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Biomedical subjects

D Reese

Publications and source records attributed to D Reese.

At least 19 recordsLinked to original sources

Modulation of omega-3/omega-6 polyunsaturated ratios with dietary fish oils in men with prostate cancer.

OBJECTIVES: The results of epidemiologic and animal studies support the role of a low-fat diet supplemented with omega-3 fatty acids contained in fish oil in preventing the development and progression of prostate cancer. As a first step in studying the role of a low-fat, fish oil-supplemented (LF/FOS) diet in a clinical setting, we conducted a prospective study in men with untreated prostate cancer to evaluate whether a 3-month dietary intervention affects the ratio of omega-3 to omega-6 fatty acids in plasma and gluteal fat. In addition, we evaluated the feasibility of studying cyclooxygenase-2 (COX-2) expression in serial prostate needle biopsy specimens before and after the diet. METHODS: Nine men with untreated prostate cancer consumed an LF/FOS diet for 3 months. Plasma, gluteal adipose tissue, and prostate needle biopsy specimens were obtained from each patient before and after the intervention. The fatty acid compositions of the plasma and gluteal adipose tissue were determined by gas-liquid chromatography, and the COX-2 expression in the prostatic tissue specimens was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Short-term intervention with an LF/FOS diet caused a significant increase in the omega-3/omega-6 fatty acid ratio in plasma (P = 0.002) and gluteal adipose tissue (P = 0.002) in men with prostate cancer. The COX-2 expression in prostatic tissue was quantitated by RT-PCR in 7 of 9 patients, and COX-2 expression decreased in 4 of these 7 patients. CONCLUSIONS: A short-term dietary intervention in men with prostate cancer leads to a significant increase in the omega-3/omega-6 fatty acid ratios in plasma and adipose tissue. The potential for this diet to prevent the development and progression of prostate cancer by way of altered COX-2 expression and prostaglandin production in prostatic tissue requires further study.

Adenocarcinoma↗

An ounce of prevention.

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Adverse Drug Reaction Reporting Systems↗

A multi-institutional phase ii study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer.

In a multi-institutional Phase II trial, we evaluated the efficacy of a platelet-derived growth factor receptor (PDGF-r) inhibitor, SU101, in patients with hormonerefractory prostate cancer. The patients received a 4-day i.v. loading dose of SU101 at 400 mg/m(2) for 4 consecutive days, followed by 10 weekly infusions at 400 mg/m(2). The primary study end points were a decline in prostate-specific antigen (PSA) and a decrease in measurable tumor. Secondary end points were time to progression and an effect on pain as measured by the Brief Pain Survey. Expression of PDGF-r was examined in both metastatic and archival primary prostate tumor samples. Forty-four patients were enrolled at four centers. The median age was 72 years, the median PSA was 223 ng/ml, and 21 patients had at least one prior chemotherapy. Thirty-nine patients are evaluable for PSA, and three patients demonstrated a PSA decline >50% from baseline (55-99.9% decrease). The median time to progression was 90 days. Of 19 patients evaluable for measurable disease, 1 patient had a partial response. Nine of 35 evaluable patients had significant improvement in pain. The most frequent adverse events were asthenia (75%), nausea (55%), anorexia (50%), and anemia (41%). PDGF-r expression was detected in 80% of the metastases and 88% of primary prostate cancers. The results of this trial may warrant further clinical studies with other PDGF-r inhibitors.

Aged↗

Insulin-inducible changes in the relative ratio of PTP1B splice variants.

The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. This was tested in 21 nondiabetic Pima Indians, a population at increased risk for obesity and type 2 diabetes. The relative ratio of the PTP1B splice variants was quantified using RT-PCR of total RNA extracted from fractionated monocytes. The ratio of the splice variants was positively correlated with fasting plasma insulin concentration (r = 0.757; P = 0.0001), 2-h plasma insulin concentration following an oral glucose tolerance test (r = 0.614; P = 0.01, n = 16), and percentage of body fat (r = 0.746; P = 0.0001). These data indicate that variability in the ratio of the two splice variants is due, in part, to in vivo levels of chronic hyperinsulinemia. This simple, noninvasive assay is therefore a potential biomarker for chronic hyperinsulinemia, similar to the HbAlc assay in use to monitor glucose management in diabetic patients.

Adult↗

Neurite growth patterns leading to functional synapses in an identified embryonic neuron.

We explored the relationship between neurite outgrowth and the onset of synaptic activity in the central neuropil of the leech embryo in vivo. To follow changes in early morphology and the onset of synaptic activity in the same identified neuron, we obtained whole-cell patch-clamp recordings and fluorescent dye fills from dorsal pressure-sensitive (P) cells, the first neurons that could be reliably identified in the early embryo. We followed the development of the P cell from the first extension of neurites to the elaboration of an adult-like arbor. After the growth of primary neurites, we observed a profuse outgrowth of transient neurites within the neuropil. Retraction of the transient neurites left the primary branches studded with spurs. After a dormant period, stable secondary branches grew apparently from the spurs and became tipped with terminals. At this time, neurites of the Retzius (R) cell, a known presynaptic partner in the adult, were observed to apparently contact the terminals. Although voltage-dependent currents were seen in the P cell at the earliest stage, spontaneous synaptic activity was only observed when terminals had formed. Spontaneous release was observed before evoked release could be detected from the R cell. Our results suggest that transient neurites are formed during an exploratory phase of development, whereas the more precisely timed outgrowth of stable neurites from the spurs signals functional differentiation during synaptogenesis. Because spurs have also been observed in neurons of the mammalian brain, they may constitute a primordial synaptic organizer.

Animals↗

In vitro and in vivo hematopoietic activities of Betafectin PGG-glucan.

Betafectin PGG-glucan is a novel beta-(1,3)glucan that has broad-spectrum anti-infective activities without cytokine induction. Here we report that PGG-glucan also has both in vitro and in vivo hematopoietic activities. In vitro studies with bone marrow target cells from the C3H/HeN mouse revealed that although PGG-glucan alone had no direct effect on hematopoietic colony-forming cell (CFC) growth, when combined with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, it increased CFC numbers 1.5- to 2.0-fold over those obtained with CSFs alone. Bone marrow cells cultured for high-proliferative-potential CFCs in the presence of interleukin (IL)-1, IL-3, macrophage CSF, and stem cell factor (SCF), or cultured for erythroid burst-forming units in the presence of IL-3, SCF, and erythropoietin, also exhibited enhanced growth in the presence of PGG-glucan. The synergistic effect of PGG-glucan was specific and could be abrogated by anti-PGG-glucan antibody. The ability of PGG-glucan to modulate hematopoiesis in vivo was evaluated in myelosuppressed rodents and primates. C3H/HeN female mice were intravenously administered saline solution or PGG-glucan (0.5 mg/kg) 24 hours before the intraperitoneal administration of cyclophosphamide (200 mg/kg), and the recovery of bone marrow cellularity and granulocyte-macrophage progenitor cells was evaluated on days 4 and 8 after cyclophosphamide treatment. At both time points, enhanced hematopoietic recovery was observed in PGG-glucan-treated mice compared with saline-treated control mice. In a final series of in vivo experiments, we evaluated the ability of therapeutically administered PGG-glucan to enhance hematopoietic recovery in cyclophosphamide-treated cynomolgus monkeys. Monkeys received intravenous infusions of cyclophosphamide (55 mg/kg) on days 1 and 2, followed on days 3 and 10 by intravenous infusion of PGG-glucan (0.5, 1.0, or 2.0 mg/kg). Compared with those in saline-treated monkeys, accelerated white blood cell recovery and a reduction in the median duration of neutropenia were observed in PGG-glucan-treated monkeys. These studies illustrate that PGG-glucan has both in vitro and in vivo hematopoietic activities and that this agent may be useful in the prevention and/or treatment of chemotherapy-associated myelosuppression.

Animals↗

Medication mishaps.

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Adverse Drug Reaction Reporting Systems↗

Expression of the c-kit proto-oncogene and its ligand stem cell factor (SCF) in normal and malignant human testicular tissue.

Recent findings suggest an important role of the proto-oncogene c-kit, a surface membrane receptor of the tyrosine kinase family, and its ligand stem cell factor (SCF) in normal spermatogenesis and possibly in the pathogenesis of certain testicular germ cell tumors. To further investigate this potential role, the expression of c-kit and SCF was studied in normal and malignant human testicular tissue specimens at the mRNA and protein level by Northern blot analysis and immunohistochemistry, respectively. The detection of the c-kit receptor in normal human germ cells and its natural ligand SCF in Sertoli cells suggests the presence of a local trophic regulatory system that may be active in human spermatogenesis. Additionally, c-kit expression was detected in the seminoma but not in the nonseminoma subtype of human testicular germ cell tumors (GCT). Stem cell factor was not expressed at the mRNA level in tissue from either subtype of GCT as determined by Northern blot analysis; however, the protein was detected immunohistochemically in the cytoplasm of rare tumor cells.

Cell Adhesion Molecules↗

Insulin-inducible changes in insulin receptor mRNA splice variants.

Alternative splicing of insulin receptor pre-mRNA has been shown to be regulated in a tissue-specific and developmental manner. We investigated whether the receptor ligand might regulate the relative distribution of alternatively spliced mRNA in insulin-sensitive cells and found that changes in the relative expression of the two alternatively spliced insulin receptor RNA isotypes expressed in hepatocytes are regulated by insulin. In addition, we observed significant differences (p < or = 0.001) in insulin receptor isotype expression in subjects who were hyperinsulinemic and insulin-resistant versus subjects who were insulin-sensitive. These results support a role for insulin in the regulation of the relative expression of alternatively spliced mRNA expressed in insulin-responsive cells and tissues.

Alternative Splicing↗