BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia.

The BCR-ABL chimeric protein is thought to play a central role in the pathogenesis of Philadelphia (Ph) chromosome-positive leukemias, notably chronic myeloid leukemia (CML). There is compelling evidence that malignant transformation by BCR-ABL is critically dependent on its protein tyrosine kinase (PTK) activity. As a result, multiple signaling pathways are activated in a kinase-dependent manner, and thus the activation of such pathways may affect the expression of genes that confer the malignant phenotype. In this study, we used differential display to investigate the alterations of gene expression in BV173, a CML cell line derived from lymphoid blast crisis, after exposure to ST1571, which selectively inhibits ABL PTK activity. We show that the expression of a set of 12 genes is correlated with the kinase activity and that the profile of these genes reflects mechanisms implicated in the pathogenesis of CML. Several of the genes show a consistent pattern of altered regulation in all Ph-positive lymphoid cell lines, whereas others appear to be unique to BV173 cells. We conclude that BCR-ABL PTK activity drives the expression of specific target genes that contribute to the malignant transformation of Ph-positive cells. The identification of downstream molecules with a consistent regulation pattern may provide suitable targets for therapeutic intervention in the future.

BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability.

Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a T-cell leukaemia line), which lacked detectable BAX expression. Apoptosis of DG75 cells induced by low serum or ionomycin was significantly delayed relative to similar Burkitt lymphoma cell lines with normal BAX levels. Although DG75 and Jurkat cells expressed several BAX RNA species including the prototypical BAX alpha RNA, the absence of BAX protein was due to single base deletions and additions in a polyguanine tract within the BAX open reading frame. These frameshift mutations result in premature termination of translation and have recently also been identified in some colon cancers with microsatellite instability. Although mismatch repair defects are not considered a common feature of haemopoietic malignancies, DG75 and Jurkat cells had widespread microsatellite instability and did not express detectable levels of MSH2. In Jurkat cells, lack of MSH2 expression was due to a point mutation in exon 13 of MSH2 resulting in premature termination of translation. Our results suggest that a pathway linking mismatch repair defects, BAX tumour suppressor frameshift mutations and resistance to apoptosis may be a key feature of some lymphomas and leukaemias.

Índice de inmunidad-inflamación sistémica en sepsis / Systemic immune inflammatory index in sepsis

Resumen ANTECEDENTES: se han estudiado índices de pronóstico de inflamación basados en células periféricas como predictores de disfunción endotelial, riesgo cardiovascular y mortalidad. En 2014 se desarrolló el índice de inmunidad-inflamación sistémica (IIS) que se ha propuesto como factor de pronóstico y de seguimiento en cáncer. OBJETIVO: determinar si existe modificación del índice de inmunidad-inflamación sistémica (IIS) en pacientes con sepsis. MATERIAL Y MÉTODO: estudio retrospectivo que incluyó aleatoriamente a pacientes hospitalizados de 2013 a 2015. Se verificó la homogeneidad de poblaciones demostrando que no existía diferencia estadística entre la edad y comorbilidades (distribución Kolmogorov-Smirnov), frecuencia de comorbilidades (χ2). Se calculó el IIS con la citometría hemática de ingreso. Se compararon las medias del IIS de pacientes con sepsis y sin sepsis (Wilcoxon) y se determinó si había correlación entre el IIS y sepsis (coeficiente de correlación biserial puntual). RESULTADOS: se incluyeron 242 pacientes (128 con sepsis, edad promedio de 70.1 años y 114 sin sepsis, edad promedio de 69.7 años). La media del índice de inmunidad-inflamación sistémica (IIS) en pacientes con sepsis fue 4444.06x109, en pacientes sin sepsis fue de 3013.94x109. Se demostró que existe correlación estadísticamente significativa entre el IIS y sepsis (rbp= 0.150253625, p=0.05), se demostró que la media del IIS fue significativamente más elevada en pacientes con sepsis (W=5,097, p=0.00001). CONCLUSIONES: el índice de inmunidad-inflamación sistémica (IIS), un índice innovador que ha mostrado mejor efectividad para describir el desequilibrio de inmunidad e inflamación, se propone como una herramienta que puede ser útil en pacientes con sepsis; sin embargo, se requieren estudios futuros para comprobar su potencial pronóstico y de seguimiento.

Abstract BACKGROUND: In the past several indices based on peripheral blood cells have been studied to prove their utility as prognostic factors in endothelial dysfunction, cardiovascular risk and mortality. In 2014 the systemic immune inflammatory index (SII) was developed and it has been proposed as a prognostic factor in the follow-up of patients with cancer. OBJECTIVE: To determine if there is a modification of the SII in patients with sepsis. MATERIAL AND METHOD: A retrospective study included randomized patients hospitalized from 2013 to 2015; homogeneity of populations was verified by demonstrating that there was no statistical difference between age and comorbidities (Kolmogorov-Smirnov distribution), frequency of comorbidities (χ2). IIS was calculated with the blood cell count on hospital admission. IIS was compared in sepsis and without sepsis patients (Wilcoxon), and we determined whether there was correlation between IIS and sepsis (correlation coefficient biserial point). RESULTS: There were included 242 patients (128 with sepsis, mean age 70.1 years and 114 without sepsis, mean age 69.7 years). The mean IIS in patients with sepsis was 4444.06x109 and without sepsis 301 3.94x109. We showed that there was statistically significant cor relation between IIS and sepsis (rbp=0.150253625, p=0.05), we also detailed that the mean IIS was significantly higher in patients with sepsis (W=5,097, p=0.00001). CONCLUSIONS: The IIS, an innovative index that has shown accuracy describing the imbalance of immunity and inflammation, is proposed as a tool that can be useful in patients with sepsis; however, further studies are required to prove its potential in prognosis and monitoring.

Correlación del índice plaqueta/ bazo con el grado de várices esofágicas / Correlation between platelet/spleen index and esophageal varices degree

Resumen ANTECEDENTES: las enfermedades hepáticas crónicas en México fueron motivo de 28,904 fallecimientos durante 2012. Su principal complicación fue la hipertensión portal, manifestada por várices esofágicas (VE) que afectan a 30% de los pacientes. OBJETIVO: utilizar la correlación del índice plaqueta/bazo (IPB) con el grado de várices esofágicas como método diagnóstico no invasivo y de decisión terapéutica. MATERIAL Y MÉTODO: estudio observacional, analítico, transversal y retrospectivo, en el que se recolectaron datos de pacientes con diagnóstico de insuficiencia hepática, atendidos en el servicio de Medicina Interna del Hospital Central Norte de Petróleos Mexicanos, entre enero de 2010 y abril de 2016; se calcularon puntos de corte para conocer el grado de asociación del IPB con el grado de várices esofágicas; el patrón de referencia fue la endoscopia digestiva alta. RESULTADOS: se encontró un nivel de significación con valor p de 0.005 y Rho de Spearman de -0.425 que traduce una correlación estadísticamente significativa entre las variables en correlación con la escala de Dagradi y nivel de significación con valor p de 0.001 y Rho de Spearman de -0.492 en correlación con la escala de Baveno. Asimismo, para la escala de Baveno un IPB mayor a 0.700 se correlacionó con várices esofágicas pequeñas, en tanto que un IPB menor a 0.700 se correlacionó con várices esofágicas grandes. CONCLUSIONES: esta correlación puede ser un método no invasivo útil que permite establecer prioridad en cuanto al abordaje diagnóstico y discernir entre iniciar tratamiento farmacológico o realizar un procedimiento endoscópico.

Abstract BACKGROUND: Chronic liver diseases in Mexico were cause of 28,904 deaths in 2012. Its main complication was portal hypertension, manifested by esophageal varices (EV) occurring in 30% of patients. OBJECTIVE: To use the correlation of platelet/spleen index (PSI) with the degree of EV as a noninvasive diagnostic method and therapeutic decision. MATERIAL AND METHOD: An observational, analytical, cross-sectional and retrospective study was done in which data were collected from patients with chronic liver failure assisted at the Department of Internal Medicine of North Central Hospital Pemex, Mexico City, from January 2010 to April 2016. Cutpoints were calculated to determine the degree of association between PSI with the degree of EV; using the upper gastrointestinal endoscopy as the gold standard. RESULTS: We found a significance level with p-value of 0.005 and -0.425 Spearman Rho, defaming a statistically significant correlation between the variables in correlation to Dagradi Scale and a level of significance with p-value of 0.001 and -0.492 Spearman Rho in correlation to Baveno Scale. For Baveno scale it was observed that a PSI higher than 0.700 correlated with small EV, while a PSI lesser than 0.700 PSI correlated with large EV. CONCLUSIONS: This correlation can be a non-invasive useful method which allows to set priority in regard to diagnostic approach and to dis cern between starting drug treatment or doing endoscopic procedure.

DNA ploidy on cytologic and tissue sections of breast lumps. A comparison using image analysis.

OBJECTIVE: Ploidy correlation between cytologic and histologic breast specimens would permit preoperative measurement of ploidy and may assist in patient management. STUDY DESIGN: DNA indices were measured on fine needle aspirates (FNAs) of 50 breast lumps and the results compared with ploidy of histologic specimens from the same lump. RESULTS: Thirty-six of 50 were histologically malignant, and 14/50 were benign. The mean DNA index of malignant tissue sections was 1.23 (range, 0.61-2.62) and on corresponding cytology was 1.49 (range, 0.79-3.18). Fourteen benign tissue sections had a mean DNA index of 0.94 (range, 0.51-1.37) and a mean DNA index of 1.06 (range, 0.74-2.13) on cytology. DNA indices of FNAs and corresponding tissue sections revealed a correlation between the two (Pearson's correlation coefficient = .386, P value = .006). CONCLUSION: Our results show that the DNA indices are comparable using image analysis on FNAs and tissue sections on the same surgical breast specimens. This demonstrates that ploidy can be achieved on cytologic breast material and may have a role in the preoperative assessment of breast cancers.

Quantitative measurement of estrogen and progesterone receptors in breast lumps using image cytometry.

OBJECTIVE: To evaluate image cytometry for detecting estrogen (ER) and progesterone receptors (PR) in breast lumps quantitatively. STUDY DESIGN: Fifty consecutive breast lumps were analyzed for ER and PR using the avidin-biotin complex on tissue sections. RESULTS: Mean ER-positive nuclear area percentage (PA%) for 25 invasive ductal carcinomas was 47.81% and for PR was 57.83%. Mean ER PA% was 40.78% and PR 58.91% for seven invasive lobular carcinomas. There were two papillary carcinomas and one in situ ductal carcinoma. Fourteen of 15 benign breast lumps were benign breast lesions. Mean ER PA% was 65.95% and PR 73.43% for 10 fibroadenomas and for 4 fibrocystic lesions was 51.57% and 44.13%, respectively. CONCLUSION: Quantitative detection of ER and PR can be achieved by image cytometry. We aim in the future to assess this method in prognostic studies and the preoperative cytology of breast cancers.

Selective allergy to sheep's and goat's milk proteins.

BACKGROUND: Cow's milk proteins are amongst the most common causes of food allergy in infants, and caseins are probably the main allergens. The existence of a high degree of cross-reactivity between milk caseins from different animals has been reported. We describe a 2-year-old boy who experienced allergic reactions after eating and touching sheep's cheese, but who tolerated cow's milk and cow's milk dairy products. He had never ingested milk or milk derivatives from sheep or goat. METHODS: Skin prick tests were carried out using whey fractions of cow's milk, whole milk and casein from goat, sheep and cow. We also performed skin prick tests with enzymes used in cheese production. Prick-by-prick tests with cheese made from cow, sheep and goat and their corresponding whole milk were also performed. Total serum IgE and specific IgE to cow's milk proteins, whole cow's milk and sheep's milk were determined. Specific IgE against casein and whole milk from the three different species were determined by ELISA. Inhibition of IgE binding to bovine casein was tested for casein and whole milk from all three species. The proteins of three types of casein and whole milk from cow, sheep and goat were separated by SDS-PAGE and were incubated with the patient's serum. RESULTS: Skin tests were positive to sheep's milk and goat and sheep casein and were negative to all cow's milk proteins and whole cow's and goat's milk. Prick-by-prick tests were positive to goat's and sheep's cheese and were negative to cow's cheese. In ELISA-inhibition, sheep's milk and goat and sheep casein were able to inhibit > 50 % of specific IgE binding to sheep casein. The results of immunoblotting showed that the patient's circulating IgEs recognized only one band in the lanes corresponding to sheep and goat casein. CONCLUSIONS: We report a patient with allergy to sheep's and goat's milk proteins but not to cow's milk proteins. Sheep casein was probably the main allergen causing sensitization in this patient. The results suggest that sheep casein shows a high degree of cross-reactivity with goat casein but not with cow casein. Our patient presented allergic symptoms caused by sheep and goat milk and cheese proteins. However, he was able to tolerate cow's milk and cow's milk dairy products without any ill effects.