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Biomedical subjects

M Jeffers

Publications and source records attributed to M Jeffers.

At least 19 recordsLinked to original sources
PubMed2006

Rapid assessment breast clinics--evolution through audit.

This observational, cohort study aimed to examine the potential utility of Rapid Assessment Breast Clinics (RABC) beyond cancer detection at presentation. One thousand four hundred and twenty nine women were studied over an 18 month period. 154 (10.7%) had breast cancer - 87.7% of whom were seen expediently with 92.9% being diagnosed at one attendance. One hundred and forty three (10%) of those with a benign diagnosis were found by routine questioning to have significant familial risk separate to their reason for referral. Despite careful triage, considerable contamination of appointment allotment occurred with many who were correctly triaged as non-urgent being seen 'urgently'. One hundred and seventy six attendees (12.3%) had neither the symptom that triggered referral, nor breast lump, nipple discharge nor family history of breast cancer, while 283 (19.8%) had no objective clinical or radiological abnormality. Although RABC reliably categorise malignant versus non-malignant diagnoses despite cluttering by low risk women, a significant proportion of non-cancer patients still require address of future risk rather than reassurance of their present status alone.

Adult↗
PubMed2004

Endometrioid carcinoma of the urinary bladder complicating vesical Mullerianosis: a case report and review of the literature.

Endometriosis of the urinary bladder is uncommon, and malignant transformation within vesical endometriosis is extremely rare. Vesical endometriosis and Mullerianosis can cause problems in differential diagnosis with vesical neoplasm, and, conversely, primary vesical neoplasm arising in endometriosis can be difficult to distinguish from secondary vesical involvement. Mullerianosis has rarely been described in the urinary bladder. A case of endometrioid adenocarcinoma of the urinary bladder is reported, which illustrates the difficulties in diagnosis and the importance of morphology and ancillary studies in establishing the correct diagnosis.

Carcinoma, Endometrioid↗
PubMed2004

Auditing a new lung cancer service.

The Adelaide and Meath Hospital (AMNCH) is a new hospital, with the respiratory service established in 1999. We report on our experience with lung cancer in this short time. We conducted a retrospective chart audit, identifying patients from the Oncology Nurse patient list, of lung cancer cases diagnosed in 2001-2002. In 2001, 47 cases were diagnosed, with 71 cases diagnosed in 2002. Time to tissue diagnosis was 14.8, 2-46 (mean, range, one subject skewing the data) days. Diagnosis by tissue type was as follows: non-small cell carcinoma (NSCLC) n=92 (77.9%), small cell lung carcinoma (SCLC) n=17 (14.4%), mesothelioma n=2 (17%), carcinoid n=1 (0.8%) and no tissue diagnosis n=6 (5.1%). Staging of NSCLC: stage 1a n=3 (3.2%), stage 1b n=6 (6.5%), stage 2a n=5 (5.4%), stage 2b n=2 (2.2%), stage 3a n=10 (10.9%), stage 3b n=22 (23.9%) and stage 4 n=44 (47.8%). Staging of SCLC: limited stage n=5 (29.4%), extensive stage n=12 (70.6%). Positive emission tomography (PET) was employed in the staging of 22 patients. In these patients PET up-staged the disease in 8 patients, and management was unchanged in 8 patients. We conclude that 1. the relatively new respiratory service in AMNCH is handling increasing numbers of lung cancer cases, 2. cases are diagnosed within an acceptable time-frame, 3. rate of tissue diagnosis is comparable to national figures, 4. most patients present with advanced disease and 5. PET is a useful imaging modality for detection of cancer spread in selected patients.

Adult↗
PubMed2003

Technical report. Intra-operative ultrasound-guided needle localization for impalpable testicular lesions.

AIMS: To describe a new technique of intra-operative ultrasound-guided needle localization of impalpable intratesticular lesions. MATERIALS AND METHODS: Three patients with impalpable testicular lesions identified on ultrasound underwent needle localization under ultrasound guidance. The procedure was performed in the operating theatre under general anaesthetic using a 7.5-8 MHz linear array probe and a portable ultrasound machine. Under direct guidance, a 21 G needle was placed through the centre of the lesion allowing resection and immediate frozen section analysis. RESULTS: In two patients malignancy was confirmed and an orchidectomy was performed. In one patient a benign lesion was detected obviating the need for orchidectomy. CONCLUSION: Patients presenting with impalpable testicular lesions can pose a diagnostic dilemma and orchidectomy is often performed. We describe an ultrasound-guided intra-operative localization technique enabling direct pathological examination so surgical approach can be re-evaluated in the presence of a benign lesion. This is particularly important in the case of a solitary testicle in order to preserve testicular function.

Adult↗
PubMed2003

Granulomatous appendicitis.

Granulomatous inflammation of the appendix is uncommon. It can be caused by a variety of conditions, including systemic disorders such as Crohn's disease and sarcoidosis, and infections such as mycobacterium tuberculosis, yersinia pseudotuberculosis, parasites and fungi. Granulomatous appendicitis as an isolated pathological entity unassociated with systemic disease is rare. Isolated granulomatous inflammation of the appendix of unknown aetiology, otherwise known as idiopathic granulomatous appendicitis is extremely rare. Patients with this condition present with the typical signs and symptoms of acute appendicitis. We present a series of patients with isolated granulomatous inflammation of the appendix, and discuss the difficulties encountered in the management of this condition.

Adolescent↗
PubMed2002

An immunohistochemical study of p21 and p53 expression in primary node-positive breast carcinoma.

AIMS: p21, an inhibitor of cyclin-dependent kinase, is involved in the p53 pathway of growth control. Its expression has been linked to cellular differentiation. It has been implicated in p53-mediated growth arrest following DNA damage and in terminally differentiated cells. This study analysed p21 and p53 expression, in a series of node-positive patients with breast carcinoma and examined histopathological parameters of the tumour and the prognostic implications of p21 and p53 expression. METHODS: One hundred and five consecutive patients with node-positive disease and at least 3 years follow-up were identified. Sections were stained for p53 and p21 using monoclonal antibodies. Results were expressed as percentage positive cells, and over 20% considered positive for p53 and over 10% considered for p21. RESULTS: p21 was overexpressed (>10% of cells positive) in 65% of patients and p53 was overexpressed (>20% of cells positive in 68%. The mean (SEM) level of p21 staining was 5.7(0.8)% and was 54.9(4.0)% for p53. There was no correlation between p21 and p53 expression (r=0.071 P=0.5). There were no significant differences in demographic criteria between patients that were p21 positive or negative and p53 positive or negative. There were no significant differences in tumour type, grade or stage between the groups. p21 expression did not have prognostic significance; however, p53 positivity was associated with a worse prognosis, which remained when controlled for stage. CONCLUSIONS: This study demonstrated p21 overexpression in 65% of patients with node-positive breast carcinoma. Levels did not correlate with p53 status and unlike p53 failed to have prognostic significance.

Adenocarcinoma↗
PubMed2001

Identification of a novel human fibroblast growth factor and characterization of its role in oncogenesis.

The fibroblast growth factor (FGF) family of signaling molecules has been implicated in normal developmental and physiological processes, as well as in human malignancy. Using a homology-based genomic DNA mining process, we identified a human gene encoding a novel member of the FGF family, that we designate FGF-20. The FGF-20 cDNA was isolated, and its sequence confirmed the gene prediction. FGF-20 is expressed in normal brain, particularly the cerebellum, and in some cancer cell lines. Recombinant FGF-20 protein induces DNA synthesis in a variety of cell types and is recognized by multiple FGF receptors. Ectopic expression of FGF-20 in NIH 3T3 cells renders the cells transformed in vitro and tumorigenic in nude mice. These results underscore the utility of mining genomic DNA databases and reveal FGF-20 to be a novel oncogene that may play a role in human cancer.

3T3 Cells↗
PubMed2001

Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways.

Hepatocyte growth factor (HGF) is a ligand of the receptor tyrosine kinase encoded by the c-Met protooncogene. HGF/Met signaling has multifunctional effects on various cell types. We sought to determine the role of HGF/Met in apoptosis and identify signal transducers involved in this process. In experiments with human SK-LMS-1 leiomyosarcoma cells, we show that the Akt kinase is activated by HGF in a time- and dose-dependent manner by phosphatidylinositol 3-kinase (PI3-kinase). Akt is also activated by active tumorigenic forms of Met, i.e., ligand-independent Tpr-Met, a truncated and constitutively dimerized form of Met, and a mutationally activated version of Met corresponding to that found in human hereditary papillary renal carcinoma. In NIH 3T3 cells transfected with wild-type Met, HGF inhibits apoptosis induced by serum starvation and UV irradiation. HGF-induced survival correlates with Akt activity and is inhibited by the specific PI3-kinase inhibitor LY294002, indicating that HGF inhibits cell death through the PI3-kinase/Akt signal transduction pathway. Furthermore, transiently transfected Tpr-Met activates Akt (both Akt1 and Akt2) and protects cells from apoptosis. Mitogen-activated protein kinase (MAPK) also is activated by HGF and rescues cells from apoptosis, although the cytoprotective effect is less marked than for PI3-kinase/Akt. Blocking MAPK with the specific MAPK kinase inhibitor PD098059 impairs the ability of HGF to promote cell survival. Similar results were obtained with NIH 3T3 cells expressing the fusion protein Trk-Met and stimulated with nerve growth factor, the Trk ligand. These results demonstrate that HGF/Met is capable of protecting cells from apoptosis by using both PI3-kinase/Akt and, to a lesser extent, MAPK pathways.

3T3 Cells↗
PubMed2001

PDGF-D, a new protease-activated growth factor.

Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer, fibrotic diseases and arteriosclerosis. The PDGF family currently consists of at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectively signal through two PDGF receptors (PDGFRs) to regulate diverse cellular functions. After two decades of searching, PDGF-A and B were the only ligands identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family, PDGF-C, a functional analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDGF-C selectively activate PDGFR-alpha, whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta. Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activation. Recombinant, purified PDGF-D induces DNA synthesis and growth in cells expressing PDGFRs. In cells expressing individual PDGFRs, PDGF-D binds to and activates PDGFR-beta but not PDGFR-alpha. However, in cells expressing both PDGFRs, PDGF-D activates both receptors. This indicates that PDGFR-alpha activation may result from PDGFR-alpha/beta heterodimerization.

3T3 Cells↗
PubMed2000

The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network.

The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), have been implicated in human tumor development and metastasis. HGF/SF induces the expression of urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), important mediators of cell invasion and metastasis. We have developed a cell-based assay to screen for inhibitors of this signaling system using the induction of endogenous uPA and uPAR and the subsequent conversion of plasminogen to plasmin as the biological end point. Assay validation was established using a neutralizing antiserum to HGF/SF and a uPA inhibitor (B428), as well as inhibitors of the MKK-MAPK1/2 pathway, shown previously to be important in the induction of uPA and uPAR. Using this assay, we found several classes of molecules that exhibited inhibition of HGF/SF-dependent plasmin activation. However, we discovered that certain members of the geldanamycin family of anisamycin antibiotics are potent inhibitors of HGF/SF-mediated plasmin activation, displaying inhibitory properties at femtomolar concentrations and nine orders of magnitude below their growth inhibitory concentrations. At nanomolar concentrations, the geldanamycins down-regulate Met protein expression, inhibit HGF/SF-mediated cell motility and invasion, and also revert the phenotype of both autocrine HGF/SF-Met transformed cells as well as those transformed by Met proteins with activating mutations. Thus, the geldanamycins may have important therapeutic potential for the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype.

3T3 Cells↗
PubMed2000

Efficacy of hydroquinone cream (USP 4%) used alone or in combination with salicylic acid peels in improving photodamage on the neck and upper chest.

BACKGROUND: Salicylic acid, hydroquinone, and glycolic acid have been proved effective in the treatment of photodamaged facial skin. Few reports are available on the treatment of photodamage on the neck and upper chest. OBJECTIVE: This study's purpose was to evaluate the efficacy of a cream containing 4% hydroquinone and 2% glycolic acid (LUSTRA) used alone or with salicylic acid peels in reversing actinic damage on the neck and upper chest. METHODS: Nineteen women with moderate to advanced photodamage on the neck and upper chest applied a cream containing 4% hydroquinone and 2% glycolic acid twice daily on photodamaged areas for 12 weeks. Nine of these subjects had salicylic acid peels every 3 weeks. Improvements were assessed by the investigator, the subjects, and Mexameter readings measuring melanin and erythema levels. RESULTS: The result shows that there was a 33-71% improvement in photodamage, hyperpigmentation, texture, fine lines, dryness, tone, and clarity in both groups. There were no significant differences between the two treatments. CONCLUSION: Hydroquinone 4% cream with 2% glycolic acid is safe and effective in improving photodamage on the neck and upper chest when used alone or in combination with salicylic acid peels.

Chemexfoliation↗
PubMed1999

Activation mechanisms of the urokinase-type plasminogen activator promoter by hepatocyte growth factor/scatter factor.

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector inducing invasion and metastasis of tumor cells that express the Met tyrosine kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen activator, a serine protease that facilitates tumor progression and metastasis by controlling the synthesis of the extracellular matrix degrading plasmin. Stimulation of NIH 3T3 cells that were stably transfected with the human Met receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and Sos1 expression construct. Further, the expression of the catalytically inactive mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells. Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins (A-Fos) abrogated inducible and basal activation of the urokinase promoter. Nuclear extract from unstimulated NIH 3T3-Methum cells contained more JunD and showed a stronger JunD supershift with the AP-1 oligonucleotides, compared with HGF/SF-stimulated cells. Consistent with the levels of JunD expression being functionally important for basal expression of the urokinase promoter, we found that overexpression of wild type JunD inhibited the induction of the urokinase promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent mitogen-activated protein kinase pathway.

3T3 Cells↗
PubMed1999

The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis.

BACKGROUND: Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-[2(dimethylamino)ethyl]carbamoyl)-6H-pyrido -(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype. METHODS: We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance. RESULTS: In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles. The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non-DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells. CONCLUSIONS: Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibitors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoisomerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes.

Antineoplastic Agents↗
PubMed1999

The unr gene: evolutionary considerations and nucleic acid-binding properties of its long isoform product.

The unr transcription unit is located just upstream of the N-ras gene in the genome of mammals, in which unr, like N-ras, is ubiquitously expressed. To determine at what point in evolution the unr/N-ras linkage was created, analysis of nucleic acids by Southern and Northern blotting was performed, allowing us to track the presence of the unr gene to the start of vertebrate evolution and the unr/N-ras linkage to the time at which the reptilian and bird lines diverged. We have investigated, with specific anti-unr antibodies, a potential relation between unr protein levels and cellular processes in which N-ras is implicated. A positive correlation in the proliferation of 3T3 cells, but not differentiation of PC12 cells induced by nerve growth factor (NGF), was found. To study the nucleic acid-binding properties of unr, a protein with multiple repeats of a nucleic acid-binding motif, we expressed the long splicing isoform in a eukaryotic cell line and purified it in native form. The results obtained-a high affinity of unr for single-stranded DNA and RNA and lower affinity for double-stranded DNA without regard to nucleic acid sequence, and its intracellular localization in both the nuclear and non-nuclear compartments, together with its ubiquious expression in mammalian tissues-provide molecular information about the function of one of the closest gene tandems in mammalian cells (unr-N-ras).

3T3 Cells↗
PubMed1999

The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells.

Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to the regulation of cell cycle cessation (G(0)) and to control of expression of various mRNAs such as for vascular endothelial growth factor. RCC cells express the Met receptor tyrosine kinase, and Met mediates invasion and branching morphogenesis in many cell types in response to hepatocyte growth factor/scatter factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive branching morphogenesis phenotype in response to HGF/SF in the three-dimensional (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not respond at all. We found that all VHL-negative RCC cells expressed reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt VHL-positive cells, implicating VHL in the regulation of this molecule. However, consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor gene is central to changes that control tissue invasiveness, and a more invasive phenotype requires additional genetic changes seen in some but not all RCC lines. These studies also demonstrate a synergy between the loss of VHL function and Met signaling.

Carcinoma, Renal Cell↗