The incidence of HPV in a Swedish series of invasive cervical carcinoma

The incidence of HPV was studied in 71 invasive squamous carcinomas of the cervix using PCR technique. We used primers, which presumably recognize all types of HPV (consensus primers), and also type-specific primers.In situ hybridization was carried out in 24 of the cases. The overall incidence of HPV was 53/71 (75 %) of which 5 cases were positive with the consensus primers only. However, 21/71 cases (30%) were negative for the consensus primers but positive for one of the type-specific primer pairs. This finding indicates that subgenomic deletions may have occurred in the viral genome upon integration in the human DNA.In situ hybridization was positive in 14/24 cases (58 %), showing excellent correlation with PCR results. The HPV types detected were, in descending order of frequency: type 16 (52 %), 31 (23 %), 18 (13 %), 33 (12 %). No cases of HPV type 6 or 11 were found in this series of invasive carcinomas.     

STRUCTURAL RELATIONSHIPS BETWEEN INDIVIDUAL H-2 SPECIFICITIES ON THE CELL SURFACE

Stepwise incubation with specific H-2 antibody and rabbit-anti-mouse Ig was used to modulate the expression of selected H-2 specificities on the surface of lymph node cells or EL 4 leukaemia cells. Modulation was reflected in a loss of sensitivity to complement-dependent lysis and a polar pattern of immunofluorescence (‘capping’). Specificity H-2.5 on H-2^a cells was co-modulated with H-2.11 and so was H-2.11 with H-2.5 on H-2^k cells. However, when H-2.11 on H-2^k cells was modulated, the cells did not loose cytotoxic sensitivity for H-2.5. This asymmetry in co-modulation of H-2.5 and H-2.11 may be accommodated by the duplication model of the H-2 complex which postulates a double determination of H-2.5 in the H-2^k (unlike H-2^a) chromosome, with one determinant being in the K region (where also the H-2.11 determinant is located) and the other in H-2D. The modulation results with H-2.5 and H-2.11 are compatible with the view that various H-2K specificities may represent distinct antigenic sites on the same glycoprotein molecule whereas H-2D specificities are on separate molecule(s). The independent modulation of H-2D.4 and H-2K.11 specificities further indicates that molecules of the two classes are also secondarily not linked in the membrane structure. Modulation-induced cytotoxicity resistance was further shown to persist even when the specific H-2 antibody is newly added; this suggests that it is a change in the distribution of the H-2 antigen to be held responsible (rather than the loss of the sensitizing antibody). A modulated expression of a certain H-2 specificity might then be expected to affect its blocking relationship to another H-2 specificity; the blocking index expresses the degree of interference by antibody attached to one of them with the attachment of antibody to the other. The blocking relationship between H-2.4 and H-2.11 was shown to be completely abolished by the independent modulation of H-2.11. In contrast to this, the blocking index for H-2.5 and H-2.11 remained practically constant following the modulation of either specificity; this indicates that the intramolecular configuration of such two H-2 sites may not be altered by the gross redistribution of the whole molecule in the plane of the membrane. The rigidity of this configuration seems to be maintained by neuraminidase-sensitive groups as suggested by the reduced blocking index in neuraminidase pretreated cell.     

Droplet digital PCR revealed high concordance between primary tumors and lymph node metastases in multiplex screening of KRAS mutations in colorectal cancer

Clinical and Experimental Medicine - The proto-oncogene KRAS belongs among the most frequently mutated genes in all types of cancer and is also very important oncogene related to colorectal tumors....     

Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency

We describe two patients with mevalonate kinase deficiency and prominent hematologic abnormalities and cholestatic liver disease. Patient R.B. was not anemic at birth, but developed petechiae and cutaneous extramedullary hematopoiesis, hepatosplenomegaly, leukocytosis, and recurrent febrile events without positive bacterial or viral cultures. Patient N.M. manifested minor anomalies, hepatosplenomegaly, anemia, thrombocytopenia, recurrent febrile crises, and facial rashes. Mevalonic aciduria was found by urinary organic acid analysis, and mevalonate kinase deficiency was documented in both. The clinical spectrum of normocytic hypoplastic anemia, leukocytosis, thrombocytopenia, and abnormal blood cell forms led to diagnoses of congenital infection, myelodysplastic syndromes, or chronic leukemia in these patients before recognition of mevalonate kinase deficiency. Mevalonate kinase deficiency represents a single-gene abnormality that may be associated with significant hematologic findings. Recognition of the variability of this disorder with some patients manifesting only mild neurologic findings, yet significant hepatosplenomegaly, normocytic anemia, thrombocytopenia, and leukocytosis is important for all specialists who need to be aware of this organic aciduria. Am. J. Med. Genet. 78:408–412, 1998. © 1998 Wiley-Liss, Inc.     

Cancer stem cell marker expression and methylation status in patients with colorectal cancer

The number of individuals diagnosed with colorectal cancer (CRC) has been on an alarming upward trajectory over the past decade. In some countries, this cancer represents one of the most frequently diagnosed types of neoplasia. Therefore, it is an important demand to study the pathology underlying this disease to gain insights into the mechanism of resistance to treatment. Resistance of tumors to chemotherapy and tumor aggressiveness have been associated with a minor population of neoplastic cells, which are considered to be responsible for tumor recurrence. These types of neoplastic cells are known as cancer stem cells, which have been previously reported to serve an important role in pathogenesis of this malignant disease. Slovakia has one of the highest incidence rates of CRC worldwide. In the present study, the aim was to classify the abundance of selected stem cell markers (CD133, CD166 and Lgr5) in CRC tumors using flow cytometry. In addition, the methylation status of selected genomic regions of CRC biomarkers (ADAMTS16, MGMT, PROM1 (CD133), LGR5 and ALCAM) was investigated by pyrosequencing in a cohort of patients from Martin University Hospital, Martin, Slovakia. Samples from both primary tumors and metastatic tumors were tested. Analysis of DNA methylation in the genomic regions of indicated five CRC biomarkers was also performed, which revealed the highest levels of methylation in the A disintegrin and metalloproteinase with thrombospondin motifs 16 and O6-methyguanine-DNA methyl transferase genes, whereas the lowest levels of methylation were found in genes expressing prominin-1, leucine-rich repeat-containing G-protein-coupled receptor 5 and activated leukocyte cell adhesion molecule. Furthermore, tumor tissues from metastases showed significantly higher levels of CD133⁺ cells compared with that in primary tumors. Higher levels of CD133⁺ cells correlated with TNM stage and the invasiveness of CRC into the lymphatic system. Although relatively small number of samples was processed, CD133 marker was consider to be important marker in pathology of CRC.     

Body mass index and body size in early adulthood and risk of pancreatic cancer in a central European multicenter case-control study

The relationship between two measures of excess body weight, body mass index (BMI) and body size score, and risk of pancreatic cancer was examined among 574 pancreatic cancer cases and 596 frequency-matched controls from the Czech Republic and Slovakia enrolled between 2004 and 2009. Analyses using multivariable logistic regression showed an increased risk of pancreatic cancer associated with elevated quartiles of BMI at ages 20 [fourth quartile: odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.23, 2.61] and 40 (fourth quartile: OR = 1.57, 95% CI: 1.09, 2.27) compared to the lowest quartile. Consistent results were observed for body size score at ages 20 (high versus low: OR = 1.66, 95% CI: 1.08, 2.57) and 40 (medium versus low: OR = 1.36, 95% CI: 1.00, 1.86), but no association was found for BMI and body size score at 2 years before the interview. Stronger risk estimates for BMI were observed in males than females, particularly at age 20, but the analysis of body size yielded similar estimates by sex. When considering excess body weight at both ages 20 and 40 jointly, the highest risk estimates were observed among subjects with elevated levels at both time periods in the analysis of BMI (OR = 1.86, 95% CI: 1.32, 2.62) and body size (OR = 1.53, 95% CI: 1.09, 2.13). These findings, based on two different measures, provide strong support for an increased risk of pancreatic cancer associated with excess body weight, possibly strongest during early adulthood.     

Association of sVAP-1, sRAGE, and CML with lactation-induced insulin sensitivity in young non-diabetic healthy women

BackgroundIn comparison with non-lactating women breast-feeding mothers display higher insulin sensitivity. Recent data suggest that advanced glycation end products, soluble receptor for advanced glycation end products (sRAGE) and soluble vascular adhesion protein-1 (sVAP-1) may play a role in insulin resistance even in healthy subjects.AimWe studied whether breast-feeding induced insulin sensitivity associates with changes in concentrations of circulating sVAP-1, sRAGE and N^ε-(carboxymethyl)lysine (CML) — chemically defined advanced glycation end product and RAGE ligand.MethodsIn 74 lactating non-diabetic mothers, 45 weaned non-diabetic mothers and 50 age-matched non-parous women insulin sensitivity was assessed using Quantitative insulin-sensitivity check index (QUICKI). sVAP-1, sRAGE and CML levels were determined.ResultsLactating mothers were more insulin sensitive than their weaned and non-parous counterparts. Lactating mothers displayed the highest concentrations of sRAGE, and higher sVAP-1 levels if compared to weaned mothers. Both groups of mothers presented with lower CML levels than the non-parous women.ConclusionLactation-induced insulin sensitivity is associated with higher sVAP-1 and a tendency towards higher sRAGE levels. Lactation-associated rise in sVAP-1 may promote effective glucose utilization in the mother. Lactation-induced insulin sensitivity vanishes shortly after weaning. In young healthy women CML levels are of no clinical relevance to insulin sensitivity.