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Biomedical subjects

R M Rossi

Publications and source records attributed to R M Rossi.

18 recordsLinked to original sources
PubMed2000

Thyroid cancer.

The management of patients with thyroid cancer can be optimized by developing multidisciplinary groups of highly specialized individuals. The completeness of surgery and its morbidity are mostly surgeon-dependent. Similarly, the decisions regarding selection of adjuvant treatments, doses, follow-up schemes, and so forth require depth of knowledge and understanding of the disease; its variables; factors that govern its course; and the values, limitations, and side effects of alternative therapies.

Female↗
PubMed2000

Evidence that the protein tyrosine phosphatase (PC12,Br7,Sl) gamma (-) isoform modulates chondrogenic patterning and growth.

One of the earliest events in bone morphogenesis is the condensation of embryonic mesenchymal cells into chondroblasts and their subsequent proliferation and differentiation into chondrocytes. During this time, certain signaling cascades operate to establish proper patterning and differentiation of the cartilaginous skeleton. Characterization of the signaling pathways involved in these processes remains to be accomplished. We have identified a novel murine cytosolic tyrosine phosphatase termed PTPPBS gamma (+/-) which is a member of the PTP PC12,Br7,Sl (PTPPBS) family. Spatio-temporal expression analysis of the members of this tyrosine phosphatase family demonstrates significant expression of the gamma (-) splice variant in the cartilaginous skeleton. Using an embryonic mandibular explant culture system to serve as a model for cartilage formation, we examined the potential roles of the PTPPBS gamma phosphatase by loss-of-function studies achieved with antisense oligodeoxynucleotides. These studies demonstrated that loss of expression of the PTPPBS gamma (-) isoform resulted in abnormal patterning of Meckel's cartilage and an increase in the size of the chondrogenic regions. In gamma antisense-treated explants, bromodeoxyuridine-pulse labeling studies revealed increased proliferation of chondroblasts bordering along precartilaginous condensations and bordering populations of maturing chondrocytes. These studies provide evidence that in early skeletal development, PTPPBS gamma may regulate the rate of chondroblast proliferation in the cartilaginous skeleton.

Alternative Splicing↗
PubMed1999

Rodent mutant models of obesity and their correlations to human obesity.

Obesity is a heath problem affecting a significant fraction of adult Americans and is on the rise globally. It is of importance to find treatments that achieve medically significant weight loss and successful long-term maintenance of a desired weight. Recent transgenic mouse studies and genetic characterization of spontaneous rodent obesity mutants, together with gene linkage analysis in humans, have led to an increased understanding of the physiologic and molecular mechanisms underlying obesity. However, much remains to be studied in this complex field of research. In this review, we discuss the physiology and genetics underlying obesity and how studies in rodents and humans are converging, producing a greater understanding of the mechanisms underlying this health problem.

Adult↗
PubMed1999

Noninsulin-dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor.

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit phenotypic characteristics associated with noninsulin-dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese-diabetes phenotype was similar to that observed in the agouti and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemically expressed the gas6-binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF-alpha production indirectly resulting in the NIDDM phenotype.

Animals↗
PubMed1997

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Adolescent↗
PubMed1996

Microsporidian sinusitis in patients with the acquired immunodeficiency syndrome.

Sinusitis in patients with human immunodeficiency virus (HIV) infection usually arises from the same organisms that are infective in the nonimmunosuppressed population. The authors of this article report that optimal antimicrobial treatment and functional endoscopic sinus surgery failed to eradicate sinonasal disease in three of five patients with acquired immunodeficiency syndrome (AIDS) and refractory sinusitis. The sinonasal disease was manifested by congested, edematous, and polypoid mucosa, often with a superimposed bacterial infection from ostial obstruction. After tissue was sent for electron microscopy (EM), the patients were eventually diagnosed with microsporidiosis of the sinonasal cavities. Microsporidia are obligate intracellular protozoans that have been seen in AIDS patients with diarrhea. These protozoans have only recently been identified in sinonasal tissue. Microsporidia are often missed on routine histopathology. The authors present case reports on their five AIDS patients with refractory sinusitis. The management of refractory sinusitis in the HIV-infected population, including mandatory EM of sinonasal tissue, is also discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE: We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS: Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS: Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION: Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

Adult↗
PubMed1994

Estimation of ifosfamide/cisplatinum-induced renal toxicity by urinary protein analysis.

Ifosfamide (IFO) chemotherapy has been reported to result in deToni-Debré-Fanconi syndrome in a minority of patients only, but evaluation of tubular transport capacities has identified a substantial number of patients as having subclinical tubular dysfunction. After completion of combination chemotherapy employing IFO (n = 37) or IFO plus cisplatinum (CPL) (n = 27), glomerular and tubular function was assessed in 64 patients by the urinary excretion of transferrin, IgG, albumin, alpha 1-microglobulin (A1M) and N-acetyl-beta-D-glucosaminidase. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was performed in 21 patients. The determination of urinary marker proteins was compared with the glomerular filtration rate, the fractional phosphate and percent amino acid reabsorption. A reduced glomerular filtration rate was observed in 9.8% of patients. Tubular dysfunction was frequent, with a predominance of renal amino acid (57%) and A1M (48%) loss. IFO-mediated renal toxicity was dose dependent. CPL treatment resulted in significant enhancement of tubular toxicity induced by IFO, whereas concomitant gentamicin therapy did not affect tubular function. Measurement of urinary protein cannot replace other tests for tubular dysfunction in IFO-treated patients, because the spectrum of IFO-induced nephrotoxicity includes dysfunction of different and independent transport mechanisms of the proximal tubular system. Increased urinary A1M excretion is an important indicator of impaired tubular protein reabsorption.

Adolescent↗
PubMed1990

Lineage directed HL-60 cell sublines as a model system for the study of early events in lineage determination of myeloid cells.

Current experimental models are poorly suited to study the early biochemical and molecular events of the lineage determination process in myeloid progenitor cells. Viable lineage-committed precursors cannot be identified until after they have expressed their mature phenotype and these precursors cannot be grown to large number while lineage is committed but still immature. Recently, we have identified stable sublines of the HL-60 human leukemia cell line which differ from each other in that they selectively differentiate to either neutrophils (UR-1-4), monocyte/macrophages (MRI), eosinophils (clones 2 and 15), or mixtures of two (clones 7 and 8) or of all three lineages (UR-1-2) when stimulated to mature with butyric acid under identical conditions. Characterization of these sublines provided evidence that the expression of lineage in HL-60 cells is a multistep process and that the lineage tendencies (lineage direction) the clones exhibited when cultured with butyric acid represent a step in that process earlier than irreversible lineage commitment but later than the multipotential wild type HL-60 cells. First, treatment of these sublines with compounds that induce differentiation of HL-60 cells to specific lineages (dimethylsulfoxide, neutrophil; 1,25-(OH)2 vitamin D3, monocyte), generally induced differentiation to the lineage associated with that inducer rather than the butyrate-associated lineage. Second, culture of neutrophil or monocyte-directed sublines in medium of elevated pH for two months leads to the development of eosinophils. Culturing the sublines first in butyric acid for variable lengths of time and switching to either DMSO or VD3 indicated that irreversible lineage commitment develops on a time course similar to the development of the commitment to mature. Markers of monocytic and eosinophilic differentiation could not be simultaneously demonstrated in single mature cells, consistent with the phenomenon of lineage fidelity. In addition, several assays were validated that could reliably classify mature HL-60 cells to their lineage. The collection of these sublines appears to constitute a model system with well-defined behavior with respect to the early events of lineage determination that can be grown to quantities sufficient for biochemical and molecular analysis. Exploring the differences between these clones may provide a new way to examine the early events of the lineage development process in myeloid cells.

Butyrates↗
PubMed1990

Characterization of sublines of HL-60 human leukemia cells resistant to induction of differentiation by butyric acid.

HL-60 human leukemia cells undergo terminal differentiation when cultured with butyric acid. To produce cells resistant to the maturation-inducing effects of butyric acid, two strategies were followed. First, HL-60 cells were mutagenized and cultured in soft agar with inducing concentrations of butyric acid. Four clones were isolated resistant to a wide variety of differentiation inducers, including butyric acid. Second, HL-60 cells were cultured in gradually increasing concentrations of butyric acid until a normal growth rate was achieved in medium containing greater than 1 mM butyric acid. These cells retained their ability to be induced to mature to neutrophils with dimethylsulfoxide, retinoic acid, and actinomycin D; and to monocyte/macrophage like cells with tetradecanoylphorbol acetate and 1,25-(OH)2 vitamin D3. However, they no longer underwent terminal differentiation when butyric acid was added in increasing concentration, even when cytotoxic concentrations were used. The mutagenized clones cells appeared permanently butyrate resistant, but the selected clones reverted to the wild-type state when grown in the absence of butyric acid. The selected cells continued to express myeloperoxidase; the mutagenized lines did not. Thus, by using two different protocols, HL-60 cells resistant to the cytotoxic and maturation-inducing effects of butyric acid can be produced that have varied phenotypic characteristics.

Butyrates↗
PubMed1990

Chemotactic capabilities of HL-60 human myeloid leukemia cells differentiated to eosinophils.

HL-60 human myeloid leukemia cells can be induced to differentiate into cells with many of the morphological, biochemical, and functional features of mature neutrophils, monocyte/macrophages, and eosinophils. HL-60 neutrophils are known to respond to several chemotactic compounds, but similar data do not exist for HL-60 eosinophils. We studied the chemotactic capabilities of eosinophil-differentiated HL-60 cells using a blind-well chamber technique. HL-60 eosinophils responded to the specific eosinophilotactic tetrapeptides Ala-Gly-Ser-Glu, Val-Gly-Asp-Glu, and Val-Gly-Ser-Glu; to the formylated tripeptide N-formyl-L-Met-L-Leu-L-Phe (fMLP); and to extracts estrogen-treated rat uteri, which contain an eosinophilotactin. Concentration optima for chemotaxis of HL-60 eosinophils were similar to those for normal human and rodent eosinophils. Neutrophil-differentiated HL-60 cells responded only to fMLP, whereas undifferentiated HL-60s showed no chemotactic ability. The time course of development of chemotactic competence paralleled other developmental changes in HL-60 eosinophilic differentiation, suggesting a common control mechanism. We conclude that the ability to respond to specific eosinophilotactic compounds is a feature of HL-60 cells that have differentiated to eosinophils and that this cell line may be used as a model system in studies of eosinophil chemotaxis.

Cell Differentiation↗
PubMed1989

Factors responsible for variable reported lineages of HL-60 cells induced to mature with butyric acid.

HL-60 is a multipotential human leukemia cell line widely used as an in vitro model to investigate myeloid differentiation. A variety of compounds can reproducibly induce these cells to differentiate towards specific lineages. However, under what appear to be similar experimental conditions, various laboratories have reported either neutrophilic differentiation or monocytic differentiation after butyric acid induction. We investigated different hypotheses to explain these dissimilar findings. First, the potential role of variable 1,25-dihydroxyvitamin D3 (VD3) concentrations in commercial fetal calf serum was assessed. Second, possible differences between laboratories inherent to the HL-60 cells themselves were explored. Lineage was assessed by morphology, histochemistry (nonspecific esterase), and neutrophil-specific (CD15) and monocyte-specific (MO2) surface antigens. We found that increasing concentrations of VD3 spanning the range reported in commercial fetal calf serum (25 to 155 pg/ml) act in synergy with butyric acid to result in higher monocyte/neutrophil ratios at the higher VD3 concentrations. Different lots of serum led to monocyte/neutrophil ratios in proportion to their VD3 concentrations. Starting with HL-60 cells obtained from different laboratories, several single-cell clones were derived which yielded either high percentages of monocytes, high percentages of neutrophils, or intermediate mixes of both cell types after induction with butyric acid. We conclude that the wide variation of VD3 concentration found in different lots of commercial fetal calf serum and intrinsic differences in HL-60 cells are two identifiable factors that can explain the discrepancies in lineage observed by different investigators after butyric acid induction of HL-60 cells.

Antigens, Differentiation↗
PubMed1987

Induction of differentiation of the human leukemia cell line, KU812.

We treated KU812 cells from different passage levels with compounds which induce differentiation of other leukemic cell lines. Early passages contained small subpopulations of basophil and erythrocyte-like cells, but later passages consisted of more uniform cells with a myelomonocytic phenotype. When cultured with 1 nM actinomycin D, the cells became nonproliferative, developed pale cytoplasm and segmented nuclei, and lost nonspecific esterase activity. Thus, KU812 cells can be induced to mature to cells with a myelomonocytic phenotype. However, their expression of previously reported basophil characteristics diminishes with continued passage, and may be a capability of only a subpopulation of the cells.

Cell Differentiation↗
PubMed1986

Suppression of humoral and cell-mediated immune responses in vitro by benzo(a)pyrene.

The effect of benzo(a)pyrene (BaP) at different molar (M) concentrations on the in vitro anti-sheep red blood cell (SRBC) plaque (antibody) forming cell (PFC) response and the one-way mixed lymphocyte response (MLR) was tested. Inhibition of the PFC response and the MLR occurred when spleen cells were exposed to a wide range of BaP concentrations from 10(-4) M to 10(-8) M. Maximum depression of the responses occurred at 10(-5) M for PFC production (47% of controls) and for the MLR (19% of controls) as measured by a stimulation index. No significant loss in cell viability was observed at this or lower molar concentrations of BaP. The non-carcinogenic analog of BaP, benzo(e)pyrene, did not suppress PFC responses at comparable concentrations. This in vitro system will facilitate manipulations of T and B lymphocytes and macrophages (adherent cells) in a controlled culture environment for precisely characterizing the sensitivity of these cells and their subpopulations on exposure to BaP.

Animals↗
PubMed1982

Neutron scattering studies and modeling of high mobility group 14 core nucleosome complex.

Considerable evidence relates the nonhistone proteins high mobility group (HMG) 14 and HMG 17 with the structure of active or potentially active chromatin. In this study, bulk nucleosome core particles prepared from chicken erythrocytes and the complex formed by binding two HMG 14 molecules per nucleosome core were studied by use of small-angle neutron scattering techniques. By varying the H2O/2H2O ratio, and hence the contrast between the solvent and the particles, it was possible to determine the radius of gyration of the protein and of the DNA independently and as a function of HMG 14 binding. The results show an increase of 0.9 +/- 0.6 A (mean +/- SEM) in the protein radius of gyration and of 2.7 +/- 0.6 A in the DNA radius of gyration upon binding of HMG 14 to the nucleosome. These changes are considered in the light of several postulated modes for the unfolding or perturbation of the nucleosome structure. Modeling calculations demonstrate that the observed changes in radius of gyration for the DNA and for the protein are too small to be consistent with an overall unfolding or opening of the core particle upon HMG 14 binding. However, the observed changes are consistent with several models that involve only minor changes in the structure. It is postulated that the differences observed may be an indication of the type of conformational change occurring in active nucleosomes.

Animals↗