Search PubMed⌕ Search

Biomedical subjects

L Williams

Publications and source records attributed to L Williams.

At least 145 records · Page 8Linked to original sources
PubMed1995

Ligand mediated activation of ectopic EGF receptor promotes matrix protein adhesion and lung colonization of rat mammary adenocarcinoma cells.

Increased expression of EGF receptor (EGFR) in metastases of human mammary carcinoma as compared to cells of the primary cancer suggests a contribution of EGFR to mammary carcinoma metastasis. To test for a positive causative link, we investigated 13762NF rat mammary adenocarcinoma cloned tumor cell lines of high (MTLn3) or low (MTC) metastatic potential. While MTC cells expressed barely detectable amounts of EGFR, MTLn3 cells expressed readily detectable levels of functional receptors. A full length cDNA of the human EGFR (HER) was introduced by infection with a retroviral vector into MTC cells. Expression of HER was stable and receptors were functional with respect to surface expression, ligand binding and EGF-stimulated phosphorylation. Independent clones of the transfectants were isolated and characterized. Ligand stimulation of MTC HER cells and derived clones led to enhanced adhesion of cells to extracellular matrix proteins. Implantation of cells intravenously into female nu/nu mice revealed ligand-dependent enhancement of lung colonizing potential of EGFR-expressing cells.

Adenocarcinoma↗
PubMed1995

A phase I study of anti-GD3 ganglioside monoclonal antibody R24 and recombinant human macrophage-colony stimulating factor in patients with metastatic melanoma.

BACKGROUND: Macrophages activated by macrophage-colony stimulating factor (M-CSF) are potent immune effector cells and can mediate both in vitro cytotoxicity and antitumor effects in vivo. A Phase I trial combining M-CSF with R24, a mouse monoclonal antibody against GD3 ganglioside that has been shown to localize to melanoma tumors, induce inflammation at tumor sites, and result in major tumor responses in some patients with melanoma was performed. METHODS: Nineteen patients with metastatic melanoma received a 14-day continuous intravenous infusion of 80 micrograms/kg/day of recombinant human M-CSF. R24 was administered daily by intravenous infusion on days 6-10 at doses of 1, 3, 10, 30, and 50 micrograms/m2/day. RESULTS: All patients developed pruritus and urticaria; 13 patients developed transient thrombocytopenia less than 100,000/mm3. The maximum tolerated dose was not reached. All patients developed a monocytosis characterized by increased expression of the antigen HLA-DR and decreased expression of CD14, a phenotype reported to represent a subpopulation of monocytes active in mediating antibody-directed cellular cytotoxicity. Other biologic effects of treatment included marked but transient decreases in total cholesterol, low density lipoprotein, and high density lipoprotein. Three patients experienced tumor regression in breast, liver, and lymph node metastases and received a second course of therapy. Six of the 19 patients, one of whom received no further therapy, survived more than 2 years and 4 of these patients remain alive 24 to 37 months after treatment. Of the six patients with liver metastases, three (50%) survived more than 2.5 years and one remains alive at 37+ months. CONCLUSIONS: Combination therapy with R24 and M-CSF resulted in both clinical and biologic effects that warrant further investigation of this combination.

Adult↗
PubMed1995

The lack of effect of aerobic exercise training on propranolol pharmacokinetics in young and elderly adults.

The effects of exercise training on the pharmacokinetics of orally administered propranolol were studied in young and elderly healthy volunteers. Twenty-three young (30 +/- 5 years of age) and 20 elderly (67 +/- 5 years of age) adults were randomly assigned to endurance training (N = 12 young subjects, 10 elderly subjects) or nonexercising control (N = 11 young subjects, 10 elderly subjects) groups. Training consisted of treadmill walking, stair climbing, or both three times per week for 40 minutes at 70-85% of maximal heart rate reserve for 16 weeks. Resting plasma propranolol concentrations after a single dose of 80 mg of oral propranolol were measured by high performance liquid chromatography with fluorescence detection, and estimated hepatic blood flow measured was measured using indocyanine green during supine test. Aerobic training increased maximal oxygen uptake (VO2 max) by 13% and 14% in the exercising young and elderly groups, respectively. There was no change in VO2 max in either control group. Adjusted mean estimated hepatic blood flow after exercise corrected for body weight for the young subjects who did not exercise (15.6 mL/min/Kg) and those who did (18.2 mL/min/Kg) groups were of borderline significance. No statistical differences were detected in the experimental propranolol pharmacokinetic parameters (maximal concentration, time of maximal concentration, terminal half-life, area under the curve, and protein binding) or derived pharmacokinetic parameters (intrinsic clearance, bioavailability, clearance, and volume of distribution). These results provide evidence that changes in aerobic fitness do not produce corresponding changes in propranolol pharmacokinetics in young or elderly adults.

Administration, Oral↗
PubMed1995

Neoadjuvant chemotherapy with vincristine and cisplatin followed by radical hysterectomy and pelvic lymphadenectomy for FIGO stage IB bulky cervical cancer: a Gynecologic Oncology Group pilot study.

Thirty-five patients with bulky (designated as > or = 4 cm size) International Federation of Gynaecology and Obstetrics (FIGO) Stage IB cervical cancer were treated with cisplatin, 50 mg/m2, and vincristine, 1 mg/m2, administered intravenously at 10-day intervals for a total of three courses before planned radical hysterectomy. One patient died of unrelated cause following one course of chemotherapy and was not evaluated for response. Of the 34 evaluable patients who completed chemotherapy, a complete clinical response was noted in two patients (6%) and a partial response in 26 patients (76%). Five patients (15%) had stable disease and one patient (3%) had disease progression. All chemotherapy was completed within 4 weeks (range 17-28 days). There was no grade 4 toxicity noted. Only one case each of reversible grade 3 granulocytopenia and stomatitis and two cases of reversible grade 3 peripheral neuropathy were noted. Of the 34 patients who received chemotherapy, the only patient with disease progression received standard pelvic radiation therapy in lieu of radical surgery. A second patient with stable disease had unresectable pelvic lymph node metastases and underwent confirmatory lymph node biopsy only and received standard radiation therapy postoperatively. The remaining 32 patients underwent radical hysterectomy and pelvic lymphadenectomy from 12 to 49 days following chemotherapy. Surgery was performed without significant difficulty. Eight of these patients (25%) had pelvic node metastases and received postoperative pelvic radiation therapy. Twenty-four months following initiation of treatment, 25 (74%) were alive and presumed free of disease, 4 had died of cancer (12%), 1 was alive with recurrence (3%), and 4 patients (12%) were lost to follow-up. A prospective randomized study is needed to assess the value of this approach compared with standard management.

Adenocarcinoma↗
PubMed1995

Increased phosphotyrosine in breast cancer tissue is associated with a worse prognosis.

We have previously demonstrated that phosphotyrosine can be identified in breast cancer cells using an immunohistochemical stain. We have subsequently used this technique to characterize 106 women with breast cancer (46 with Stage 1 and 60 with Stage 2) who have been followed for at least four years by one oncologist. We analyzed all primary breast cancer tissue using immunohistochemical staining and the amount of phosphotyrosine (PT) was scored on a 0 to 3 range. The PT score of the primary tumor was unrelated to either breast cancer stage or estrogen and progesterone receptor analysis, as high PT scores were noted in both disease stages and all receptor categories. We did find that patients with either no or trace (1+) amounts of PT survived longer than those patients with higher amounts of PT. The patients with low PT had significantly lower chance of relapse (Chi Square = 15.8, p < 0.001) and a lower mortality (Chi Square = 13.1, p = 0.001). We conclude that immunohistochemical methods to determine the PT score may identify patients at higher risk for disease relapse independent of tumor stage or hormonal status.

Breast Neoplasms↗
PubMed1995

A phase II trial of merbarone (NSC 336628) as salvage therapy for squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.

Twenty-seven patients with previously irradiated unresectable recurrent squamous carcinoma of the cervix who had failed one prior cytotoxic regimen received 1,000 mg/m2 per day of merbarone given by continuous i.v. infusion for 5 days every 4 weeks through a central line. One patient was never treated, and four were inevaluable for response, leaving 26 patients evaluable for toxicity and 22 evaluable for response. The major adverse effect was myelosuppression with 6/26 (23%) experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 leukopenia. There were two episodes (3.8%) of GOG grade 3 SGOT elevation. There were two patients (9.0%) who developed mental status changes classified as grade 3 neurotoxicity. This neurotoxicity may have been secondary to iatrogenic hyponatremia caused by the large volumes of 5% glucose infusion required at the original infusate concentration. After the concentration of the merbarone infusate was increased to 4 mg/ml, no further problems with hyponatremic neurotoxicity were encountered. The overall response rate was 2/22 (9.0%) (95% confidence interval 1.1-29.2%). In this pretreated population with recurrent squamous cervical carcinoma, merbarone exhibited only minimal activity.

Adult↗
PubMed1995

Structuring managed care joint ventures.

Providers that undertake joint ventures to secure managed care contracts must understand the important governance, operational, legal, and political issues involved. Careful planning in all these areas can help ensure that the joint venture will meet its goals and avoid problems such as inappropriately negotiated contracts and legal violations.

Financial Management↗
PubMed1995

Immunoglobulin germline mu transcripts in acute myelogenous leukemia cells vary in splicing pattern and are heterogeneous.

Germline transcription of the immunoglobulin (Ig) locus is felt to play an important role in B cell differentiation. Similar transcripts are also found in neoplastic myeloid cells, but are of unknown significance. We have mapped these RNAs using reverse transcriptase polymerase chain reaction amplification. Unlike B cell transcripts, the majority of myeloid mu transcripts do not contain amplifiable enhancer sequence or complete 5' sequence. The extent of this deletion is related to the degree of myeloid maturation, with transcripts in the most primitive myeloid cells more closely resembling those in B cells. Variable 3'-splicing patterns are also observed in myeloid cells, unlike the single pattern identified in early B cells. Using primers which span the region from the 3' end of C mu 4 to the 5' end of the second membrane exon (M2), the splice sites between C mu 4 and M1, and between M1 and M2 have been analyzed. Our data suggest that factors important in initiation of germline mu transcription are present in both B lymphoid and myeloid cells, but that lineage-specific modifying factors alter this expression during myeloid maturation. Thus, the finding of Ig transcripts and other evidence of B lymphoid differentiation in acute myelogenous leukemia most likely reflects a retained common hematopoietic gene program.

B-Lymphocytes↗
PubMed1994

Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung.

Mouse lung development begins when two lung buds sprout from the epithelium of the embryonic gut. Patterning of the airways is then accomplished by the outgrowth and repetitive branching of the two lung buds, a process called branching morphogenesis. One of the four fibroblast growth factor (FGF) receptor genes, FGFR2, is expressed in the epithelium of a number of embryonic organs including the lung buds. To block the function of FGFR2 during branching morphogenesis of the lung without affecting its function in other embryonic tissues, the human surfactant protein C promoter was used to target expression of a dominant negative FGFR2 exclusively to lung bud epithelium in transgenic mice. Newborn mice expressing the transgene were completely normal except that instead of normally developed lungs they had two undifferentiated epithelial tubes that extended from the bifurcation of the trachea down to the diaphragm, a defect that resulted in perinatal death. Thus, the dominant negative FGF receptor completely blocked airway branching and epithelial differentiation, without prohibiting outgrowth, establishing a specific role for FGFs in branching morphogenesis of the mammalian lung.

Animals↗
PubMed1994

Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma.

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.

Adult↗
PubMed1994

HIV infection of placental macrophages: their potential role in vertical transmission.

Placental macrophages were isolated and cultured in vitro to investigate their susceptibility to HIV infection and possible role in vertical transmission of HIV. After 10 days of in vitro culture the cells were positive for nonspecific esterase and acid phosphatase and negative for myeloperoxidase and placental alkaline phosphatase. They expressed cell surface HLA-ABC, HLA-DR, CD45, as well as CD68 intracellularly, as detected by flow cytometry, confirming their macrophage lineage. Approximately 80% of cells expressed surface CD14. CD4 antigen was expressed at very low levels and was confirmed by antibody blocking experiments. Infection of placental macrophage cultures with HIV resulted in a transient peak of viral replication 3 to 7 days after infection, but no later rise in HIV was detected with culture of up to 60 days. HIV replication was not up-regulated by coculture with phytohemagglutinin-stimulated lymphocytes or by treating infected cultures with tumor necrosis factor alpha or granulocyte-macrophage colony-stimulating factor.

Acid Phosphatase↗
PubMed1994

Effects of magnesium deficiency on strength, mass, and composition of rat femur.

Magnesium (Mg) participates in the normal formation and remodeling of bone. However, little is known about effects of Mg status on the biomechanical function of bone. We examined gross morphometry and composition as well as biomechanical properties of the femurs of male rats fed diets adequate or deficient in Mg. Comparison of deficient animals and controls yielded a number of differences (all significant at P < 0.05). Mg-depleted animals exhibited slow growth, inefficient food utilization, and greatly reduced concentrations of Mg in both serum and femur ash. Compared with controls, femurs from depleted animals were shorter, but wet weights, diameters, and midfemoral cross-sectional areas showed no differences. Bone length was reduced to a greater degree than could be accounted for by differences in body weights between the groups. Bones of Mg-deficient rats contained less dry matter and less ash (which contained more Ca/g) than those of controls, along with a higher percentage of moisture. Significantly reduced bone strength in depleted animals was evident from the lighter loads supported at the elastic limit (yield point) and at fracture and from decreased stresses accompanying those loads. Modulus of elasticity, however, was not affected by Mg depletion. Different yield and breaking loads were related to different body weights of groups, but stresses were reduced for deficient bones even after adjusting for body size. Our data establish abnormal biomechanical behavior of cortical bone in Mg-deficient animals and emphasize the importance of measuring such functional properties of bone in the assessment of responses to altered metabolic conditions under experimental conditions.

Animals↗
PubMed1994

Emergency vaccination against foot-and-mouth disease: rate of development of immunity and its implications for the carrier state.

Emergency foot-and-mouth disease (FMD) vaccines prepared from antigens held in the International Vaccine Bank at Pirbright were administered to cattle and pigs and the levels of protection were assessed following challenge by contact with infected pigs. Both Al(OH)3/saponin and oil-based cattle vaccines proved to be extremely effective and protected soon after vaccination (4 days postvaccination), whereas the pigs were seldom protected before 21 and 28 days postvaccination, probably due to lower levels of antibody and overwhelming challenge conditions. Early production of cattle occurred in the absence of significant levels of circulating antibody as measured by enzyme-linked immunosorbent assay, a neutralization assay and a passive protection test. A large number of the cattle vaccinated with the O1 Lausanne strain of FMD and subsequently challenged with this virus became persistently infected and there appeared to be a correlation with the time interval between vaccination and challenge. When the same cattle were vaccinated approximately 4 months later with a different strain of FMD, C1 Oberbayern, and challenged with this strain, the number of persistently infected animals was considerably lower. The results are discussed in the context of the use of emergency vaccines to prevent the dissemination of FMD from disease foci.

Animals↗
PubMed1994

Handedness and hand injuries.

Data are reported from a study of 1,003 patients attending with hand injuries at an Accident and Emergency Department. Among both left- and right-handers, injuries to the right hand were more common than to the left hand, except for accidents to right-handers at work. For this group there were more injuries to the left hand. Male and female patients differ in the frequency with which they present for medical attention but show similar types of injury.

Accidents↗
PubMed1994

Comparative mortality risks of chronic dialysis and cadaveric transplantation in black end-stage renal disease patients.

In view of the relatively low mortality risk on dialysis and the high risk of allograft loss among black compared with white end-stage renal disease (ESRD) patients, we studied the relative mortality risks of all black renal transplant candidates in Michigan from 1984 to 1989. There were 770 black ESRD patients followed from wait-listing for cadaveric (CAD) kidney transplantation until the time of transplantation, death, or December 31, 1989. The time on dialysis prior to wait-listing exceeded 1 year in 24% of these patients. Black diabetic patients on the waiting list have more than twofold relative mortality risk (RR) compared with nondiabetic individuals (RR = 2.73, P < 0.001) while the RR by diabetes status among CAD transplant recipients was small. Overall, CAD transplantation was associated with elevated risk of mortality in the first month posttransplantation (RR = 3.39, P < 0.03). Cadaveric donor transplant and wait-listed dialysis patients have equal death rates 112 days after transplantation. Thereafter, death rates were lower for transplant recipients compared with transplant candidates on dialysis. One year after transplantation, CAD transplant recipients on the average have approximately half the risk of death compared with dialysis patients who remain on the waiting list (RR = 0.49, P < 0.03). The cumulative survival probabilities are superior in transplant recipients just beyond 1 year after transplantation. Therefore, CAD transplantation in black ESRD patients is associated with a high risk of mortality in the early period after transplantation. Beyond 1 year, black transplant recipients have a substantial survival advantage over corresponding dialysis patients on the waiting list.

Adolescent↗