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Biomedical subjects

C Ford

Publications and source records attributed to C Ford.

At least 55 records · Page 3Linked to original sources
PubMed1997

A phase II study of repetitive cycles of dose-intense carboplatin plus paclitaxel chemotherapy and peripheral blood stem cells in metastatic breast cancer.

To assess the feasibility of administering sequential cycles of dose-intensive therapy, 14 patients without prior chemotherapy for metastatic breast cancer were registered to be treated with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) at an initial dose of 250 mg/m2 over 24 hours (day 1), followed by carboplatin dosed to an area under the concentration-time curve of 16 (calculated according to the Calvert formula), every 3 weeks for four cycles. This combination was supported with peripheral blood stem cells collected following granulocyte colony-stimulating factor with or without cyclophosphamide and paclitaxel. One patient failed to peripheralize CD34 cells after cyclophosphamide/paclitaxel therapy and was taken off protocol. The remaining 13 patients entered the paclitaxel/carboplatin phase of the program, and nine completed all four cycles. The median duration of severe neutropenia (absolute neutrophil count < 100/microL) was 6 days, despite the absence of routine use of granulocyte colony-stimulating factor. Only five of a total of 42 chemotherapy cycles (12%) were associated with febrile neutropenia requiring hospitalization. Most patients did not require platelet transfusions. The most significant nonhematologic toxicity was gastrointestinal (grade 3 in three patients, two of whom had received local radiation for relapse before chemotherapy). Most patients developed grade 1 or 2 sensory neuropathy by the final cycle. Of the nine patients who entered the paclitaxel/carboplatin phase and were evaluable for response, five achieved a complete remission. This doublet of high-dose therapy can be given in an entirely ambulatory setting and is associated with modest hematologic toxicity. The value of this option in the treatment of metastatic breast cancer compared with more conventional approaches to high-dose therapy will require a greater number of patients evaluable for response and longer follow-up.

Adult↗
PubMed1996

Influence of macrophage depletion on bacterial translocation and rejection in small bowel transplantation.

Rejection and sepsis can be intimately related following small bowel transplantation when rejection compromises normal intestinal barrier mechanisms and bacterial translocation results. Macrophages play a role in controlling the egress of intestinal luminal bacteria--and they have also been implicated in allograft rejection. In this study, the role of macrophages in rejection and bacterial translocation was evaluated by depleting macrophages in donors and/or recipients of rat small bowel allografts with injection of liposome-encapsulated dichloromethylene diphosphonate (CL2MDP). In preliminary studies, we demonstrated that a single intraperitoneal injection of liposome-encapsulated CL2MDP (350 mg/kg) depleted ED2-positive macrophages by > 90% in the liver mesenteric lymph nodes and proximal and distal small bowel, and by approximately 50% in the spleen. ED1-positive macrophages were depleted by > 90% in the liver and by approximately 50% at the other sites. ED3-positive macrophages were completely depleted. Dendritic cells were > 90% depleted in the spleen and mesenteric lymph nodes, but were not depleted in the small bowel. Macrophage depletion in the donor resulted in increased translocation of bacteria to the peritoneal cavity (P = 0.03) if recipient macrophages were present. With histopathologic analysis, a significantly milder rejection with less arteritis was seen in the allografts of the recipient macrophage-depleted group compared with nondepleted controls (P = 0.045). This suggests that recipient macrophages play an important role in rejection. With macrophage depletion in both the donor and the recipient, graft survival was prolonged significantly (13.2 +/- 1.9 days) compared with non-macrophage-depleted controls (9.2 +/- 1.3 days) (P = 0.003). These studies suggest that strategies targeting recipient macrophages may be useful in controlling small bowel allograft rejection without increasing bacterial translocation.

Animals↗
PubMed1996

Effect of replacing helical glycine residues with alanines on reversible and irreversible stability and production of Aspergillus awamori glucoamylase.

To decrease irreversible thermoinactivation of Aspergillus awamori glucoamylase, five Gly residues causing helix flexibility were replaced with Ala residues. Mutation of Gly57 did not affect thermostability. Mutation of Gly137 doubled it at pHs 3.5 and 4.5 but barely changed it at pH 5.5. The Gly139-->Ala mutation did not change thermostability at pH 3.5, improved it at pH 4.5 and worsened it at pH 5.5. The Gly 137/Gly139-->Ala/Ala mutation gave 1.5-2-fold increased thermostabilities at pHs 3.5-5.5. Mutations of Gly251 and Gly383 decreased it at all pHs. Gly137-->Ala and Gly137/Gly139-->Ala/Ala glucoamylases are the most stable yet produced by mutation. Guanidine treatment at pH 4.5 decreased the reversible stabilities of Gly137-->Ala, Gly139-->Ala and Gly137/Gly139-->Ala/Ala glucoamylases at infinite dilution while not changing those of Gly251-->Ala and Gly383-->Ala glucoamylases, which is, in general, opposite to what occurred with thermoinactivation. Mutation of Gly57 greatly improved the extracellular glucoamylase production by yeast, that of Gly137 barely affected it and those of Gly139 and of both Gly137 and Gly139 strongly impeded it. These observations suggest that alpha-helix rigidity can affect reversible and irreversible glucoamylase stability differently, that the effects of multiple mutations within one alpha-helix to improve stability are not always additive and that even single mutations can strongly affect extracellular enzyme production.

Alanine↗
PubMed1996

Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes.

Genetic and biochemical studies have provided convincing evidence that the 5' noncoding region (5' NCR) of hepatitis C virus (HCV) is highly conserved among viral isolates worldwide and that translation of HCV is directed by an internal ribosome entry site (IRES) located within the 5' NCR. We have investigated inhibition of HCV gene expression using antisense oligonucleotides complementary to the 5' NCR, translation initiation codon, and core protein coding sequences. Oligonucleotides were evaluated for activity after treatment of a human hepatocyte cell line expressing the HCV 5' NCR, core protein coding sequences, and the majority of the envelope gene (E1). More than 50 oligonucleotides were evaluated for inhibition of HCV RNA and protein expression. Two oligonucleotides, ISIS 6095, targeted to a stem-loop structure within the 5' NCR known to be important for IRES function, and ISIS 6547, targeted to sequences spanning the AUG used for initiation of HCV polyprotein translation, were found to be the most effective at inhibiting HCV gene expression. ISIS 6095 and 6547 caused concentration-dependent reductions in HCV RNA and protein levels, with 50% inhibitory concentrations of 0.1 to 0.2 microM. Reduction of RNA levels, and subsequently protein levels, by these phosphorothioate oligonucleotides was consistent with RNase H cleavage of RNA at the site of oligonucleotide hybridization. Chemically modified HCV antisense phosphodiester oligonucleotides were designed and evaluated for inhibition of core protein expression to identify oligonucleotides and HCV target sequences that do not require RNase H activity to inhibit expression. A uniformly modified 2'-methoxyethoxy phosphodiester antisense oligonucleotide complementary to the initiator AUG reduced HCV core protein levels as effectively as phosphorothioate oligonucleotide ISIS 6095 but without reducing HCV RNA levels. Results of our studies show that HCV gene expression is reduced by antisense oligonucleotides and demonstrate that it is feasible to design antisense oligonucleotide inhibitors of translation that do not require RNase H activation. The data demonstrate that chemically modified antisense oligonucleotides can be used as tools to identify important regulatory sequences and/or structures important for efficient translation of HCV.

Base Sequence↗
PubMed1996

Vocal fold scarring: current concepts and management.

Scarring of the vocal folds can occur as the result of blunt laryngeal trauma or, more commonly, as the result of surgical, iatrogenic injury after excision or removal of vocal fold lesions. The scarring results in replacement of healthy tissue by fibrous tissue and can irrevocably alter vocal fold function and lead to a decreased or absent vocal fold mucosal wave. The assessment and treatment of persistent dysphonia in patients with vocal fold scarring presents both diagnostic and therapeutic challenges to the voice treatment team. The common causes of vocal fold scarring are described, and prevention of vocal fold injury during removal of vocal fold lesions is stressed. The anatomic and histologic basis for the subsequent alterations in voice production and contemporary modalities for clinical and objective assessment will be discussed. Treatment options will be reviewed, including nonsurgical treatment and voice therapy, collagen injection, fat augmentation, endoscopic laryngoplasty, and Silastic medialization.

Cicatrix↗
PubMed1996

At risk nephrons and the decline in renal function in response to treatment of hypertension.

An examination of change in renal function following blood pressure lowering in more than 4,400 individuals in several clinical trials revealed that renal function declined following initiation of antihypertensive treatment in both essential hypertension and hypertensive diabetics for a period of two years before stabilizing at or near zero change. This initial decline can be related to the severity of preexisting hypertension but does not appear related to the type of antihypertensive regimen used. This phenomenon appears most readily explained by progressive obsolescence of previously damaged nephrons and not by the type of antihypertensive therapy employed. These finding raise questions about validity of interpretation of clinical trials designed to test efficacy of specific drug regimens in preserving renal function when outcome results are predominantly influenced by events during the first two years of intervention.

Antihypertensive Agents↗
PubMed1996

Vitamin B12 levels in human milk during the first nine months of lactation.

Vitamin B12 concentration was measured by competitive binding radioassay in 48 samples of human milk from healthy mothers eating unrestricted diets. Specimens were collected 1-35 weeks after full-term delivery and were subjected to proteolytic digestion before radioassay in order to destroy binding proteins. The distribution of the results was skewed, but the distribution of the logged values was not significantly different from normal. The geometric mean vitamin B12 level remained almost unchanged during the first 12 weeks postpartum (261-297 pmol/l) and then declined to a low of 139 pmol/l at 27-35 weeks. A significant (P = 0.033) decline in vitamin B12 concentration between 6-12 weeks and 19-25 weeks postpartum was observed.

Animals↗
PubMed1995

DNA replication. Almost licensed.

Exact duplication of all the DNA in a cell occurs during each S phase, and only once in each cell cycle. Recent results show that conserved proteins of the MCM family contribute to these precisely regulated events.

Animals↗
PubMed1995

Cyclin B/p34cdc2 triggers phosphorylation of DNA ligase I during Xenopus laevis oocyte maturation.

Phosphorylation of DNA ligase I has been analyzed during Xenopus laevis early development. The enzyme, which is involved in DNA replication and DNA repair events, is accumulated during oogenesis to reach a maximum in the stage VI oocyte, and remains at a constant level during maturation. When maturation of the oocyte is induced (in vivo or in vitro), this leads to a post-translational modification of the protein. In stage VI oocytes, a DNA ligase I of apparent molecular mass 180 kDa is detected immunologically whereas a 190-kDa form is found in unfertilized eggs and persists until the tadpole stage. This modification is due to phosphorylation performed by a protein kinase that is turned on 3-4 h after induction of the maturation. Activation of the kinase requires protein synthesis, and appearance of phosphorylated DNA ligase coincides with activation of histone H1 kinase activity. Induction of DNA ligase I modification and maturation are induced in the absence of protein synthesis following injection of maturation promoting factor into oocytes. Immunoprecipitated oocyte DNA ligase I is phosphorylated and its molecular mass modified by purified cyclin B/p34cdc2 in vitro. DNA ligase I phosphorylation is not induced in oocyte extract where only mitogen-activated-protein kinase is induced. Phosphorylation of DNA ligase I induced by cdc2 kinase occurs at the time new DNA replication and recombination activities appear in eggs.

Animals↗
PubMed1995

Deletion analysis of the starch-binding domain of Aspergillus glucoamylase.

The large form of glucoamylase (GAI) from Aspergillus awamori (EC 3.2.1.3) binds strongly to native granular starch, whereas a truncated form (GAII) which lacks 103 C-terminal residues, does not. This C-terminal region, conserved among fungal glucoamylases and other starch-degrading enzymes, is part of an independent starch-binding domain (SBD). To investigate the SBD boundaries and the function of conserved residues in two putative substrate-binding sites, five gluco-amylase mutants were constructed with extensive deletions in this region for expression in Saccharomyces cerevisiae. Progressive loss of both starch-binding and starch-hydrolytic activity occurred upon removal of eight and 25 C-terminal amino acid residues, or 21 and 52 residues close to the N-terminus, confirming the requirement for the entire region in formation of a functional SBD. C-terminal deletions strongly impaired SBD function, suggesting a more important role for one of the putative binding sites. A GAII phenocopy showed a nearly complete loss of starch-binding and starch-hydrolytic activity. The deletions did not affect enzyme activity on soluble starch or thermo-stability of the enzyme, confirming the independence of the catalytic domain from the SBD.

Amino Acid Sequence↗