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Biomedical subjects

D B Thomas

Publications and source records attributed to D B Thomas.

At least 127 records · Page 7Linked to original sources

The effects of changes in health care delivery on the reported incidence of cutaneous melanoma in western Washington State.

The reported incidence of malignant melanoma of the skin has steadily increased in the United States during the past three decades. Since the treatment of melanoma increasingly has been provided solely on an outpatient basis in recent years, it is likely that some cases of this disease are being missed by population-based tumor registries that do not consistently ascertain cases from sources outside the hospital setting. The population-based tumor registry of western Washington state has been identifying office-treated cases of cutaneous melanoma from records of private and hospital pathology laboratories. However, since laboratory records have often lacked information on place of residence, these cases have not been previously included in the calculation of incidence rates. In the present study, by determining the place of residence of these cases at the time of their diagnosis (by contacting the physician listed on their pathology reports), the authors found that there had been a growing amount of underreporting of cutaneous melanoma from 1974 through 1984. In western Washington state, the incidence of melanoma of the skin had been underestimated in registry rates by approximately 2% in 1974 and approximately 21% in 1984. This trend in the level of underenumeration has spuriously blunted the true increasing incidence of melanoma and may limit the ability to monitor and study this disease in the future.

Delivery of Health Care↗

Breast cancer in Argentina: case-control study with special reference to meat eating habits.

An exploratory case-control study of the role of diet in the etiology of breast cancer was conducted in Buenos Aires, Argentina, where the mortality rate for this disease is high and the consumption of meat, mainly beef, is unusually elevated (76.2 kilograms per head were reported for 1987). One hundred and ninety-six women with breast cancer admitted to the Institute of Oncology "Angel H. Roffo" and 205 controls were interviewed to obtain information on demographic, socio-economic and reproductive variables, on frequency of consumption of 40 food items, and on methods of cooking. Special emphasis was given to different kinds of meat. After controlling for other risk factors for breast cancer the major dietary associations observed were a statistically insignificant trend of increasing risk with amount of beef consumed, an increase in risk in women who ate more than 3 eggs per week, and an increase in risk in women who ate a variety of fried foods.

Adult↗

The role of the endoplasmic reticulum in antigen processing. N-glycosylation of influenza hemagglutinin abrogates CD4+ cytotoxic T cell recognition of endogenously processed antigen.

Evidence is presented for an endogenous route of Ag processing for CD4+ T cell recognition of influenza hemagglutinin that requires obligatory traffic of de novo synthesized hemagglutinin across the lumen of the endoplasmic reticulum for processing in a cytosolic compartment. I-Ad-restricted T cell clones that recognize synthetic peptides corresponding to two distinct antigenic regions of the HA1 subunit, HA1 56-76 and HA1 177-199, are cytotoxic and, dependent on epitope specificity can recognize endogenously processed Ag and lyse class II+ target cells infected with a recombinant vaccinia-X31 HA virus. HA1 56-76 specific T cell clones fail to recognize (target cells infected with) influenza X31 viruses, containing a single residue change, HA1 63 Asp----Asn that introduces an oligosaccharide attachment site: Asp63Cys64Thr65. Recognition is restored, however, by tunicamycin treatment of mutant virus infected target cells. Inasmuch as N-glycosylation of nascent hemagglutinin polypeptides occurs in the lumen of the endoplasmic reticulum, this indicates a route of endogenous processing for hemagglutinin, requiring transport across the endoplasmic reticulum, which has been confirmed by the failure of CD4+ T cells to recognize a recombinant VACC-hemagglutinin virus in which the same single residue change, HA1 63 Asp----Asn has been introduced by site directed mutagenesis.

Amino Acid Sequence↗

Defects in antigen presentation of mutant influenza haemagglutinins are reversed by mutations in the MHC class II molecule.

A functional analysis was undertaken of the effects of mutating single amino acid residues in the alpha chain of the I-Ak molecule (to alanine; residues 50-79) on the ability of I-Ak transfectants to process and present influenza haemagglutinin to CD4+ T cell clones specific for two major antigenic sites of the HA1 subunit. In each instance, T cells were insensitive to a majority of substitutions in Ak with the exception of a few critical residues that differed for individual T cell clones. But more significantly, the failure of T cell clones to respond to mutant influenza viruses, containing drift substitutions within a T cell recognition site, in association with wild type I-Ak, could be reversed by single substitutions in Ak alpha. A T cell clone specific for HA1 120-139 failed to respond to a laboratory mutant virus (HA1 135 Gly----Arg) whereas optimal responses were observed with a mutant Ak transfectant (Ak alpha 56 Arg----Ala). Similarly, mutant transfectant 62 (Ak alpha 62 Gly----Ala) was able to present a natural variant virus A/TEX/77 to a T cell clone specific for HA1 48-67. We propose that Ak alpha 56 and Ak alpha 62 increase the affinity of association of mutant HA1 peptides for class II and therefore confer T cell recognition of variant viruses.

Amino Acid Sequence↗

Antibody response to pneumococcal polysaccharide vaccine in myasthenia gravis: effect of therapeutic plasmapheresis.

The removal of specific antibody in experimental animals has been reported to result in a subsequent increase in antibody to levels equal to (rebound) or exceeding those existing prior to removal (overshoot). Anecdotal reports suggest that rebound antibody synthesis after plasmapheresis may occur in humans with autoimmune disorders. We measured the antibody response to 12 pneumococcal polysaccharide antigens in patients with myasthenia gravis (MG) receiving a variety of therapies in order to determine whether the T-cell-independent IgG response to these antigens was augmented by plasmapheresis. MG patients receiving no immunotherapy or receiving prednisone had pre- and post-immunization titers similar to those of control patients. MG patients receiving prednisone and chronic plasmapheresis had higher pre-immunization titers than did other patient groups and had significantly higher post-immunization titers against multiple pneumococcal serogroups. Aggregate post-immunization geometric mean titers were more than three-fold higher in the plasmapheresis group as compared with other MG treatment groups. Enhancement of antibody response by plasmapheresis was abolished by the concomitant administration of azathioprine. Antibody rebound and overshoot after antibody removal may have important implications for the therapy of immune disorders by plasmapheresis.

Adult↗

Age distribution of adult female screwworms (Diptera: Calliphoridae) captured on sentinel animals in the coastal lowlands of Guatemala.

The age structure of screwworm, Cochliomyia hominivorax (Coquerel), populations was studied in the Guatemalan lowlands with the pteridine technique of age determination. Flies (95% were 4-15 d old) were captured on sentinel animals. Mean age was 7.5 d. The oldest fly captured was 21 d old. Most flies visiting wounds were reproductively mature females. Of these, about one-half oviposited once, one-third oviposited twice, and 1 in 10 completed three ovarian cycles (assuming a 3-d interval between clutches). Periodicity in adult capture rates may be related to the reproductive cycle. Results suggest that local populations are composed of a high proportion of synchronized cohorts.

Animals↗

Cigarette smoking and acute nonlymphocytic leukemia.

In a case-control study of acute nonlymphocytic leukemia in western Washington state, cigarette smokers experienced a twofold increased risk of acute nonlymphocytic leukemia compared with nonsmokers. Risk increased significantly with the number of pack-years smoked (p = 0.0008) and decreased with the number of years stopped smoking (p = 0.15). The increased risk in smokers appeared to be limited to those who inhaled into the chest. The authors suggest that further studies of this potential relation are warranted, especially since the prevalence of cigarette smoking is relatively high in our society.

Case-Control Studies↗

Single amino acid residues in a synthetic peptide of influenza haemagglutinin, HA 1 177-199, distinguish I-Ad- and I-Ed-restricted T-cell epitopes.

A majority of Iad-restricted, CD4+ T-cell clones, derived from BALB/c mice infected with X31 (H3N2) influenza virus and specific for the HA 1 subunit of the viral haemagglutinin (HA), has previously been shown to recognize the synthetic peptide HA 1 177-199, corresponding to the primary amino acid sequence of a major antibody binding site. Here it is demonstrated that both I-Ad- and I-Ed-restricted T-cell clones recognize HA 1 177-199, and that inter- and intra-allelic differences in Iad-restricted recognition are defined by single amino acid residues. A panel of truncated HA 1 synthetic peptides defined three distinct but overlapping CD4+ epitopes within the common antigenic site (HA 1 177-199): two I-Ad-restricted epitopes mapped within HA 1 186-198 and HA 1 177-199, and peptide HA 1 178-195 identified an I-Ed-restricted epitope. Moreover, fine specificity differences in the recognition of synthetic peptides, truncated at the carboxy terminus of HA 1 177-199, identified residues HA 1 A 198 and HA 1 S 199 as being critical for defining inter- and intra-allelic differences, respectively, in the Iad-restricted T-cell recognition of HA.

Amino Acids↗

Regulation of haematopoietic stem cell proliferation by stimulatory factors produced by murine fetal and adult liver.

Haematopoietic stem cells in murine fetal liver are in a proliferative state unlike those in normal bone marrow which are quiescent. A regulatory activity is produced by cells in the fetal liver which will switch quiescent normal bone marrow haematopoietic stem cells into cell cycle in vitro. This regulator from Day 15 fetal liver cells is produced by adherent cells and by cells fractionated on a Percoll gradient in the 1.064 and 1.076 g per cm3 density bands but not in the 1.123 g per cm3 band. Colony-stimulating factor cannot be detected in the supernatants containing the stem cell regulatory activity. The stimulator can be detected in supernatants produced from cell suspensions of liver cells at Day 15 and Day 17 of gestation and 24 hours and 72 hours after birth. However by 1 week after birth the production of the stimulator decreases and is undetectable 3 and 10 weeks after birth. The total numbers of haematopoietic stem cells (CFU-S) in fetal liver decrease from Day 15 of gestation and only small numbers are present 1 week after birth. Thus the decline in the production of haematopoietic stem cell proliferation stimulator correlates with the decrease in haematopoietic stem cell numbers in the liver through gestation and after birth.

Animals↗

A case-control study of risk factors for sarcomas of the uterus. The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives.

Using data collected as part of the hospital-based World Health Organization (WHO) Collaborative Study of Neoplasia and Steroid Contraceptives, the authors examined potential risk factors for sarcoma of the uterus. Twenty-nine patients with uterine sarcoma who were between 15 and 56 years of age and diagnosed at one of nine centers were matched on age and center to 198 controls selected from hospital admissions to other than obstetric and gynecologic wards. All women were interviewed regarding their medical and reproductive history, methods of birth control, and history of sexual relationships and of sexually transmitted infections. The risk of uterine sarcoma was lower in parous women compared to nulliparous women (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.1, 3.3), and the risk decreased with increasing number of live births. A greater proportion of cases than controls reported giving birth to their first child at the age of 25 or later, even after adjustment for parity (OR = 3.5; 95% CI = 1.2, 10.9). Cases were also more likely than controls to report a history of a spontaneous abortion (OR = 2.5; 95% CI = 0.8, 7.4) or an induced abortion (OR = 1.6; 95% CI = 0.4, 6.3). Late menarche and early menopause were both positively associated with the risk of uterine sarcoma. No association was observed with a history of infertility, use of oral contraceptives, or measures of sexual activity. The findings with respect to childbearing and menstrual history differ from those of a recent cohort study, and indicate the need for larger investigations to assess the role of these and other risk factors in the occurrence of sarcomas of the uterus.

Abortion, Spontaneous↗

Differences in incidence rates of cancers of the respiratory tract by anatomic subsite and histologic type: an etiologic implication.

Data from nine population-based cancer registries participating in the Surveillance, Epidemiology, and End Results Program (1973-1982) were analyzed to determine whether the incidence of different histologic types of respiratory tract cancers varies by anatomic location. The variation in cancer incidence among respiratory tract subsites was remarkable for squamous cell carcinoma, but the variation was less prominent for adenocarcinoma. The rates of squamous cell carcinoma and adenocarcinoma along the airways correspond closely with the deposition pattern of large and small smoke particles, respectively. Also, the rates of adenocarcinoma parallel the distribution of surface glandular cells of the respiratory tract. Our results support the hypothesis that anatomy and physiology, in conjunction with size of particles in inhaled cigarette smoke, play an important role in the genesis of specific histologic types of respiratory tract cancers.

Adenocarcinoma↗

I-Ad restricted T cell recognition of influenza hemagglutinin. Synthetic peptides identify multiple epitopes corresponding to antibody-binding regions of the HA1 subunit.

In a recent study, we reported extensive diversity in the Iak-restricted T cell repertoire for the hemagglutinin molecule (HA) of influenza A viruses (H3 subtype). Synthetic peptides identified six nonoverlapping epitopes on the HA1 subunit, and CD4+ T cell clones, specific for these regions, discriminated between natural variant viruses that had accumulated amino acid substitutions during antigenic drift. Here, we demonstrate similar specificity and diversity for the Iad haplotype and have identified multiple T cell epitopes within the sequences HA1 56-76, 71-91, 81-97, 177-199, 186-205, and 206-227. These also include recognition sites for neutralizing antibodies and correlations can be made between antigenic drift substitutions in H3 subtype viruses and the specificity of individual CD4+ clones for mutant HA. Moreover, these peptides appear not to exhibit structural homology and fail to compete for Ag presentation, indicating heterogeneity in peptide-Ia interaction. To explain the observation that CD4+ T cells, from two major haplotypes, recognize antibody binding regions of the HA molecule, we propose that surface Ig receptors of the Ag-specific B memory cell exert a direct effect on the processing of HA peptides and subsequent selection of the class II-restricted T cell memory repertoire after natural infection.

Amino Acid Sequence↗

Histologic types of breast carcinoma in relation to international variation and breast cancer risk factors. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

Associations between breast cancer risk factors and histologic types of invasive breast carcinoma were studied in 2,728 patients. Lobular and tubular carcinomas occurred with increased relative frequency in most high-risk groups. The proportion of these types increased with age to a maximum at 45-49 years and decreased in the following decade. Significantly increased proportions of lobular and tubular carcinomas were also associated with high-risk countries, prior benign breast biopsy, bilateral breast cancer, concurrent mammary dysplasia, high age at first live birth, never-pregnant patients compared to those with a first live birth before age 20, private pay status, and length of education. Nonsignificant increases were associated with family history of breast cancer, less than 5 live births, less than 25 months total of breast feeding, use of oral contraceptives or IUD, and high occupational class. As a general trend, the higher the overall relative risk, the higher the proportion of lobular and tubular carcinomas. The occurrence of other histologic types also increased with increased breast cancer risk, but to a smaller degree than for lobular/tubular carcinomas. It is suggested that all hormonally related, socio-economic and geographic risk factors exert their effect by selectively increasing number of lobular cells at risk. Family history of breast carcinoma and age over 49 years did not follow the general trend parallel increases in the proportion of lobular/tubular carcinomas and breast cancer risk, and may operate through other mechanisms.

Adult↗

Diversity of the class II (I-Ak/I-Ek)-restricted T cell repertoire for influenza hemagglutinin and antigenic drift. Six nonoverlapping epitopes on the HA1 subunit are defined by synthetic peptides.

H-2k-restricted T cell clones derived from CBA mice infected with X31 (H3N2) influenza virus, were shown to recognize distinct, nonoverlapping sequences within the HA1 subunit of the viral hemagglutinin (HA) using synthetic peptides. Three I-Ak-restricted T cell sequences were identified within HA1 68-83, 120-139, and 269-288, and two recognition sites presented in the context of the I-Ek molecule were mapped to HA1 sequences 226-245 and 246-265. T cell clones specific for these regions of HA1 demonstrated varying abilities to differentiate between natural variant viruses that had accumulated substitutions within their HA molecules as a result of antigenic drift. Clones that recognized sequences HA1 226-245 and HA1 246-265 failed to discriminate between natural variants and focused on conserved sequences within these epitopes. A majority of T cell clones were sensitive to amino acid substitutions that have featured in antigenic drift occurring within three major antigenic sites of the HA1 subunit; substitutions at HA1 residues 78 (V)/83(K) and 275(D)/278(I) within the HA1 subunit of mutant viruses correlated with a 75% reduction in the proliferative response for T cell clones specific for sequences HA1 68-83 and HA1 269-288, respectively. Furthermore, a clone that recognized HA1 120-139 was nonresponsive to a mutant virus HK/71, implicating amino acids at HA1 position 129(G) and/or 132(Q) within this sequence as crucial for recognition. Our data, together with the previous finding that sequence HA1 53-63 is also a major I-Ak-restricted T cell recognition site, demonstrate a level of diversity in the T cell recognition of influenza HA, within a single mouse haplotype hitherto unrecognized, and imply that the T cell repertoire diversity against foreign antigens may be greater than previously assumed. Furthermore, the frequency at which HA-specific T cells have been identified that focus on amino acids within the HA1 subunit of HA also featuring in antigenic drift, suggests that a failure of MHC class II-restricted T cells to recognize specific epitopes within mutant HA molecules may contribute significantly to the capacity of variant influenza viruses to evade immune recognition.

Amino Acid Sequence↗

The immune response of BALB/c mice to influenza hemagglutinin: commonality of the B cell and T cell repertoires and their relevance to antigenic drift.

An extensive analysis of the class II (I-Ad)-restricted T cell repertoire for influenza hemagglutinin (HA) of the H3 subtype, elicited by natural infection, has shown that majority of CD4+ memory T cell clones focus on antibody-binding regions of HA, sites B and E, and are sensitive to the residue substitutions that have occurred in these regions during antigenic drift. The proliferative responses of CD4+ clones to synthetic peptides have identified T cell epitopes within site B, HA1 177-199 and HA1 182-199, and site E. HA1 56-76. The recognition specificity of T cell clones for antibody-selected mutant viruses, with single amino acid substitutions within these recognition sites identified residues 63, 189, 193 and 198 as being important for T cell recognition and thus established that BALB/c, CD4+ T cell clones were sensitive to the same substitutions known to abrogate BALB/c antibody recognition of the native HA. Our findings indicate extensive commonality of the B cell and T cell repertoires for HA, which may be relevant to an understanding of the immune pressures for antigenic drift, and, moreover, suggest that the antigen-specific B memory cell may be instrumental in selection of the peripheral T cell repertoire.

Animals↗

The structural requirements for class II (I-Ad)-restricted T cell recognition of influenza hemagglutinin: B cell epitopes define T cell epitopes.

A majority of I-Ad-restricted CD4+ clones elicited by influenza X31 (H3N2) virus infection, recognize a synthetic peptide of hemagglutinin (HA) corresponding to an antibody binding region of the HA1 subunit (site B: HA1 177-199). The structural requirements for class II-restricted T cell recognition were investigated by determining the proliferative responses of representative CD4+ clones to truncated HA1 peptides and synthetic peptide analogues. Two distinct T cell epitopes were identified and CD4+ clones, specific for either determinant, were sensitive to the same single amino acid substitutions in synthetic peptides at HA1 193 S----N or HA1 198 A----E, that had featured in antigenic drift and abrogated antibody binding to native HA. Competitive inhibition studies, between stimulatory HA1 peptides and non-stimulatory analogue peptides, for antigen presentation to CD4+ clones established that the 193 S----N and 198 A----E substitutions could affect either interaction with the T cell receptor or class II molecule, according to the specificity of the CD4+ clone examined. The structural requirements for class II-restricted T cell recognition of the linear sequence determinants of HA are, therefore, integrally linked to conformation-dependent antibody recognition of the native molecule.

Amino Acid Sequence↗

Differences in the sex ratio of laryngeal cancer incidence rates by anatomic subsite.

The incidence data from nine population-based cancer registries participating in the Surveillance, Epidemiology and End Results program in the U.S. suggest that squamous cell carcinoma arising from different parts of the larynx have different etiologic influences. The male to female rate ratio for laryngeal cancers was substantially higher in the glottic region (9.2 among whites and 11.8 among blacks) than in other subsites (approx. 3-5 in both races). The sex rate ratios were uniformly higher for glottic tumors in all age groups, and these ratios increased more rapidly with age for glottic than for supraglottic tumors. Factors that are closely related to sex other than smoking and drinking behavior are responsible for the considerably high ratio of male to female rates of the glottic tumors. Future etiologic studies should investigate the possible differential effect of hormonal or other sex-related factors on different anatomic subsites within the larynx.

Alcohol Drinking↗

Acute myelocytic leukemia and prior allergies.

The relationship between prior allergies and adult acute myelocytic leukemia was investigated in a population-based case-control study. Based on data from personal interviews of 98 cases and 133 controls, a history of any type of allergy was associated with a significantly decreased risk of acute myelocytic leukemia (OR = 0.35, 95% CI = 0.20-0.60). Risk declined with the total number of specific allergies reported (p less than 0.001), and was reduced in relation to a history of prior asthma, eczema and hives. The implications of these findings in relation to natural immune surveillance against developing neoplasms are discussed.

Adult↗