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Biomedical subjects

K L Weber

Publications and source records attributed to K L Weber.

16 recordsLinked to original sources
PubMed2001

Ewing's sarcoma: presentation and management.

Great strides have been made in the diagnosis and treatment of patients with Ewing's sarcoma. With the advent of modern chemotherapy, the long-term survival has improved to approximately 70%. Standard treatment for local control of the primary lesion has, historically, been chemotherapy and radiation. Currently, surgical resection has become a more effective option in the multidisciplinary treatment of patients with this disease. These current concepts and developments in the presentation and management of Ewing's sarcoma are discussed.

Bone Neoplasms↗
PubMed2001

Chondrosarcoma of the pelvis. A review of sixty-four cases.

BACKGROUND: Treatment of pelvic chondrosarcoma is a difficult problem for the musculoskeletal oncologist. Poor rates of survival and high rates of local recurrence after surgical treatment have been reported in previous studies. The present study was designed to review the long-term oncologic and functional outcomes of surgical management in a large series of patients with pelvic chondrosarcoma who were treated at a single institution. METHODS: The cases of sixty-four patients with localized pelvic chondrosarcoma that had been surgically treated between 1975 and 1996 were reviewed retrospectively. The study was limited to patients who had received no previous treatment for chondrosarcoma. There were forty-one male and twenty-three female patients who had a mean age of forty-seven years (range, fifteen to eighty-eight years). The patients were followed for a minimum of three years or until death. The median duration of follow-up of the living patients was 140 months (range, thirty-nine to 295 months). RESULTS: Thirty-three of the sixty-four patients were first seen with grade-1 chondrosarcoma; twenty-three, with grade-2; one, with grade-3; and seven, with grade-4 (dedifferentiated chondrosarcoma). Thirteen patients had a hemipelvectomy to achieve local tumor control, whereas fifty-one patients underwent a limb-salvage procedure. Twelve patients (19%) had local recurrence, and eleven (17%) had distant metastases. At the time of the final follow-up, forty-four patients (69%) were alive without evidence of disease, thirteen (20%) had died of the disease, six (9%) had died of unrelated causes, and one (2%) was alive with disease. Less than a wide surgical margin correlated with local recurrence (p = 0.014). High-grade tumors correlated with poor overall survival (p < 0.001). All patients who had a limb-salvage procedure were able to walk at the time of the final follow-up, and they had a mean functional score of 77%, according to the system of the Musculoskeletal Tumor Society. CONCLUSIONS: Aggressive surgical resection of pelvic chondrosarcoma results in long-term survival of the majority of patients. There is a high correlation between tumor grade and overall or disease-free survival.

Adolescent↗
PubMed2000

Microtubules remodel actomyosin networks in Xenopus egg extracts via two mechanisms of F-actin transport.

Interactions between microtubules and filamentous actin (F-actin) are crucial for many cellular processes, including cell locomotion and cytokinesis, but are poorly understood. To define the basic principles governing microtubule/F-actin interactions, we used dual-wavelength digital fluorescence and fluorescent speckle microscopy to analyze microtubules and F-actin labeled with spectrally distinct fluorophores in interphase Xenopus egg extracts. In the absence of microtubules, networks of F-actin bundles zippered together or exhibited serpentine gliding along the coverslip. When microtubules were nucleated from Xenopus sperm centrosomes, they were released and translocated away from the aster center. In the presence of microtubules, F-actin exhibited two distinct, microtubule-dependent motilities: rapid ( approximately 250-300 nm/s) jerking and slow ( approximately 50 nm/s), straight gliding. Microtubules remodeled the F-actin network, as F-actin jerking caused centrifugal clearing of F-actin from around aster centers. F-actin jerking occurred when F-actin bound to motile microtubules powered by cytoplasmic dynein. F-actin straight gliding occurred when F-actin bundles translocated along the microtubule lattice. These interactions required Xenopus cytosolic factors. Localization of myosin-II to F-actin suggested it may power F-actin zippering, while localization of myosin-V on microtubules suggested it could mediate interactions between microtubules and F-actin. We examine current models for cytokinesis and cell motility in light of these findings.

Actins↗
PubMed2000

Sacropelvic resection for recurrent anorectal cancer. A multidisciplinary approach.

A multimodal approach including preoperative external beam radiation, surgical resection, and intraoperative electron radiation was used in 23 patients with locally advanced anal or recurrent rectal cancers involving the sacrum. The proximal extent of complete sacral resection was S2 in three patients, S3 in 12 patients, S4 in two patients, and S5 in one patient. The tumor was confined to the anterior sacral cortex in five patients. The resection was marginal in 10, contaminated marginal in 11, and intralesional in two patients. At 19 to 54 months of followup, five patients are alive without evidence of disease and four are alive with disease. Twelve patients died of their disease, and two died of other causes. There was a mean survival of 32.9 months for the patients who were alive at followup. Kaplan-Meier survival for all patients was 82% at 1 year and 73% at 2 years, with death of disease as an endpoint. Thirteen (57%) patients had another local recurrence develop at a mean of 17.2 months. Eight (35%) patients had metastatic disease develop at a mean of 16.3 months. Proper patients selection is important in ensuring a favorable outcome from this aggressive surgery.

Adenocarcinoma↗
PubMed1999

Direct observation of microtubule-f-actin interaction in cell free lysates.

Coordinated interplay of the microtubule and actin cytoskeletons has long been known to be crucial for many cellular processes including cell migration and cytokinesis. However, interactions between these two systems have been difficult to document by conventional approaches, for a variety of technical reasons. Here the distribution of f-actin and microtubules were analyzed in the absence of fixation using Xenopus egg extracts as an in vitro source of microtubules and f-actin, demembranated Xenopus sperm to nucleate microtubule asters, fluorescent phalloidin as a probe for f-actin, and fluorescent tubulin as a probe for microtubules. F-actin consistently colocalized in a lengthwise manner with microtubules of asters subjected to extensive washing in flow chambers. F-actin-microtubule association was heterogenous within a given aster, such that f-actin is most abundant toward the distal (plus) ends of microtubules, and microtubules heavily labeled with f-actin are found in close proximity to microtubules devoid of f-actin. However, this distribution changed over time, in that 5 minute asters had more f-actin in their interiors than did 15 minute asters. Microtubule association with f-actin was correlated with microtubule bending and kinking, while elimination of f-actin resulted in straighter microtubules, indicating that the in vitro interaction between f-actin and microtubules is functionally significant. F-actin was also found to associate in a lengthwise fashion with microtubules in asters centrifuged through 30% sucrose, and microtubules alone (i.e. microtubules not seeded from demembranated sperm) centrifuged through sucrose, indicating that the association cannot be explained by flow-induced trapping and alignment of f-actin by aster microtubules. Further, cosedimentation analysis revealed that microtubule-f-actin association could be reconstituted from microtubules assembled from purified brain tubulin and f-actin assembled from purified muscle actin in the presence, but not the absence, of Xenopus oocyte microtubule binding proteins. The results provide direct evidence for an association between microtubules and f-actin in vitro, indicate that this interaction is mediated by one or more microtubule binding proteins, and suggest that this interaction may be responsible for the mutual regulation of the microtubule and actomyosin cytoskeletons observed in vivo.

Actins↗
PubMed1999

Osteoid osteoma of the elbow: a diagnostic challenge.

BACKGROUND: Osteoid osteoma is a painful benign neoplasm that is rarely found in the elbow region. METHODS: The study included fourteen patients, and we believe that this is the largest reported series of patients with osteoid osteoma of the elbow evaluated at one institution. Most of the patients had had symptoms for a prolonged period and had had multiple invasive procedures before an accurate diagnosis was made. Although findings on physical examination generally are nonspecific and are not always accurate in localizing the lesion, plain tomograms and computed tomography scans were most helpful in identifying the nidus in the present study. Thirteen of the patients had limited motion of the elbow before the definitive diagnosis was made, and ten of these thirteen had a mean flexion contracture of 38 degrees. RESULTS: Removal of the nidus resulted in relief of pain and improvement in the range of motion of the elbow in all fourteen patients. A persistent postoperative flexion contracture was more common in the patients who had had a previous arthrotomy of the elbow than in those who had not had that procedure. CONCLUSIONS: It is important to recognize this uncommon entity to avoid the morbidity associated with a prolonged delay in diagnosis. Because the symptoms resolve after excision of the lesion, the surgeon can avoid unnecessary soft-tissue dissection and release of the contracture.

Adolescent↗
PubMed1999

Reoperation for failed prosthetic replacement used for limb salvage.

Patients with segmental bone and joint replacement prostheses because of tumors increasingly need revision surgery because of their long term survival. Between 1970 and 1990, 208 custom prosthetic replacements were performed for limb salvage in patients with tumors. Reoperations were required in 52 patients. The mean time to reoperation was 37 months. The reoperation procedures included 35 prosthetic revisions, 11 amputations, four arthrodeses, one vascularized fibular graft, and one open reduction and internal fixation of a fracture with supplemental bone graft. Functional assessment using the new Musculoskeletal Tumor Society scoring system was available for the 36 living patients, and their mean rating was 63% (18.9) at 12 years' mean followup. Of the 35 patients who received a new prosthesis, 12 (33%) patients needed a third operation at mean followup of 68 months. The probability of prosthetic survival in the group of 35 patients needing revision to the same or another prosthesis was 79% at 5 years and 65% at 10 years. The chance and frequency of needing reoperation increased as patients survived longer. Reoperations for tumor recurrence or infection usually resulted in amputation. Reoperation for failed initial segmental bone and joint prosthetic replacement is feasible and effective and can be done without jeopardizing subsequent patient and implant survival or without significantly affecting functional results compared with the values before reoperation.

Adolescent↗
PubMed1998

Evidence for the upregulation of osteogenic protein-1 mRNA expression in musculoskeletal neoplasms.

Little is known about bone and cartilage tumors at the molecular level; thus, the identification of genes associated with these tumors may be useful as markers and therapeutic targets. To address this issue and to test the hypothesis that abnormal expression of one or more growth factors in the transforming growth factor-beta superfamily is associated with musculoskeletal neoplasia, degenerate primers based on the conserved sequences in these genes were made for screening tumor samples by reverse transcription-polymerase chain reaction. First, these primers were used to obtain a comparative profile between a low-grade chondrosarcoma and its dedifferentiated high-grade counterpart in the same patient. This experiment identified an amplified DNA product in the high-grade sample that was identical to osteogenic protein-1/bone morphogenetic protein-7. Osteogenic protein-1 mRNA expression was 17-fold greater in this high-grade sample than in the low-grade one. Osteogenic protein-1 was highly expressed (three of three) in human osteosarcoma cell lines but was not expressed (zero of four) in normal osteoblast samples. Screening for gene expression of osteogenic protein-1 in 57 osteosarcomas and chondrosarcomas indicated that 44% (range: 38-52%) of them were positive for osteogenic protein-1 mRNA. Screening of breast and prostate tumors revealed a similar association with osteogenic protein-1 mRNA expression.

Bone Morphogenetic Protein 7↗
PubMed1998

Selective differential fingerprinting. A method for identifying differentially expressed genes in a family between two samples.

A method termed selective differential fingerprinting (SDF) has been developed that enables one to investigate the level of expression for a family of genes between two samples. SDF produces a fingerprint (on a sequencing gel) on reverse transcription polymerase chain reaction (RT-PCR) of a sample with degenerate primers designed from conserved regions of a family of genes. By comparing fingerprints obtained after SDF with primers representing the transforming growth factor-beta (TGF beta) family of growth factors between a low-grade and a high-grade tumor from the same patient, a TGF beta family member known as osteogenic protein 1 (OP-1) or bone morphogenic protein 7 (BMP-7) was found to be greatly overexpressed in the high-grade tumor compared to the low-grade one. SDF also has the potential to identify novel genes. SDF offers a general way to identify differentially expressed genes for a family between two given samples.

Bone Morphogenetic Protein 7↗
PubMed1998

Rapid acquisition of unknown DNA sequence adjacent to a known segment by multiplex restriction site PCR.

The determination of unknown DNA sequences around a known locus has important applications in molecular genetics, specifically in genomic walking and genome mapping. Several PCR-based methods have been reported to address this issue, but they often involve multiple, time-consuming steps. We have previously described a technique known as restriction site PCR (RS-PCR) that allows sequence acquisition faster than the existing methods. The method involves PCR using four separate universal primers that are representative of given restriction enzyme sites (RS primers), and a specific primer from one end of the known sequence. We have now significantly improved the technique by mixing the four universal primers into one PCR tube with the first specific primer. This is followed by a nested PCR with the mixed RS primers and an internal specific primer, after which the product is sequenced by direct automated sequencing. The technique, called multiplex RS-PCR (mRS-PCR), is reproducible and can be used to obtain unknown sequence adjacent to known sequences in both the upstream and downstream directions. We illustrate the application of mRS-PCR in the acquisition of approximately 780 bp of genomic sequence starting from a known sequence of approximately 120 bp. Multiplex RS-PCR appears to be the fastest of all methods that address the issue of unknown sequence retrieval adjacent to a known region.

Binding Sites↗
PubMed1996

Dependence of fluorodeoxyuridine-induced cytotoxicity and megabase DNA fragment formation on S phase progression in HT29 cells.

The relationship between cell cycle progression and induction of DNA double-strand breaks and cytotoxicity by exposure to fluorodeoxyuridine (FdUrd) was studied in HT29 human colon cancer cells. Fractionation of drug-treated populations by centrifugal elutriation yielded subpopulations having widely divergent abilities to progress through S phase in the presence of the drug. One of these subpopulations, which appeared to undergo coordinated growth arrest, was resistant to FdUrd cytotoxicity and DNA damage. In contrast, the subpopulation which was able to progress furthest through S phase in the presence of FdUrd underwent unbalanced growth arrest (i.e., increase in size and mass out of proportion to DNA synthesis), and displayed both DNA double-strand break formation (assayed by pulsed field gel electrophoresis) and loss of clonogenicity. When cells were elutriated prior to drug treatment, producing fractions enriched in cells at various cell cycle stages, no significant differences in sensitivity to FdUrd-induced cytotoxicity were detected among elutriation fractions. These findings support the model that, in HT29 cells, progression into and through S phase during drug treatment is an important determinant of FdUrd-induced DNA damage and cytotoxicity, but that the cell cycle position at the start of drug exposure is not a critical factor for these effects.

Antimetabolites, Antineoplastic↗
PubMed1996

Revision of a failed cemented total hip prosthesis with insertion of an acetabular component without cement and a femoral component with cement. A five to eight-year follow-up study.

Sixty-one consecutive so-called hybrid revision total hip arthroplasties were performed in fifty-five patients by one surgeon, from 1986 through 1988, for mechanical failure of a cemented total hip prosthesis. In all of the patients, the acetabular and femoral components were revised to a porous-coated Harris-Galante acetabular component inserted without cement and an Iowa femoral component inserted with cement. Contemporary cementing techniques were used, but structural bone graft was not. The over-all prevalence of repeat revision for aseptic loosening was 0 per cent for the acetabular components and 3 per cent (two hips) for the femoral components. In addition, 2 per cent (one) of the acetabular components and 5 per cent (three) of the femoral components demonstrated radiographic evidence of loosening. In the forty-three patients (forty-nine hips) who were alive at an average of seventy-four months (range, sixty to ninety-five months) after the revision, none of the acetabular components and 2 per cent (one) of the femoral components were revised again for aseptic loosening. An additional 2 per cent (one) of the acetabular components and 6 per cent (three) of the femoral components were radiographically loose. Ninety-eight per cent (forty-one) of the forty-two living patients (98 per cent [forty-seven] of the forty-eight hips) who had a clinical examination at least five years after the revision had increased function; 90 per cent (thirty-eight) of these patients (forty-four [92 per cent] of the hips) were satisfied with the result. The group that had a hybrid revision was compared with a group of seventy patients (seventy-four hips) who had had a revision total hip arthroplasty with use of contemporary cementing techniques for both components. These revisions had been performed by the same surgeon, before he performed the hybrid revisions, and the prevalence of repeat revision of the acetabular component was 7 per cent (five hips) and that of the femoral component was 4 per cent (three hips). In addition, 16 per cent (twelve) of the acetabular components and 3 per cent (two) of the femoral components were radiographically loose. The comparison group was not a consecutive series, as only the patients who had had radiographs made five to eight years after the revision were evaluated. In the fifty-two such patients (fifty-six hips) who were alive at five years after the revision with cement (average duration of radiographic follow-up, seventy-seven months; range, sixty to ninety-nine months), 9 per cent (five) of the acetabular components and 5 per cent (three) of the femoral components were revised again for aseptic loosening. An additional 21 per cent (twelve) of the acetabular components and 4 per cent (two) of the femoral components were radiographically loose. The results of the present study demonstrated a significant improvement (p = 0.0001) in the survival of the acetabular component of so-called hybrid revision total hip arthroplasties compared with that of revision total hip arthroplasties with cement performed by the same surgeon and followed for a comparable period.

Acetabulum↗
PubMed1991

An in vivo animal model of gene therapy for leukocyte adhesion deficiency.

Leukocyte adhesion deficiency (LAD) is an inherited disorder of leukocyte function that is caused by defects in the CD18 gene and is associated with diminished cell surface expression of CD11/CD18 proteins. We have developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human CD18 gene into murine bone marrow cells which were transplanted into lethally irradiated syngeneic recipients. A reliable flow cytometric assay for human CD18 in transplant recipients was developed based on: (a) the availability of human specific CD18 monoclonal antibodies and (b) the observation that human CD18 can form chimeric heterodimers with murine CD11a on the cell surface. Human CD18 was detected on leukocytes in a substantial number of transplant recipients for at least 6 mo suggesting that the gene had been transduced into stem cells. Expression was demonstrated in several lineages of a variety of hematopoietic tissues, but was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C. No apparent untoward effects of human CD18 expression were noted in transplant recipients. These studies suggest a specific strategy for LAD gene therapy that may be effective and safe.

Animals↗