Search PubMed⌕ Search

Biomedical subjects

J G Smith

Publications and source records attributed to J G Smith.

At least 37 records · Page 2Linked to original sources
PubMed2001

Stem cell factor: biology and relevance to clinical practice.

The type III tyrosine kinase receptor c-KIT and its ligand stem cell factor (SCF; also known as KIT ligand, mast cell growth factor and steel factor) are closely involved in the regulation of a wide range of tissues at different stages of life. This review provides an outline of the discovery, structure and expression of SCF and c-KIT but concentrates on their respective roles in the regulation of human haemopoiesis and how this knowledge might be exploited in the clinical setting.

Animals↗
PubMed2001

C-kit mutation screening in patients with acute myeloid leukaemia: adaptation of a Giemsa-stained bone-marrow smear DNA extraction technique.

The scarcity of viable tissue samples for leukaemia research is widely recognised and currently restrictive. Archival bone-marrow smears present a valuable resource that can be exploited easily for mutational analysis. Here, a modified technique to extract DNA is described, and used subsequently for mutation/polymorphism screening of the stem-cell factor receptor proto-oncogene c-kit in 23 patients with acute myeloid leukaemia (AML). The selected method was straightforward and used bone-marrow material scraped from periodic acid-Schiff, sudan black B and May-Grünwald/Giemsa-stained preparations, and treated initially with proteinase K prepared in digestion buffer to digest all proteinaceous matter. Following incubation, saturated sodium chloride was added and DNA extracted from the supernatant by phenol/chloroform/isoamyl alcohol treatment. Retrieved DNA was precipitated with ethanol at -20 degrees C overnight, washed with 95% ethanol, air-dried, resuspended using purite water and stored at -20 degrees C prior to use in mutational analysis. The extraction method described was compared with a commercial reagent for combined DNA, RNA and protein isolation using cryopreserved cells from 20 patients with AML. The quality of extracted DNA isolated by the two methods was comparable by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) techniques. Bone-marrow biopsies are performed regularly on each AML patient to monitor the disease; therefore, an extraction method using this resource could liberate a valuable source of DNA for study (e.g. molecular investigations, including mutation/polymorphism screening etc.). This would allow fresh and programme-frozen cells to be reserved for those investigations requiring intact, viable cells. The use of archived bone-marrow smears would permit vast increase in the scope for retrospective testing and large-scale analyses.

Acute Disease↗
PubMed2000

Infrared spectroscopic characterization of the interaction of cationic lipids with plasmid DNA.

Fourier transform infrared spectroscopy was used to characterize the interaction of the cationic lipids 1,2-dioleoyl-3-trimethylammonium-propane and dioctadecyldimethylammonium bromide with plasmid DNA. The effect of incorporating the neutral colipids cholesterol and dioleoylphosphatidylethanolamine on this interaction was also examined. Additionally, dynamic and phase analysis light scattering were used to monitor the size and zeta potential of the resulting complexes under conditions similar to the Fourier transform infrared measurements. Results suggest that upon interaction of cationic lipids with DNA, the DNA remains in the B form. Distinct changes in the frequency of several infrared bands arising from the DNA bases, however, suggest perturbation of their hydration upon interaction with cationic lipids. A direct interaction of the lipid ammonium headgroup with and dehydration of the DNA phosphate is observed when DNA is complexed with these lipids. Changes in the apolar regions of the lipid bilayer are minimal, whereas the interfacial regions of the membrane show changes in hydration or molecular packing. Incorporation of helper lipids into the cationic membranes results in increased conformational disorder of the apolar region and further dehydration of the interfacial region. Changes in the hydration of the DNA bases were also observed as the molar ratio of helper lipid in the membranes was increased.

Cholesterol↗
PubMed2000

Immunogenicity of a hexavalent combination vaccine in rhesus monkeys.

Preclinical immunogenicity studies were conducted in rhesus monkeys to determine whether there is immune interference in the response to one or more components of a hexavalent vaccine (Hexavac) that contains antigens from Haemophilus influenzae (Hib), hepatitis B (HB), diphtheria (D), tetanus (T), acellular pertussis (aP) and inactivated polio virus (IPV). Antibody responses were measured following co-administration of the components at three separate anatomical sites or administration as a hexavalent combination in a single site. After three injections of the hexavalent vaccine, the peak antibody responses to each component of the vaccine were >100-fold above pre-immune titers and persisted at levels >10-fold above pre-immune titers at approximately 1 year. Immune interference was observed in the peak response to HB, D and pertussis toxin, but was not seen at later time points. The results indicate that the rhesus monkey model may be useful for pre-clinical evaluation of combination vaccines.

Animals↗
PubMed2000

Study of charmless hadronic B meson decays to pseudoscalar-vector final states.

We report results of searches for charmless hadronic B meson decays to pseudoscalar( pi(+/-), K+/-, pi(0), or K(0)(S))-vector( rho, K(*), or omega) final states. By using 9.7x10(6) BB pairs collected with the CLEO detector, we report the first observation of B(-)--->pi(-)rho(0), B(0)-->pi(+/-)rho(-/+), and B(-)-->pi(-)omega, which are expected to be dominated by hadronic b-->u transitions. The measured branching fractions are (10.4(+3.3)(-3.4)+/-2.1)x10(-6), (27.6(+8.4)(-7.4)+/-4.2)x10(-6), and (11.3(+3.3)(-2.9)+/-1. 4)x10(-6), respectively. Branching fraction upper limits are set for all of the other decay modes investigated.

Journal Article↗
PubMed2000

Search for CP violation in B+/- --> J/psiK+/- and B+/- --> psi(2S)K+/- decays.

We present a search for direct CP violation in B+/--->J/psiK+/- and B+/--->psi(2S)K+/- decays. In a sample of 9.7x10(6) B&Bmacr; meson pairs collected with the CLEO detector, we have fully reconstructed 534 B+/--->J/psiK+/- and 120 B+/--->psi(2S)K+/- decays with very low background. We have measured the CP-violating charge asymmetry to be [+1.8+/-4.3(stat)+/-0.4(syst)]% for B+/--->J/psiK+/- and [+2.0+/-9. 1(stat)+/-1.0(syst)]% for B+/--->psi(2S)K+/-.

Journal Article↗
PubMed2000

A role for radiotherapy in neuropathic bone pain: preliminary response rates from a prospective trial (Trans-tasman radiation oncology group, TROG 96.05)

PURPOSE: Radiotherapy (RT) has a proven role in palliation of pain from bone metastases with numerous randomized trials obtaining response rates (RRs) of typically 70-80% regardless of the fractionation employed. However RT for neuropathic bone pain (NBP), i.e., pain with a radiating cutaneous component due to compression/irritation of nerves by tumor has not previously been studied, and its role is thus uncertain. METHODS AND MATERIALS: In February 1996, the Trans-Tasman Radiation Oncology Group (TROG) initiated a multicenter randomized trial comparing a single 8 Gy fraction with 20 Gy in 5 fractions for NBP with an accrual target of 270. Formal interim analyses were planned at 90 and 180 patients. The 90th patient was accrued in June 1998, and data from the first interim analysis with both arms combined form the basis of this report. RESULTS: Forty-four patients were randomized to a single 8 Gy, 46 to 20 Gy in 5 fractions. The commonest primary sites were prostate (34%), lung (28%) and breast (10%). Median age was 68 years (range 37-89). The index site was spine (86%), rib (13%), base of skull (1%). On an intention-to-treat basis, the overall RR was 53/90 = 59% (95% CI = 48-69%), with 27% achieving a complete response and 32% a partial response. The overall RR for eligible patients was 49/81 = 60% (95% CI = 49-71%) with 27% and 33% achieving complete and partial responses respectively. Estimated median time to treatment failure was 3.2 months (95% CI = 2.1-5.1 months), with estimated median survival of 5.1 months (95% CI = 4.2-7.2 months). To date, six spinal cord/cauda equina compressions and four new or progressive pathological fractures have been detected at the index site after randomization, although one cord compression occurred before radiotherapy was planned to commence. In February 1999, the Independent Data Monitoring Committee strongly recommended continuation of the trial. CONCLUSION: Although these results are preliminary, it seems clear that there is indeed a role for RT in the treatment of NBP. Analysis of outcome by treatment arm awaits completion of the randomized trial.

Adult↗
PubMed2000

Enhanced type I immune response to a hepatitis B DNA vaccine by formulation with calcium- or aluminum phosphate.

DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models. When compared with conventional vaccines, however, DNA vaccines often induce lower antibody titers. We have now found that formulation of a DNA vaccine encoding hepatitis B surface antigen with calcium- or aluminum phosphate adjuvants can increase antibody titers by 10-100-fold and decrease the immunogenic dose of DNA by 10-fold. Furthermore, boosting an HBs protein-primed response with the adjuvanted DNA vaccine resulted in a dramatic increase in the HBs-specific IgG2a response reflecting a shift towards a TH1 response. The mechanism by which aluminum phosphate exerts its adjuvant effect is not through increased expression of HBsAg in vivo; rather, the adjuvant appears to increase the number and affinity of HBs peptide antigen-specific IFN-gamma and IL-2 secreting T cells.

Adjuvants, Immunologic↗
PubMed2000

Radiation with concurrent late chemotherapy intensification ('chemoboost') for locally advanced head and neck cancer.

The aim of this study was to review our experience with a treatment regimen that combined conventionally fractionated radiation therapy (70 Gy over 7 weeks) with chemotherapy (cisplatin and fluorouracil), given concurrently in the last 2 weeks of radiation therapy in patients with previously untreated advanced squamous cell cancer of the head and neck region.Twenty-eight patients, all but two having UICC stage IV disease, were treated at the Peter MacCallum Cancer Institute between November 1995 and April 1998. Planned chemotherapy consisted initially of continuous infusion at 10 mg/m(2) per day of cisplatin and 400 mg/m(2) per day of fluorouracil on days 1-5 of weeks 6 and 7 of a conventionally fractionated course of radiotherapy. After the first 14 patients, the dose of fluorouracil was reduced to 360 mg/m(2) per day because of acute toxicity.36.8 months), with an estimated 50% surviving at 2 years (CI, 29-71%). Sixteen patients (57%) developed confluent mucositis and 11 (39%) developed patchy mucositis. The median duration of mucositis for these 27 patients was 1.5 months. Seventeen patients (61%) required nutritional support for a median duration of 1.4 months. Fourteen patients (50%) had grade three skin reactions, and 12 (43%) had one or more other significant (Grade 3) toxicities, predominantly infective. Grade 3 late toxicity has been observed in three patients to date (three xerostomia, including one with severe depression), and one patient had chronic ulceration of the oral tongue (grade 4). This chemoradiation regimen achieved an excellent complete response rate and good locoregional control at 2 years in patients with a poor initial prognosis. Acute toxicity was significant but manageable. The regimen offers an alternative to surgery and postoperative radiation therapy in locally advanced head and neck cancer.

Adult↗
PubMed2000

Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice.

The in vivo efficacy of the echinocandin antifungal caspofungin acetate (caspofungin; MK-0991) was evaluated in models of disseminated aspergillosis and candidiasis in mice with cyclophosphamide (CY)-induced immunosuppression. Caspofungin is a 1, 3-beta-D-glucan synthesis inhibitor efficacious against a number of clinically relevant fungi including Aspergillus and Candida species. Models of CY-induced transient or chronic leukopenia were used with once daily administration of therapy initiated 24 h after microbial challenge. Caspofungin was effective in treating disseminated aspergillosis in mice that were transiently leukopenic (significant prolongation of survival at doses of > or =0.125 mg/kg of body weight and a 50% protective dose [PD(50)] of 0.245 mg/kg/day at 28 days after challenge) or chronically leukopenic (50 to 100% survival at doses of > or =0.5 mg/kg and PD(50)s ranging from 0.173 to 0.400 mg/kg/day). Caspofungin was effective in the treatment and sterilization of Candida infections in mice with transient leukopenia with a 99% effective dose based on reduction in log(10) CFU of Candida albicans/gram of kidneys of 0.119 mg/kg and 80 to 100% of the caspofungin-treated mice having sterile kidneys at caspofungin doses from 0.25 to 2.0 mg/kg. In Candida-infected mice with chronic leukopenia, caspofungin was effective at all dose levels tested (0.25 to 1.0 mg/kg), with the log(10) CFU of C. albicans/gram of kidneys of caspofungin-treated mice being significantly lower (>99% reduction) than that of sham-treated mice from day 4 to day 28 after challenge. Also, 70 to 100% of the caspofungin-treated, chronic leukopenic mice had sterile kidneys at caspofungin doses of 0.5 to 1.0 mg/kg from day 8 to 28 after challenge. Sterilization of Candida infections by caspofungin in the absence of host leukocytes provides compelling in vivo evidence for fungicidal activity against C. albicans. Further human clinical trials with caspofungin against serious fungal infections are in progress.

Animals↗
PubMed1999

Nodal radiation therapy for metastatic melanoma.

PURPOSE: The aim of this retrospective study was to review our experience of radiation therapy to regional nodes in patients with proven nodal metastases, with respect to regional control, late toxicity, and overall survival. METHODS AND MATERIALS: All patients with a histological diagnosis of malignant melanoma, with involvement of the regional nodes but without distant metastases, who commenced nodal irradiation between January 1985 and July 1995 at Peter MacCallum Cancer Institute were studied. The study population of 113 patients was divided into two categories: those with no residual macroscopic disease following nodal surgery (adjuvant group, 42 patients) and those who had no surgery (8) or had macroscopic residual disease following nodal surgery (63) (palliative group, 71 patients). RESULTS: In the adjuvant group at 5 years following commencement of nodal irradiation 26% were estimated to be failure-free. Of the 74% who had experienced treatment failure by 5 years, an estimated 20% failed first with nodal relapse, 52% with distant metastases, and 2% with both nodal relapse and distant metastases. The estimated 5-year overall survival for this group was 33%. In the palliative group 16 patients (23%) had an objective complete response. Altogether 48 patients (68%) had a symptomatic response. At 5 years the overall survival in this group was 8% and an estimated 4% were failure-free. Of the 96% who had failed by 5 years, 68% failed first in the regional nodes, 25% had distant metastases as the first failure, and 3% had both nodal relapse and distant metastases. CONCLUSION: We recommend adjuvant postoperative radiation therapy for patients with proven nodal metastases and high risk of regional recurrence (multiple nodes, extracapsular extension, or recurrent nodal disease) in addition to adjuvant interferon.

Adult↗
PubMed1999

Randomized trials on radioactive iodine ablation of thyroid remnants for thyroid carcinoma--a critique.

PURPOSE: The dose of radioactive iodine ((131)I) required to ablate thyroid remnants following surgery for differentiated thyroid carcinoma is controversial. Typical administered activities range from less than 30 mCi up to 100 mCi, reflecting local practice and regulations governing allowable outpatient doses. This review examines the available randomized trials designed to assess the optimal ablative dose in this setting. METHODS AND MATERIALS: The authors identified three such trials published in 1987, 1991, and 1996, and critically reviewed them from a scientific and statistical point of view. RESULTS: Two of these studies were small and lacked adequate statistical power to answer the question, and the third was very poorly conducted. CONCLUSION: In our opinion, the appropriate dose of (131)I for ablation of thyroid remnants remains undetermined.

Combined Modality Therapy↗
PubMed1999

Results of external beam radiotherapy alone for incompletely resected carcinoma of rectosigmoid or rectum: Peter MacCallum Cancer Institute experience 1981-1990.

PURPOSE: To study the results of external beam radiotherapy treatment for incompletely resected nonmetastatic rectosigmoid and rectal carcinoma. METHODS AND MATERIALS: A retrospective review was carried out of all patients (57) presenting to Peter MacCallum Cancer Institute from 1981 to 1990 with incompletely resected nonmetastatic rectosigmoid or rectal cancer who were treated with external beam radiotherapy. Three radiotherapy schedules were used: radical (50 to 60 Gy, 27 patients), high-dose palliative (45 Gy, 25 patients), and low-dose palliative (less than 45 Gy, 5 patients). Symptomatic response, overall survival, and the effect of prognostic factors on treatment outcome were evaluated. The median follow-up period for survivors was 49 months. RESULTS: Symptomatic response rates were 83% and 79% for the radical and high-dose palliative groups respectively. The estimated median survival time from presentation for all patients was 16.4 months (radical 26.1 months, high-dose palliative 15.7 months). Patients with microscopic residual disease survived significantly longer than patients with macroscopic residual disease (estimated median survival time 30.7 months vs. 14.3 months, p = 0.013). CONCLUSIONS: No dose response effect was seen between the radical group and high-dose palliative group. Microscopic residual disease at presentation was the only significant predictor of better survival. The conventionally fractionated course of 50 to 60 Gy was not significantly better in terms of palliation and overall survival than a shorter palliative course of 45 Gy. In future, preoperative chemoradiation should improve outcome by reducing the number of patients with incompletely resected cancer.

Adult↗
PubMed1999

Kinetic characteristics of de novo and secondary AML cells influence their response to haemopoietic growth factor (HGF) priming and correlate with clinical outcome.

This study has assessed the effect of in vitro haemopoietic growth factor (HGF) priming on the S phase activity of cells from patients with de novo AML and AML secondary to MDS. The occurrence of receptors for G-CSF, GM-CSF, IL-3 and SCF on marrow cells was assessed using immunofluorescent ligand binding assays. Additionally, patients responses to first phase induction chemotherapy was recorded to examine whether in vitro kinetic data might correlate with clinical outcome. All kinetic and receptor assays were performed in normal marrow cells to ascertain their response to priming. Incubation of AML cells in serum free medium (SFM) +/- G + GM-CSF, IL-3, SCF, G + GM-CSF + SCF or IL-3 + SCF prior to S phase assessment revealed that priming permutations inclusive of SCF were most effective but also that the baseline level of S phase activity with SFM alone influenced the subsequent response to priming. Regardless of AML group, samples with low baseline S phase activity (< 10%) were significantly more responsive than those with high (> 10%) SFM S phase levels. However there was no corresponding difference in the percentages of cells bearing receptors. In both AML groups, low baseline S phase activity was observed more frequently in samples from patients who achieved CR. Normal samples possessed receptors for all HGFs and were responsive to all priming permutations except SCF alone. This study raises four points: (a) it may be prudent to reserve the use of priming HGFs for those patients with low baseline S phase activity whose cells respond in vitro and to use SCF in these priming cocktails; (b) the presence of receptors capable of ligand binding in AML samples did not guarantee kinetic response; (c) normal progenitors were responsive to priming which may have implications for haemopoietic reconstitution post therapy; and (d) the kinetic characteristics of AML progenitors may influence clinical outcome regardless of whether treatment includes HGFs.

Acute Disease↗
PubMed1999

Monocyte dysfunction in patients with multiple myeloma and lymphoplasmacytic disorders is related to serum paraprotein levels.

We have investigated monocyte function in 30 patients with lymphoplasmacytic disorders and in 21 age and sex matched normal controls. Marked abnormalities of all facets of monocyte function were demonstrated in six patients with multiple myeloma (MM) and a single patient with Waldenström's macroglobulinaemia (WM) plus significant paraproteinaemia. Serious infection occurred in three of these patients. An inverse relationship between the level of the serum paraprotein and impairment of monocyte phagocytosis plus killing of Candida albicans was observed. Crossover studies suggested that these abnormal findings were constitutive and not reversed by removal of the serum paraprotein. The data suggest that monocyte function is constitutively abnormal in patients with MM and can be further, but reversibly, inhibited by high paraprotein levels. Further research is required to confirm these findings, ascertain whether monocyte function can be normalized using chemotherapy or growth factors, and if so, whether their tumouricidal functions could be harnessed in the treatment of this currently incurable condition.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Excision of the conjugative transposon Tn916 in Lactococcus lactis.

In Lactococcus lactis excision of Tn916 is limited by the concentration of integrase and is increased by providing more excisionase. However, even with increased excision of Tn916 in L. lactis, no conjugative transfer is detectable. This suggests that L. lactis is deficient in a host factor(s) required for conjugative transposition.

Conjugation, Genetic↗