Biomedical subjects

Sarah Moore

Publications and source records attributed to Sarah Moore.

11 recordsLinked to original sources

PubMed2026

Mapping articular cartilage maturation across postnatal development by proteomics.

OBJECTIVE: Articular cartilage has a specialised extracellular matrix that provides tensile strength and resistance to compression, but repair capacity is limited. Matrix remodelling during growth is essential for long-term tissue function, yet the underlying protein-level adaptations remain poorly characterised in large-animal models relevant to human joint biology. DESIGN: Using non-targeted, label-free mass spectrometry-based proteomics, we profiled full-thickness articular cartilage from goats across seven postnatal ages from neonatal to adult (n = 3 per age). Cartilage proteins were extracted using guanidine-based solubilisation and analysed by mass spectrometry. Selected proteins were further examined by immunohistochemistry. RESULTS: We identified 799 proteins across the seven ages, of which 157 matrisome components grouped into six categories. Development was associated with increased abundance of proteins involved in matrix organisation and stabilisation, including COL6A1, LOX, TIMP3 and CILP. Enrichment analysis revealed a shift from collagen biosynthesis and fibrillogenesis in early postnatal cartilage to elastic fibre organisation, integrin-matrix interactions and glycosaminoglycan metabolism in mature tissue, consistent with transition from matrix assembly to maintenance. Lysozyme increased with age, suggesting a structural role that warrants further study. Several proteins enriched in mature cartilage, including CILP, HTRA1, FN1 and SPP1, have also been implicated in osteoarthritis, suggesting that some molecular features of mature ECM maintenance are shared with diseased tissue. Immunohistochemistry confirmed stable COL2 localisation, loss of deep-zone COL10 staining with maturation and emergence of superficial PRG4 expression in adult cartilage. CONCLUSIONS: Our findings define the proteomic trajectory of cartilage maturation and provide a molecular reference for joint development and matrix ageing.

Animals↗

PubMed2006

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

CCAAT enhancer-binding protein (CEBP) transcription factors play pivotal roles in proliferation and differentiation, including suppression of myeloid leukemogenesis. Mutations of CEBPA are found in a subset of acute myeloid leukemia (AML) and in some cases of familial AML. Here, using cytogenetics, fluorescence in situ hybridization (FISH), and molecular cloning, we show that 5 CEBP gene family members are targeted by recurrent IGH chromosomal translocations in BCP-ALL. Ten patients with t(8;14)(q11;q32) involved CEBPD on chromosome 8, and 9 patients with t(14;19)(q32;q13) involved CEBPA, while a further patient involved CEBPG, located 71 kb telomeric of CEBPA in chromosome band 19q13; 4 patients with inv(14)(q11q32)/t(14;14)(q11;q32) involved CEBPE and 3 patients with t(14;20)(q32;q13) involved CEBPB. In 16 patients the translocation breakpoints were cloned using long-distance inverse-polymerase chain reaction (LDI-PCR). With the exception of CEBPD breakpoints, which were scattered within a 43-kb region centromeric of CEBPD, translocation breakpoints were clustered immediately 5' or 3' of the involved CEBP gene. Except in 1 patient with t(14;14)(q11;q32), the involved CEBP genes retained germ-line sequences. Quantitative reverse transcription (RT)-PCR showed overexpression of the translocated CEBP gene. Our findings implicate the CEBP gene family as novel oncogenes in BCP-ALL, and suggest opposing functions of CEBP dysregulation in myeloid and lymphoid leukemogenesis.

Burkitt Lymphoma↗

PubMed2006

Consolidation with high-dose combination alkylating agents with bone marrow transplantation significantly improves disease-free survival in hormone-insensitive metastatic breast cancer in complete remission compared with intensive standard-dose chemotherapy alone.

We conducted this study to determine event-free and overall survival among women with hormone-insensitive or hormone-resistant metastatic breast cancer receiving consolidation with high-dose chemotherapy (HDC) and hematopoietic support versus no further chemotherapy after intensive induction chemotherapy. Eligible patients received induction doxorubicin, 5-fluorouracil, and methotrexate (AFM) for 2 to 4 cycles. Women in complete remission were randomized to immediate HDC with cyclophosphamide, cisplatin, and carmustine followed by autologous hematopoietic support or to no further therapy. Patients on the observation arm of therapy were offered salvage HDC at the time of relapse. Partial responders to AFM were offered immediate HDC. A total of 425 patients were enrolled onto the study. The median event-free survival for women randomized to induction therapy alone was 3.8 months, compared with 9.7 months for women who completed HDC (P < .006). Of the patients randomized to observation, 5 (10%) of 51 remain event free, compared with 13 (26%) of 49 patients who underwent immediate HDC (P = .03). Of women converted to a complete response by salvage HDC after a partial response to AFM, overall survival was similar to that in women randomized to immediate HDC. Follow-up is now in excess of 5 years. The 5-year event-free survival is 15% (95% confidence interval, 12%-18%), and the 5-year overall survival is 20% (95% confidence interval, 17%-25%). Immediate HDC after a complete response to AFM produced some durable long-term responses in hormone-insensitive/-resistant metastatic breast cancer. Salvage HDC converted 30% of partial responders to complete responders with similar survivals. The addition of novel targeted therapies to intensive-dose chemotherapy regimens may further improve survival in metastatic breast cancer.

Adult↗

PubMed2005

Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA.

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

AIDS Vaccines↗

PubMed2005

TEL-AML1 frequency in multi-ethnic Malaysian pediatric acute lymphoblastic leukemia.

Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.

Bone Marrow↗

PubMed2004

Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA.

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.

Africa, Southern↗

PubMed2004

Repeated downsizing contact: the effects of similar and dissimilar layoff experiences on work and well-being outcomes.

In this longitudinal study, the authors compared 1,244 white- and blue-collar workers who reported 0, 1, or 2 contacts with layoffs; all were employees of a large manufacturing company that had engaged in several mass waves of downsizing. Consistent with a stress-vulnerability model, workers with a greater number of exposures to both direct and indirect downsizing reported significantly lower levels of job security and higher levels of role ambiguity, intent to quit, depression, and health problems. Findings did not support the idea that workers became more resilient as they encountered more layoff events. The authors found only partial evidence that the similarity or dissimilarity of the type of repeated downsizing exposure played a role in how workers reported changes in these outcome variables.

Adult↗

PubMed2004

Heterogeneous t(4;11) fusion transcripts in two infants with acute lymphoblastic leukemia.

An RT-PCR assay detected the t(4;11) translocation in two infants with acute lymphoblastic leukemia (ALL). Case P76 was a 10-month-old, female infant, who presented with a WBC of 137.4 x 10(9)/l and a pre-pre-B ALL immunophenotype. Case P120 was a 6-month-old female infant, with a WBC > 615 x 10(9)/l and a pre-pre-B ALL immunophenotype. RT-PCR of cDNA from both these cases generated a 656 bp and a 542 bp respectively, which sequencing confirmed as t(4;11) fusion transcripts. The primers and conditions selected for this assay are compatible with a one-step multiplex PCR for the main translocations in childhood ALL.

Base Sequence↗

PubMed2003

Acute lymphoblastic leukemia characterized by t(8;14)(q11.2;q32).

The t(8;14)(q11.2;q32) is emerging as an uncommon, though recurrent cytogenetic finding. As of yet, too few cases of acute lymphoblastic leukemia (ALL) characterized by this translocation have been studied to determine its prognostic significance with confidence. We therefore report three new patients (two male children and one adult female) and present their hematologic, immunophenotypic, and clinical data. The clinical and laboratory characteristics of 26 other patients with t(8;14)(q11.2;q32) are summarized. The total number of patients now reported in the literature is 29 with a mean age of 14 years. Early relapse, that is, relapse within 6 months, does not appear to be a common feature of this group. The gender distribution is 19 males: 9 females (gender not reported in one case). Twenty-three t(8;14) patients show a pre-B immunophenotype and 24 of 24, on whom information is available, achieved complete remission after induction chemotherapy for B-ALL. Approximately one third of patients with t(8;14) have Down syndrome, 19 of 27 have additional acquired cytogenetic abnormalities, 5 of these have the t(9;22), and 4 show duplication of the abnormal chromosome 14, which is derived from the t(8;14). Hemoglobin and platelet counts are low at presentation in 10 of 10 and 8 of 9 patients, respectively, and the average white blood count is 38.9 x 10(9)/L. Of the 7 patients for whom IgH status has been determined, all show rearrangement of the IgH locus. Two of the present three patients are included in this group; their IgH rearrangement was demonstrated by fluorescence in situ hybridization with IgH break-apart probes.

Adolescent↗

PubMed2003

A longitudinal exploration of alcohol use and problems comparing managerial and nonmanagerial men and women.

The purpose of the present study was to compare the job attitude and drinking context correlates of alcohol beliefs, consumption, and problems between managerial and nonmanagerial women and men. Using longitudinal, self-report data from 1244 workers in a large manufacturing organization, we found that managerial women reported significantly higher levels of alcohol problems on a number of measures on both Times 1 and 2 surveys. Using partial correlations and controlling for Time 1 levels of the alcohol-related dependent variables, we found that few work attitudes predicted the outcomes of escape drinking reasons, alcohol consumption, and alcohol problems. However, those correlations that were significant reflected a differential pattern for managerial women as compared to managerial men and nonmanagerial women and men. Due to the small subsample size of managerial women, we regard these findings as suggestive only. We discuss the findings in terms of the stress-reduction hypothesis of alcohol consumption.

Alcohol Drinking↗

PubMed2002

Isolated cardiac recurrence of acute lymphoblastic leukemia characterized by t(11;19) two years after unrelated allogeneic bone marrow transplantation.

A 33-year-old male presented with acute lymphoblastic leukemia (ALL) characterized by translocation (11;19)(q23;p13.3). He received an allogeneic bone marrow transplant from a matched unrelated donor. Two years later his disease relapsed with an isolated intracardiac mass, presenting as right heart failure. He had no evidence of concomitant relapse in the bone marrow. Tumor cytogenetics revealed clonal evolution with the karyotype 46,XY,t(3;16)(q23;p13),t(11;19)(q23;p13.3), the chromosome 16 breakpoint involving the band where the genes for multidrug resistance-associated protein and CREB binding protein are known to reside. To our knowledge, this is the first report of an isolated extramedullary relapse of ALL in the heart.

Adult↗