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Biomedical subjects

C Cutler

Publications and source records attributed to C Cutler.

At least 19 recordsLinked to original sources
PubMed2006

Quality of life associated with acute and chronic graft-versus-host disease.

Acute and chronic graft-versus-host diseases (GVHD) are associated with increased morbidity and mortality after hematopoietic stem cell transplantation (HCT). We prospectively measured the quality of life (QOL) of patients undergoing allogeneic transplantation. Ninety-six subjects completed self-assessment surveys before HCT, and at 6 and/or 12 months post-HCT that included the Medical Outcomes Study Short Form 12 (SF12) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale. Eighty-three percent of survivors responded at 6 and 12 months. Physical and mental functioning assessed by the SF12 was not associated with either acute or chronic GVHD. In contrast, the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant was sensitive to occurrence of either acute or chronic GVHD. GVHD is a major determinant of the long-term QOL of survivors. The adverse effects of acute GVHD are detectable with the TOI at 6 months post transplantation after which development of chronic GVHD is the most strongly correlated with worse QOL.

Acute Disease↗
PubMed2006

HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation.

HLA-C matching is an important determinant of outcome after myeloablative unrelated donor (URD) hematopoietic stem cell transplantation. However, its importance in non-myeloablative stem cell transplantation (NST) is not known. We report a retrospective analysis of 111 patients who underwent URD NST, of whom 78 were 10/10 matched at HLA-A, B, C, DRB1, DQB1 and 33 were mismatched at one or more HLA-C antigen/allele (24 HLA-C only; nine HLA-C+other locus mismatch). Patients were conditioned with busulfan (0.8 mg/kg/day i.v. x 4 days) and fludarabine (30 mg/m(2)/day i.v. x 4 days). Graft-versus-host disease prophylaxis included cyclosporine/prednisone- or tacrolimus/mini-methotrexate-based regimens. HLA-C disparity did not impair engraftment. Median marrow donor chimerisms were >or=90% donor at day+30 and +100 in both groups. Overall survival at 2 years was 30% in HLA-C-mismatched and 51% in 10/10-matched patients (P=0.008). In Cox regression, HLA-C mismatch was an independent predictor of death (hazard ratio 1.85, P=0.04). Treatment-related mortality was higher in the HLA-C-mismatched group: 48 versus 16% (P=0.0001). Cumulative relapse incidence was 35% in the HLA-C-mismatched and 55% in the 10/10-matched cohort, P=0.09. HLA-C mismatch is associated with inferior survival after URD NST.

Adolescent↗
PubMed2005

Limits on gravitational-wave emission from selected pulsars using LIGO data.

We place direct upper limits on the amplitude of gravitational waves from 28 isolated radio pulsars by a coherent multidetector analysis of the data collected during the second science run of the LIGO interferometric detectors. These are the first direct upper limits for 26 of the 28 pulsars. We use coordinated radio observations for the first time to build radio-guided phase templates for the expected gravitational-wave signals. The unprecedented sensitivity of the detectors allows us to set strain upper limits as low as a few times 10(-24). These strain limits translate into limits on the equatorial ellipticities of the pulsars, which are smaller than 10(-5) for the four closest pulsars.

Journal Article↗
PubMed2005

Routine screening for psychosocial distress following hematopoietic stem cell transplantation.

The diagnosis and treatment of cancer is often associated with high levels of psychosocial distress, yet exploration of these issues is rarely included in routine oncologic care. We conducted a pilot study to evaluate the feasibility of screening for psychosocial distress after autologous and allogeneic stem cell transplantation. A total of 80 adults were enrolled in Boston, MA, USA. Subjects completed self-administered assessments prior to hospital admission, at their first clinic visit after hospital discharge, and at 100 days post transplant. Assessments included validated instruments assessing psychosocial distress and quality of life (QOL). Elevated levels of anxiety and/or depression were detected in 55% of those providing pre-transplant assessments and were associated with compromised QOL. Post transplant screening was successfully performed in 69% of subjects and identified that 44% had symptoms of depression, anxiety or post traumatic stress disorder. Pre-transplant distress was associated with detection of distress after transplantation (81 vs 13%, P< 0.0001). In summary, we detected high levels of distress in transplant patients using self-administered tools. Pre-transplant distress appears to be highly predictive of distress post transplant and is a feasible marker to target screening and intervention programs.

Adaptation, Psychological↗
PubMed2004

Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation.

Sirolimus is a novel macrolide immunosuppressant widely used in solid organ transplantation. We have conducted three clinical trials using this compound as prophylaxis against GVHD after allogeneic stem cell transplantation. Our studies have demonstrated excellent GVHD control even when mismatched and unrelated donors were used. The morbidity and mortality associated with transplantation were reduced due to the omission or reduction in methotrexate dose. Furthermore, CMV reactivation and fungal infection rates were low. However, we have noted that sirolimus may be associated with increased rates of thrombotic microangiopathy after transplantation. Sirolimus has other uses, such as the treatment of established acute and chronic GVHD, and may be useful for treatment of post transplant lymphoproliferative disorder and perhaps as an antineoplastic agent against a wide variety of hematologic and solid neoplasms.

Graft Rejection↗
PubMed2004

Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease.

Prior studies suggest that depletion of CD8+ T cells from donor bone marrow or donor lymphocyte infusions can reduce graft-versus-host disease (GVHD) without compromising graft-versus-leukemia. We explored CD8 depletion in patients undergoing matched related donor (MRD, n=25) and unrelated donor (URD, n=16) peripheral blood stem cell transplantation following myeloablative conditioning with cyclophosphamide (60 mg/kg/day i.v. x 2) and total body irradiation (200 cGy x 7 fractions). Ex vivo incubation of mobilized donor peripheral blood cells with anti-CD8 antibody coated high-density microparticles removed 99% of CD8+ cells. The median number of CD8+ cells infused was 3.9 x 10(5) cells/kg (2.2 x 10(5) in MRD, and 8.1 x 10(5) in URD patients). Post transplant immune suppression included tacrolimus in the MRD cohort, and tacrolimus plus mini-methotrexate (5 mg/m2 days +1, 3, 6, 11) in the URD cohort. All 41 patients engrafted. Grade 2-4 acute GVHD incidence was 61% (44% MRD, 88% URD). Chronic GVHD incidence was 50% (48% MRD, 55% URD). Relapse incidence was 4.9%. Estimated event-free and overall survival rates were 65 and 63%, respectively, at 1 year and 56 and 57%, respectively, at 2 years. There was no correlation between CD8+ number and GVHD or survival. A 2-log depletion of CD8+ cells from PBSC is insufficient to prevent GVHD.

Adult↗
PubMed2001

Empty capsids in column-purified recombinant adenovirus preparations.

Empty capsids from adenovirus, that is, virus particles lacking DNA, are well documented in the published literature. They can be separated from complete virus by CsCl density gradient centrifugation. Here we characterize the presence of empty capsids in recombinant adenovirus preparations purified by column chromatography. The initial purified recombinant adenovirus containing the p53 tumor suppressor gene was produced from 293 cells grown on microcarriers and purified by passage through DEAE-Fractogel and gel-filtration chromatography. Further sequential purification of the column-purified virus by CsCl and glycerol density gradient centrifugations yielded isolated complete virus and empty capsids. The empty capsids were essentially noninfectious and free of DNA. Analysis of empty capsids by SDS-PAGE or RP-HPLC showed the presence of only three major components: hexon, IIIa, and a 31K band. This last protein was identified as the precursor to protein VIII (pVIII) by mass spectrometric analysis. No pVIII was detected from the purified complete virus. Analysis by electron microscopy of the empty capsids showed particles with small defects. The amount of pVIII was used to determine the level of empty capsid contamination. First, the purified empty capsids were used to quantify the relation of pVIII to empty capsid particle concentration (as estimated by either light scattering or hexon content). They were then used as a standard to establish the empty capsid concentration of various recombinant adenovirus preparations. Preliminary research showed changes in empty capsid concentration with variations in the infection conditions. While virus purification on anion-exchange or gel-filtration chromatography has little effect on empty capsid contamination, other chromatographic steps can substantially reduce the final concentration of empty capsids in column-purified adenovirus preparations.

Adenoviridae↗
PubMed2001

Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis.

PURPOSE: Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures. METHODS: An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed. RESULTS: Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P=.006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P <.001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P <.001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05). CONCLUSION: Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

Acute Disease↗
PubMed2001

Carboxyalkylated histidine is a pH-dependent product of pegylation with SC-PEG.

PURPOSE: Pegylation of therapeutic protein usually results in a mixture of monopegylated proteins with differing sites of modification. With rh-interferon-alpha2A pegylation, we have found that this heterogeneity includes two classes of pegylation site chemistry, the relative proportions of which can be adjusted by reaction pH. METHODS: The effect of pegylation reaction pH on the relative proportion of three peaks produced was investigated. Products were purified and characterized by peptide mapping, chemical stability to neutral hydroxylamine, and biologic activity. RESULTS: Reactions at basic pH levels produced a mixture of products pegylated at lysine residues as has been observed elsewhere. However, the dominant product of reactions at mildly acidic levels of pH showed distinct chemistry and higher cytopathic effect activity. The primary site of modification at this pH was His34. We developed a quantitative assay using sensitivity to neutral hydroxylamine to measure the proportion of urethane bonds involving carboxyalkylated histidines. This assay showed that histidine was pegylated preferentially at low pH levels with another protein, rh-Interleukin-10. CONCLUSIONS: Reaction pH can be used to select the preferred pegylation site chemistry.

Alkylation↗
PubMed2001

A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models.

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.

Amino Acid Motifs↗
PubMed2001

Peripheral blood stem cells for allogeneic transplantation: a review.

Peripheral blood stem cells (PBSCs) have become increasingly popular for use in hematopoietic stem cell transplantation. PBSCs are readily collected by continuous-flow apheresis from patients and healthy donors after the administration of s.c. recombinant colony-stimulating factors with only minimal morbidity and discomfort. Although the precise identification of PBSCs remains elusive, they can be phenotypically identified as a subset of all circulating CD34(+) cells. There are important phenotypic and biologic distinctions between PBSCs and bone marrow (BM)-derived progenitor cells. PBSCs express more lineage-specific antigens but are less metabolically active than their BM-derived counterparts. The use of PBSCs for allogeneic transplantation has been compared to BM in several randomized trials and cohort studies. The use of PBSCs in leukemia, myeloma, non-Hodgkin's lymphoma, and myelodysplasia has resulted in shorter times to neutrophil and platelet engraftment at the expense of increased rates of chronic graft-versus-host disease. The increase in graft-versus-host disease is mainly due to a log-fold increase in donor T cells transferred with the graft. Relapse rates after transplantation may be lower after PBSC transplantation but a convincing survival advantage has not been demonstrated overall. It is possible that a stronger graft-versus-tumor effect may exist with PBSCs when compared with BM although the mechanisms leading to this effect are not clear.

Animals↗
PubMed1996

99mTc-2GAM: a tracer for renal imaging.

We propose a renal imaging agent, the 99mTc complex of the bidentate-N,S chelate N-(mercaptoacetyl)glycine (99mTc-2GAM), with the imaging characteristics of 99mTc-DMSA but a faster kidney uptake; chemical evidence supports the formulation of 99mTc-2GAM as [Tc(v)(O)(GAM)2]-. After biodistribution and toxicity studies in animals, 99mTc-2GAM was evaluated in five normal volunteers. 99mTc-2GAM is rapidly cleared from the blood (t1/2 = 9 min) and 50% of the ID is excreted in the urine in the first 2 h. Dynamic data show a rapid renal uptake that increases up to 1 h with no significant wash-out between 1 and 8 h. The uptake in each kidney ranges from 11.3% to 20.7% ID. Low, stable liver uptake is observed. No significant activity is detected in other organs. We showed no differences between 99mTc-2GAM and 99mTc-DMSA compared in three patients with unilateral kidney disease. We conclude that 99mTc-2GAM has good practical and dosimetric features for renal imaging.

Adult↗
PubMed1996

Cutaneous malignant melanoma in women is uncommonly associated with a family history of melanoma in first-degree relatives: a case-control study.

Sun exposure is the principal cause of malignant melanoma, but other risk factors may be important. During their reproductive years women are at a greater risk for melanoma than men. We performed an age-matched case-control study of cutaneous malignant melanoma in 159 women attending a single oncology clinic in Montreal. A reported family history of cutaneous malignant melanoma in first-degree relatives was associated with a significantly increased risk of melanoma (adjusted relative risk: 4.28, P = 0.046). No subject was a member of a hereditary melanoma family (three or more cases of melanoma in first-degree relatives). As expected, variables related to sun exposure were also strong determinants of risk. Height was a significant risk factor, but the difference between the mean heights of cases and controls was only 2 cm (P = 0.009). The age of menarche of cases was lower than in controls (mean 12.70 and 13.08 years respectively, P = 0.036) but there was no significant elevation in risk associated with other reproductive variables. This study suggests that a family history of malignant melanoma is a significant risk factor, but that hereditary melanoma may be less common than is currently believed.

Adolescent↗
PubMed1995

Linkage analysis of 26 Canadian breast and breast-ovarian cancer families.

We have examined 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking the BRCA1 gene on chromosome 17q12-q21. Of the 15 families that contain cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. A genetic recombinant in a breast-ovarian cancer family indicates a placement of BRCA1 telomeric to D17S776, and helps to define the region of assignment of the cancer susceptibility gene. Other cancers of interest that appeared in the BRCA1-linked families included primary peritoneal cancer, cancer of the fallopian tube, and malignant melanoma.

Adult↗