exons and introns. A proportion (c. 50%) of the validated genic SNPs were assigned to the F(1)(NA(6) x AU(6)) genetic map, showing high levels of coincidence with previously mapped RFLP loci. The perennial ryegrass SNP resource will enable genetic map integration, detailed LD studies and selection of superior allele content during varietal development.

Breeding↗
PubMed2006

Assessment of genetic diversity in cultivars of white clover (Trifolium repens L.) detected by SSR polymorphisms.

White clover (Trifolium repens L.) is an important temperate pasture legume that plays a key role as a companion to grass species, such as perennial ryegrass (Lolium perenne L.). Due to the outbreeding nature of white clover, cultivars are highly heterogeneous. Genetic diversity was assessed using 16 elite cultivars from Europe, North and South America, Australia, and New Zealand. Fifteen simple sequence repeat markers that detect single, codominant polymorphic genetic loci were selected for the study. The genetic relationships among individuals were compared using phenetic clustering, and those among cultivars were compared using nonmetric multidimensional scaling. Intrapopula tion variability exceeded interpopulation variability, with substantial overlap among populations and weak interpopula tion differentiation. No obvious or significant differentiation was observed on the basis of morphology or geographic origin of the cultivars. The number of parental genotypes used to derive each cultivar was not a major determinant of genome-wide genetic diversity. The outcomes of this assessment of genetic variation in elite white clover germplasm pools have important implications for the feasibility of molecular marker-based cultivar discrimination, and will be used to assist the design of linkage disequilibrium mapping strategies for marker-trait association.

Base Sequence↗
PubMed2006

Association of population and practice factors with potentially avoidable admission rates for chronic diseases in London: cross sectional analysis.

OBJECTIVES: To examine the association between underlying ill health, material deprivation and primary care supply factors and hospital admission rates for potentially avoidable admissions in primary care trusts in London. DESIGN: Cross sectional analysis at primary care trusts level using routine data from multiple sources. SETTING: All 31 primary care trusts in London with a total resident population of 7 million patients. MAIN OUTCOME MEASURES: Age-standardized hospital admission rates for asthma, diabetes, heart failure, hypertension and chronic obstructive pulmonary disease. RESULTS: Admission rates varied widely for the conditions examined across the 31 primary care trusts. In 2001, age adjusted admission rates for asthma varied from 76 to 189 per 100,000 and for diabetes from 38 to 183 per 100,000. There was a significant association between higher admission rates and measures of underlying ill health and material deprivation but not quantitative measures of primary care service provision. Provision of specialist chronic disease services in primary care for diabetes but not for asthma were significantly associated with reduced admission rates. There was no association of prescribing levels in primary care trusts with admission rates for any of the conditions examined. CONCLUSIONS: Although hospital admission for some chronic diseases is potentially avoidable and rates of hospital admission for these conditions are possible indicators of the quality of care, they should be interpreted in conjunction with measures of population composition and deprivation. Failure to do this may result in primary care trusts and general practitioners being criticized for aspects of health care utilization that are not under their direct control.

Adolescent↗
PubMed2004

Tree-based model for breast cancer prognostication.

PURPOSE: To define prognostic groups for recurrence-free survival in breast cancer, assess relative effects of prognostic factors, and examine the influence of treatment variations on recurrence-free survival in patients with similar prognostic-factor profiles. PATIENTS AND METHODS: We analyzed 1,055 patients diagnosed with stage I-III breast cancer between 1990 and 1996. Variables studied included socioeconomic factors, tumor characteristics, concurrent medical conditions, and treatment. The primary end point was recurrence-free survival (RFS). Multivariable analyses were performed using recursive partitioning and Cox proportional hazards regression. RESULTS: The most significant difference in prognosis was between patients with fewer than four and those with at least four positive nodes (P <.0001). Four distinct prognostic groups (5-year RFS, 97%, 78%, 58%, and 27%) were developed, defined by the number of positive nodes, tumor size, progesterone receptor (PR) status, differentiation, race, and marital status. Patients with fewer than four positive nodes and tumor < or = 2 cm, PR positive, and well or moderately differentiated had the best prognosis. RFS in this group was unaffected by type of adjuvant therapy (P =.38). Patients with at least four positive nodes and PR-negative tumors had the worst prognosis, and those treated with tamoxifen plus chemotherapy had the best outcome in this group (P =.0001). Among patients in the two intermediate-risk groups, those treated with tamoxifen or a combination of tamoxifen and chemotherapy had the best outcome. CONCLUSION: Lymph node status, PR status, tumor size, differentiation, race, and marital status are valuable for prognostication in breast cancer. The prognostic groups derived can provide guidance for clinical trial design, patient management, and future treatment policy.

Adult↗
PubMed2003

Factors affecting medical decision-making in patients with osteoarthritis of the hip: allocation of surgical priority.

PURPOSE: The purpose was to determine (1) how well doctors' assessments of patients matched the patients'own self assessments and (2) what doctors looked for in terms of patient factors (such as pain and dysfunction, radiographic evidence) that influenced their decisions to allocate priority for hip replacement. METHOD: Data collected independently from patients and surgeons after consultation were used to investigate medical decision-making. Patients were 74 consecutive patients who were offered total hip replacement in an orthopaedic outpatient department at a single hospital. Main measures were (1) assignment to priority group; (2) surgeons' ratings of patient pain, function, stoicism and predicted benefit; (3) patients' pain ratings, function (Arthritis Impact Measurement Scale) and timed walk, and predicted benefit; (4) hip radiographs were assessed independently using composite grading scores. RESULTS: Surgeon- and patient-rated current pain and function were reasonably correlated; predicted benefit from surgery in pain and function were not, although surgeons predicted greater benefit. High priority for surgery was associated with higher surgeon-rated patient pain and function, by higher pain ratings by patients, more severe radiographic abnormalities, by being female and over 70. Some patients with relatively low pain scores and low levels of dysfunction were offered hip replacements. CONCLUSIONS: Doctors made reasonable estimates of patients' pain and function by direct history taking and examination. There was no systematic underestimation of patients' pain, in contrast to previous studies. Doctors' estimate plus radiological changes account for most of the priority differences. Patients' and surgeons' expectation of improvement, relatively unrelated to severity of pain and dysfunction, in the absence of agreed minimal clinical criteria, may drive surgical demand. There was a wide range in measures of pain and function. Introduction of formal measurement of pain and function, and setting formal clinical criteria, could assist medical decision-making.

Age Factors↗
PubMed2002

Prostate specific antigen progression after radical prostatectomy in African-American men versus white men.

BACKGROUND: It is well established that African-American men (AAM) have a worse mortality from prostate carcinoma (PC) than White men (WM). Outcome data for men treated with radical prostatectomy for clinically localized PC demonstrate more advanced tumors and higher biochemical recurrence rates among AAM compared with WM. The objective of the current study was to characterize the pattern of prostate specific antigen (PSA) progression by race in patients experiencing disease recurrence after undergoing radical prostatectomy. Racial differences in the pattern of rising PSA would warrant different intervention strategies for reducing the disproportionality in survival outcomes between the two racial groups. METHODS: Between 1991-1996, 1080 consecutive men underwent radical prostatectomy for clinically localized PC at Wayne State University-affiliated Harper Hospital. Two hundred forty-one patients developed a biochemical recurrence on or before January, 1, 1999. The median follow-up was 39 months. Longitudinal PSA profiles of 77 men who met the study inclusion criteria were analyzed. Average relative velocities of PSA were compared between AAM and WM. Linear mixed effects regression was used to test the hypothesis that, after adjusting for age, preoperative PSA, stage and grade of disease, PSA levels increase at a faster rate in AAM compared with WM. RESULTS: The mean average relative velocity for AAM and WM experiencing a disease recurrence was 0.25 ng/mL and 0.11 ng/mL per month, respectively (P = 0.21). The relative rate of PSA increase in patients who developed a disease recurrence after radical prostatectomy was 18.9% per month for AAM and 16.3% per month for WM (P = 0.73). CONCLUSIONS: AAM and WM appear to have similar rates of PSA progression after undergoing radical prostatectomy.

Adult↗