Exploring cancer register data to find risk factors for recurrence of breast cancer – application of Canonical Correlation Analysis

Background  

A common approach in exploring register data is to find relationships between outcomes and predictors by using multiple regression analysis (MRA). If there is more than one outcome variable, the analysis must then be repeated, and the results combined in some arbitrary fashion. In contrast, Canonical Correlation Analysis (CCA) has the ability to analyze multiple outcomes at the same time.     

Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and -DRB1 genomically identical volunteers?

The aim of this study was to identify significant prognostic factors by using unrelated genomically HLA-A, -B and -DRB1-identical donors. Such data could help to choose the best donor. We studied 136 consecutive patients with hematologic malignancies and a median age of 32 years (range, 0-55 years) who received hematopoietic stem cell transplantation. Bone marrow grafts were given to 83 and peripheral blood stem cells to 53 patients. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 30% and of chronic GVHD was 54%. At 5 years, the overall transplant-related mortality (TRM) was 34%, and patient survival was 50%. In Cox multivariate analysis, 32 potential risk factors were analyzed. Monoclonal antibody OKT-3 during conditioning was correlated with grade II to IV acute GVHD, chronic GVHD, and TRM. HLA-DP mismatch was associated with poor TRM and poor survival. Cytomegalovirus-seropositive patients with a seronegative donor had a decreased leukemia-free survival. Five-year TRM was 14% with no risk factor, 38% with 1 risk factor, and 87% with 2 risk factors. The 5-year survival was 72%, 48%, and 30% with 0, 1, and 2 risk factors, respectively. We concluded that unrelated hematopoietic stem cell transplantation may be improved if an optimal donor and immunosuppression are chosen.     

Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation.

Mesenchymal stem cells (MSCs) may be derived from adult bone marrow, fat, and several fetal tissues. In vitro, MSCs can be expanded and have the capacity to differentiate into several mesenchymal tissues, such as bone, cartilage, and fat. They escape the immune system in vitro, and this may make them candidates for cellular therapy in an allogeneic setting. They also have immunomodulatory effects, inhibit T-cell proliferation in mixed lymphocyte cultures, prolong skin allograft survival, and may decrease graft-versus-host disease (GVHD) when cotransplanted with hematopoietic stem cells. MSCs induce their immunosuppressive effect via a soluble factor. Some candidates have been suggested, and various mechanisms have also been suggested, although contradictory data exist; this may be due to differences in the cells and systems tested. A major problem has been that it has been difficult to identify and isolate MSCs after transplantation in vivo. However, MSCs seem to enhance hematopoietic engraftment in recipients of autologous and allogeneic grafts. Recently, they were found to reverse grade IV acute GVHD of the gut and liver. No tolerance was induced, however. Controlled studies are warranted. Thus, in allogeneic stem cell transplantation, MSCs may be used for hematopoiesis enhancement, as GVHD prophylaxis, and for the treatment of severe acute GVHD. They are also of potential use in the treatment of organ transplant rejection and in autoimmune inflammatory bowel disorders where immunomodulation and tissue repair are needed.     

Repertoires of antibodies to culture filtrate antigens in different mouse strains infected with Mycobacterium bovis BCG.

Two susceptible (Bcgs) mouse strains, BALB/c and C57BL/6, were compared by Western blot (immunoblot) analysis for their immunoglobulin G response to 14-day-old BCG culture filtrate (CF) following intravenous infection with live Mycobacterium bovis BCG. The two strains demonstrated a completely different antibody repertoire. BALB/c antibodies were directed against a wide range of CF antigens between 20 and about 100 kilodaltons (kDa), with a preferential recognition of the 65-kDa heat shock protein and the 32-kDa fibronectin-binding protein. C57BL/6 sera, on the other hand, showed a much more restricted antibody pattern, almost exclusively directed against three antigens with estimated molecular sizes of 37, 38, and 40 kDa. Whereas the 37- and 38-kDa antigens were also recognized by BALB/c mice, the 40-kDa antigen was very intensely stained by C57BL/6 sera only. F1 mice had the restricted antibody pattern of C57BL/6 after one injection of BCG and had a hybrid BALB/c-C57BL/6 phenotype following a boost injection of BCG 2 months after the initial infection. Analysis of seven recombinant inbred strains derived from the BALB/c x C57BL/6 cross and of congenic mice differing in major histocompatibility complex-coding chromosome 17 fragments suggests that a gene in the K-IA region of the H-2 locus is associated with the preferential recognition of certain CF antigens. Inoculation with the same dose of killed BCG failed to elicit an antibody response to these filtrate antigens.     

The DQA1*0104 allele is carried by DRB1*1001- and DRB1*1401-positive haplotypes in Caucasians, Africans and Orientals

Abstract: The DQA1*0104 allele is known to differ from DQA1*0101 by a single nucleotide in the sequenced part of the first exon. DQA1*0104 has a guanine in the second position of the second expressed codon, whereas DQA1*0101 and all other sequenced DQA1 alleles have an adenine in that position, changing aspartic acid to glycine. The DQA1*0104 allele was originally described in African Americans with the DRB1*12, DRB3*0101, DQA1*0104, DQB1*0501, DRB1*12, DRB3*0202, DQA1*0104, DQB1*0605 or DRB1*14, DQA1*0104, DQB1*0503 haplotypes. When developing DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP), we observed that all DR10- and DR14-positive samples carried the DQA1*0104 allele, wheres all DRB1*01 -positive DNAs carried the closely related DQA1*0101 allele. In the present study, samples representing the major ethnic groups with DR-DQ haplotypes known to carry the DQA1*0104 allele or the very similar DQA1*0101 allele were investigated by Taq I RFLP analysis, PCR-SSP typing and nucleotide sequencing. The DQA1*0104 allele was found to differ from DQA1*0101 not only in the second expressed codon, but also by a productive mutation in the signal peptide. All investigated DRB1*1001 -(n = 24) and DRB1*1401 -positive (n = 25) haplotypes, defined by homozygosity or association, of Caucasian, African or Oriental origin carried the DQA1*0104 allele, whereas the DQA1*0101 allele was found on all DRB1*01 -positive (n = 32) haplotypes. These findings demonstrate that in the assignment of HLA class II alleles, polymorphism outside the second exon sometimes must be considered. The maintenance of the DQA1*0104 allele on a few distinct haplotypes indicates that the allele is old and might also be compatible with a functional difference between the DQA1*0101 and DQA1*0104 alleles.     

Jejunal endocrine tumour composed of somatostatin and gastrin cells and associated with duodenal ulcer disease

Summary A case of malignant endocrine tumour of the jejunum, associated with severe duodenal ulcer is described. The tumour and a local metastasis were examined by immunohistochemistry and found to contain abundant somatostatin-immunoreactive cells together with less numerous cells displaying gastrin immunoreactivity. This is to our knowledge the first case of intestinal somatostatinoma. The presence of gastrin cells in the tumour may explain the ulcer diathesis.     

Stereoselective inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by 4-dimethylamino-2,α-dimethylphenethylamine (FLA 336)

Summary The in vitro inhibition by amiflamine [FLA 336(+)] and related compounds of the activity of rat monoamine oxidase (MAO)-A and-B, rat semicarbazide sensitive amine oxidase (SSAO) and human platelet poor plasma benzylamine oxidase was studied. Amiflamine was an MAO-A selective inhibitor, but also inhibits SSAO with both a reversible (competitive, K _i=200 mol/l) and a small time-dependent component which was irreversible in nature. The optical isomer FLA 336(–) was ten times less potent towards MAO-A. However, this compound was much more potent an inhibitor of SSAO (competitive, K _i=4.6 mol/l). The amiflamine metabolites FLA 788(+) and FLA 668(+) inhibited SSAO, but only at concentrations considerably higher than required for MAO-A inhibition. Ex vivo experiments indicated that there was no significant irreversible inhibition of rat heart and lung SSAO after both single and repeated administration of amiflamine at doses up to 20 times higher than required for inhibition of MAO-A within central serotoninergic neurones.