Biomedical subjects

A Malcolm

Publications and source records attributed to A Malcolm.

16 recordsLinked to original sources

PubMed1992

Immunoglobulin heavy chain variable region gene utilization by B cell hybridomas derived from rheumatoid synovial tissue.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects synovial joints. Activated B lymphocytes and plasma cells are present in the synovial tissue and are thought to contribute to the immunopathology of the rheumatoid joint. To investigate rheumatoid synovial B lymphocytes, we have generated B cell hybridomas from synovial tissue of an RA patient. Here we describe the immunoglobulin VH gene repertoire of eight IgM- and 10 IgG-secreting synovial-derived hybridomas. The VH4 gene family is highly represented (38.5%) in this panel of hybridomas compared with the frequency of VH4 gene expression in circulating B lymphocytes reported previously (19-22%) and with the VH4 gene frequency we observed in a panel of hybridomas derived in the same manner from the spleen and tonsil of normal individuals (19%). The increased frequency of VH4 gene expression was not due to the expansion of a single B cell clone in vivo as none of these hybridomas was clonally related. Two synovial-derived hybridomas secreted autoantibodies; one (VH3+) secreted an IgM-rheumatoid factor (RF) and the other (VH4+) secreted IgM with polyreactive binding to cytoskeletal proteins and cardiolipin. The antibodies secreted by the remaining synovial-derived hybridomas were not reactive with the autoantigens tested. The VH gene usage in a proportion (5/17) of synovial-derived hybridomas that expressed CD5 antigen provided preliminary evidence that CD5+ B cells in RA synovium have a similar increase of VH4 gene expression reported for CD5+ B cells from normal individuals and patients with chronic lymphocytic leukaemia.

Adult↗

PubMed1991

Neoadjuvant cisplatin plus vinblastine chemotherapy in locally advanced non-small cell lung cancer.

Twenty-eight patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) received neoadjuvant chemotherapy with cisplatin (120 mg/m2 on days 1 and 29) and vinblastine (4 mg/m2 weekly for 6 weeks). At the completion of induction chemotherapy, all patients were assessed for resectability. Those patients judged to be resectable underwent thoracotomy. All remaining patients received thoracic radiation therapy (5500 cGy) followed by additional chemotherapy in those patients responding to neoadjuvant treatment. There were 15 partial responses to neoadjuvant chemotherapy for an overall response rate of 54% (95% confidence interval, 36% to 71%). Only five partially responding patients (18%) were thought to have had sufficient tumor regression to allow for a potentially curative resection. However, a complete resection was done in only two patients. Overall median survival was 12 months (range, 4 to 72 months) with 1-year, 2-year, and 3-year survival rates of 54%, 39%, and 11%, respectively. The primary toxicity associated with neoadjuvant chemotherapy was moderate to severe (Eastern Cooperative Oncology Group Grade 3 or 4) nausea and emesis in 25% of patients. Hematologic toxicity was relatively modest; only one patient had Grade 4 leukopenia (less than 1000/microliter). Fever and neutropenia were uncommon, and there were no documented septic episodes or treatment-related deaths. Compared with historic controls treated with radiation therapy alone, cisplatin-based neoadjuvant chemotherapy appeared to improve the median and long-term survival of Stage III NSCLC patients modestly.

Adenocarcinoma↗

PubMed1990

Chronic pericardial disease in patients with rheumatoid arthritis: a longitudinal study.

We have reviewed the clinical and investigative findings in 13 patients with chronic pericardial disease and seropositive rheumatoid arthritis. In eleven cases the diagnosis was made on clinical grounds, while the diagnosis was confirmed only at post-mortem in two patients. Pleural effusions were present in seven patients, while pulsus paradoxus was found in only one case. Echocardiograms were undertaken in ten patients and all showed evidence of pericardial effusions, which were usually small and sited posteriorly. A delayed ventricular filling pattern indicating abnormal ventricular relaxation was seen in two patients with cardiac tamponade. The surviving 11 patients were reviewed a median of three years after diagnosis of their pericardial disease. Pericardectomy had been performed in six, all of whom were asymptomatic and had a normal chest radiograph. Steroids alone had been given to the other five, and three of these remained dyspnoeic with cardiomegaly. The clinical features distinguishing chronic pericardial disease from other causes of right heart failure in rheumatoid arthritis patients are subtle. As management is fundamentally different, serious consideration should be given to the diagnosis of chronic pericardial disease in any patient with rheumatoid arthritis who presents with right-sided heart failure.

Adult↗

PubMed1989

Neoadjuvant chemotherapy in marginally resectable stage III M0 non-small cell lung cancer: long-term follow-up in 41 patients.

Forty-one patients with marginally resectable stage III M0 non-small cell lung cancer (NSCLC) were entered into a study evaluating neoadjuvant cyclophosphamide, adriamycin, and cisplatin chemotherapy (CAP) followed by radiotherapy and subsequent resection. Postoperative radiotherapy and additional CAP were also administered. The objective disease regression rate prior to surgery was 72% (2 complete, 12 partial, and 7 minimal responses). Thoracotomy was carried out in 37 patients (90%), with resection of all gross disease in 36 patients (97%). Relapse occurred in 22 (61%) of the resected patients, involving chest only (four patients), chest and extra thoracic (nine patients), and extra thoracic only (nine patients). Subsequent CNS relapse developed in 9 (25%) of 36 postop patients in association with other sites of relapse (five patients) or as a solitary location (four patients). Only one of seven patients receiving prophylactic cranial irradiation (PCI) developed CNS relapse compared with 7 (26%) of 27 patients not receiving PCI. The median long-term follow-up for 14 living patients is 53+ months, with a rang of 38+ to 71+ months. Median survival for all patients is 32 months, with 1-year survival being 75%. The survival curve shows a plateau of 31% from 3 to 5+ years. Using a log rank test, no prognostic subgroups could be identified that significantly affected response rate, disease-free survival, or overall survival. While neoadjuvant CAP followed by radiotherapy appears to improve survival, more effective chemotherapy along with randomized studies are needed to determine the role of initial chemotherapy in marginally resectable NSCLC.

Adult↗

PubMed1989

Chromosome 22 abnormalities in Ewing's sarcoma.

A child with disseminated Ewing's sarcoma underwent cytogenetic investigations which showed different structural rearrangements of chromosome 22 at diagnosis (?ring22), and at relapse [t(10;22)], but the classic translocation t(11;22) was not detectable. This case provides further evidence of the importance of chromosome 22 in this disease, while raising some questions about the central importance of the translocation between chromosomes 11 and 22.

Bone Neoplasms↗

PubMed1988

Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light.

Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and physical retardation. Some patients are photosensitive. A previous study by Stefanini et al. (Hum. Genet., 74: 107-112, 1986) showed that cells from four photosensitive patients with TTD had a molecular defect in DNA repair, which was not complemented by cells from xeroderma pigmentosum, complementation group D. In a detailed molecular and cellular study of the effects of UV light on cells cultured from three further TTD patients who did not exhibit photosensitivity we have found an array of different responses. In cells from the first patient, survival, excision repair, and DNA and RNA synthesis following UV irradiation were all normal, whereas in cells from the second patient all these responses were similar to those of excision-defective xeroderma pigmentosum (group D) cells. With the third patient, cell survival measured by colony-forming ability was normal following UV irradiation, even though repair synthesis was only 50% of normal and RNA synthesis was severely reduced. The excision-repair defect in these cells was not complemented by other TTD cell strains. These cellular characteristics of patient 3 have not been described previously for any other cell line. The normal survival may be attributed to the finding that the deficiency in excision-repair is confined to early times after irradiation. Our results pose a number of questions about the relationship between the molecular defect in DNA repair and the clinical symptoms of xeroderma pigmentosum and TTD.

Cell Survival↗

PubMed1988

Observations on the causes of rheumatoid arthritis.

Inflammatory, symmetrical peripheral polyarthritis is observed in a small proportion of patients following a variety of parasitic, viral and microbial infections. The development of such a post-infective arthritis disorder may depend on a sequence of events, which need not be confined to one extrinsic pathogenic organism.

Arthritis, Infectious↗

PubMed1987

The tertiary structure of salt-extracted ribosomal proteins from Escherichia coli as studied by proton magnetic resonance spectroscopy and limited proteolysis experiments.

Ribosomal proteins from Escherichia coli have been isolated by a mild purification procedure. Their tertiary structure has been explored by two techniques, proton magnetic resonance and limited proteolysis. A number of proteins when subjected to limited proteolysis produce resistant fragments in good yields. In most cases this does not depend on the specificity of the enzyme used. The proteins S15, S16, S17 and L30 are not degraded at all, whereas a few proteins are very susceptible to proteolysis. 1H-NMR experiments show that the majority of the ribosomal proteins have a uniquely folded tertiary structure. This is particularly pronounced in the four proteins mentioned above which resist proteolysis. In general, a good agreement is observed between the degree of proteolytic resistance and the amount of folding indicated by NMR spectroscopy. Similar studies on a few ribosomal proteins purified under denaturing conditions show that, in contrast, these protein preparations are not structurally homogeneous and that they contain a mixture of denatured and renatured molecules. The results are interpreted in terms of a compactly folded tertiary structure for the four proteinase-resistant proteins while the majority of the other proteins appear to have two domains, one compactly folded and resistant to proteinase and the other flexible and susceptible to proteolysis. A few proteins seem to have a completely flexible structure and can therefore be easily degraded.

Bacterial Proteins↗

PubMed1985

Acid modification of thermal damage and its relationship to nutrient availability.

The purpose of this present investigation was to determine if the presence of exogenous nutrients constitutes a prerequisite for acid modification of thermal damage and to determine if thermal cytotoxicity is affected by nutrient availability under acid conditions. To this end, Chinese hamster ovary cells (CHO) were heated (42 degrees or 43 degrees C) and/or irradiated in either McCoy's medium containing 10% fetal bovine serum or glucose free Hanks Balanced Salt Solution (HBSS). Both thermal sensitivity and thermal radiosensitization were increased when CHO cells were treated under acid conditions (e.g., pH 6.8) compared to alkaline conditions (e.g., pH 7.2), independent of the media used. Furthermore, decreasing nutrient availability increased thermal cytotoxicity, but the increase was greatest at pH 7.2 compared to pH 6.8. This study indicates that thermal sensitivity is more dependent upon pH than upon nutrient availability.

Animals↗

PubMed1985

Combination chemotherapy followed by radiation therapy in patients with regional stage III unresectable non-small cell lung cancer.

A chemotherapy combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was administered to 30 patients with stage III M0 or M1 (supraclavicular nodes) unresectable non-small cell lung cancer before and after radiotherapy. All patients had mediastinal metastases and most had T2 or T3 primary lesions. The response rate (complete plus partial) after two cycles of CAP was 47%, which increased to 66% (24% complete response rate) following radiotherapy. The overall median survival from initiation of chemotherapy was 9 months. CNS relapse occurred in five (26%) of 19 responding patients who did not receive prophylactic cranial irradiation in the early part of the study.

Adenocarcinoma↗

PubMed1985