Major histocompatibility complex status in breast carcinogenesis and relationship to apoptosis

Major histocompatibility complex (MHC) molecules are of central importance in regulating the immune response against tumors. In this study we used immunohistochemistry to study human leukocyte antigen (HLA) class I and II antigen expression in normal breast tissues and benign, preneoplastic, primary, and metastatic breast lesions using antibodies against beta-2-microglobulin (beta2-m), heavy-chain, and HLA-DR antigens. Whereas all normal tissues and benign lesions were positive for beta2-m and HLA-A, -B, and -C antigens, total loss of HLA class I antigens was found in 37% (11 of 30) of in situ carcinomas, in 43% (56 of 131) of the primary tumors, and in 70% (31 of 45) of the lymph node metastases. HLA-DR was also underexpressed in breast cancer cells; thus 20% (6 of 30) of in situ carcinomas, 15% of invasive carcinomas (20 of 131), and only 1 metastatic case were positive for this antigen. Both HLA class I and II antigen expression were more frequently down-regulated in metastatic lesions than in primary breast lesions (P <0.05), and a tendency toward a simultaneous defective expression of HLA class I and II antigens was observed in primary carcinomas (P = 0.07). However, no correlation was found between the expression of any of the aforementioned molecules and pathological parameters or survival. Interestingly, HLA class I expression was expressed more frequently in tissues with high apoptotic activity and was significantly associated with the expression of the proapoptotic bax gene (P = 0.02), and was inversely associated with expression of the antiapoptotic bcl-2 gene (P = 0.03). We conclude that alterations in HLA class I and II antigen expression are early events in breast carcinogenesis and play significant roles in metastatic progression. In addition, their expression is correlated with apoptosis-regulating proteins, which may influence the cytotoxicity of T cells against HLA class I-specific tumor antigens.     

Tuberculosis: a current problem

Tuberculosis is a public health problem. If the current trends continue, is expected to arrive to 10.2 million of new cases in 2005. There are three studies accomplished in 1995 in Mexican patients. The results show important difficulty in the application and the follow-up of the program of control of the tuberculosis, what has caused accumulation of chronic cases, moderate rate of primary resistance and alarming levels of primary and secondary multiresistance (23%). Mechanism of protective immunity against mycobacterium tuberculosis (MTB) in humans have not been clarified. Different subpopulations of lymphocytes CD4, CD8 and other populations as well as macrophages, and monocytes, have an important role. In industrialized countries, the managing of the MDRTB is based on the use of individualized treatments with second line drugs according to susceptibility test, however the foregoing has not been possible to apply it middle or low income countries. WHO has launches the initiative "DOTS plus" that consist in the administration of a standarized regimen on the basis of epidemiology of resistance in the country or region.     

Gastroesophageal reflux in asthmatic patients: an incidence study and clinical correlation

The prevalence of gastroesophageal reflux (GER) in asthmatic patients is elevated, but the exact frequency remains unknown. The relationship between GER and asthma has not been investigated in Mexico. The objective of this study is to know the frequency of GER in Mexican asthmatic patients and the possible relationship with the severity of asthma. Fifty patients with adult-onset asthma were studied. AII of them fulfill the diagnostic criteria of the National Institutes of Health, U.S. The evaluation included a symptoms questionnaire, spirometry, esophageal manometry, 24-h esophageal pH-recording, and an upper gastrointestinal endoscopy. Twenty-three patients had mild asthma (46%), 16 moderate (32%) and 11 had severe asthma (22%). Twenty-seven (54%) reported heartburn and regurgitation at least twice a week. The esophageal pH-recording showed pathologic GER in 37 subjects (74%) and endoscopic esophagitis was found in 7 cases (14%). The pH-recording showed pathologic GER in 13 patients with mild asthma (57%), in 13 with moderate asthma (81%) and in all patients with severe asthma (100%). The frequency of GER in Mexican asthmatic patients is high and increases proportionately with the severity of asthma. This factor must be considered in the integral evaluation of these patients.     

Identification of two homologous antigenic peptides derived from L1 HPV-16 and 18 proteins specific for the HLA-B*3901 allele

Summary.  In this work we present evidence that the homologous peptides IHSMNSTIL and IHSMNSSIL derived from L1 HPV-16 and 18 proteins respectively, and with high specificity for the allele HLA-B^*3901, according with an algorithm prediction program, induced T cell stimulation in patients with advanced cervical cancer positive for HPV-16 or 18 infection and for the HLA-B^*3901 allele. Interestingly, T lymphocytes derived from a patient with HPV-18 infection and stimulated with the peptide IHSMNSTIL were capable to kill a cervical cancer cell line named Rova, derived from the tumor of the same patient. In addition, the cytotoxic activity was strongly increased when this cell line was previously treated with hrIFN-γ. These results suggest that the CTL immune response to L1 HPV-16 and 18 protein derived epitopes is maintained in patients with advanced cervical cancer within specific alleles, and opens the possibility that homologous epitopes may be used in the generation of prophylactic vaccines for cervical tumors bearing different HPV-types. Received March 4, 2002; accepted May 20, 2002     

Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor in advanced brain tumor patients: preliminary study

High levels of growth factors and their receptors have been demonstrated in human tumors. Gliomas and meningiomas are characterized by overexpression of epidermal growth factor receptor (EGF-R). Ior egf/r3, is a neutralizing murine monoclonal antibody (MAb) against EGF-R, and was generated at the Cuban Institute of Oncology. The antibody recognizes EGF-R with high affinity, inhibiting tyrosine kinase activation. A clinical trial was conducted in brain tumor patients to evaluate toxicity, immunogenicity, and clinical benefit of escalating doses of the antibody. Nine patients with histologically confirmed gliomas or meningiomas, who had active or recurrent disease after receiving conventional treatment, received four intravenous doses of ior egf/r3. Total dosages ranged from 160 to 480 mg. As inclusion criteria, radioimmunoscintigraphy with the same MAb labeled with 99mTechnetium (99mTc) was performed. Immune response against the murine antibody was also evaluated. After four doses of ior egf/r3 MAb, no significant toxicity was found, except in one patient who developed a grade 4 allergic adverse event. This reaction was probably related with previous sensitization to the same MAb and the development of human anti-mouse antibodies (HAMA) response. Despite no major objective antitumor responses, eight patients had stable disease on the 6-month evaluation, and two patients remain alive after four years of MAb therapy.     

Chlamydophila abortus (Chlamydia psittaci serotype 1) clearance is associated with the early recruitment of neutrophils and CD8(+)T cells in a mouse model

The immune mechanisms in response to Chlamydophila abortus (Chlamydia psittaci serotype 1) infection were studied in C57BL/6 and CBA mice. The infection was monitored and the following aspects of the immune response were evaluated: the nature of the leucocyte infiltrate in the liver, the percentages of polymorphonuclear neutrophils (PMNs), macrophages and lymphocytes in the spleen, and the concentrations of cytokines in serum. In addition, the serum concentrations of IgG1 and IgG2a were determined. Both mouse strains showed a Th1-like immune response, with high concentrations of IFN-gamma and minimal levels of IL-4; however, C57 mice differed from CBA mice in showing milder clinical signs and earlier resolution of infection. The greater ability of C57 mice than CBA mice to eliminate chlamydophilae was related to the establishment of an earlier innate immunity, based on a more pronounced PMN response, and on a greater presence of CD8(+)T cells.     

Two new mutations and three novel polymorphisms in the<Emphasis Type="Italic"> RB1</Emphasis> gene in Ecuadorian patients

RB1 is the gene responsible for retinoblastoma, the most common malignant intraocular tumor of infancy and early childhood. There are no reports about this gene in Ecuadorian populations, and only a few studies have been published in Latin America about this subject. There is a spectrum of more than 370 mutations described in the RB1 gene mutation database (http://www.d-lohmann.de/Rb/mutations.html), and alterations have been found in 25 of the 27 exons. During the exon-by-exon analysis of 31 tumor and blood samples from Ecuadorian patients, we found two new mutations and three novel polymorphisms. One of the polymorphisms is located in intron 26 where no alterations of the gene have been described previously. The polymorphisms were found in all of the patients tumor samples, but not in normal population, suggesting there might be a relationship between these polymorphisms and the development of retinoblastoma in the Ecuadorian population.The nucleotide sequence data reported are available in the GenBank database under the accession numbers: AY243567, AY260472, AY260473, AY273783     

Extended-spectrum beta-lactamases in clinical isolates of enterobacteria in Mexico

Resistance to extended-spectrum cephalosporins within members of the family Enterobacteriaceae occurs virtually world-wide. Nevertheless, nothing was known about this problem among isolates from Mexico. To address this issue, we studied oximino-cephalosporin resistant isolates of Klebsiella pneumoniae (13), Escherichia coli (7), and Enterobacter cloacae (23) recovered from patients in Mexico City hospitals during 1990 to 1992. In the presence of clavulanic acid, these strains increased susceptibility to cefotaxime and ceftazidime (MIC90 64 and >256 microg/ml, respectively). The ability of these isolates to transfer resistance to both antibiotics by conjugation was most successfully demonstrated by K. pneumoniae. In all the clinical isolates tested, the largest plasmid coded for the extended-spectrum beta-lactamases (ESBL). Characteristics of pI, by isoelectric focusing (IEF)/bioassay and DNA hybridization with specific probes of TEM and SHV, indicated that in most of the clinical isolates and all transconjugates, the most frequent beta-lactamase coded were SHV-derived (20 strains as 41% of isolates) and a plasmid-encoded beta-lactamase (12 strains as 25% of isolates) (with a pI of >8.2), which is not related to TEM/SHV. Apparently, isolates from Mexico show characteristics similar to isolates from other geographic areas. The type of beta-lactamases coded in these resistant isolates is documented for the first time in Mexico.