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Monovalent-cation homeostasis, crucial for all living cells, is ensured by the activity of various types of ion transport systems located either in the plasma membrane or in the membranes of organelles. A key prerequisite for the functioning of ion-transporting proteins is their proper trafficking to the target membrane. The cornichon family of COPII cargo receptors is highly conserved in eukaryotic cells. By simultaneously binding their cargoes and a COPII-coat subunit, cornichons promote the incorporation of cargo proteins into the COPII vesicles and, consequently, the efficient trafficking of cargoes via the secretory pathway. In this review, we summarize current knowledge about cornichon proteins (CNIH/Erv14), with an emphasis on yeast and mammalian cornichons and their role in monovalent-cation homeostasis. Saccharomyces cerevisiae cornichon Erv14 serves as a cargo receptor of a large portion of plasma-membrane proteins, including several monovalent-cation transporters. By promoting the proper targeting of at least three housekeeping ion transport systems, Na+, K+/H+ antiporter Nha1, K+ importer Trk1 and K+ channel Tok1, Erv14 appears to play a complex role in the maintenance of alkali-metal-cation homeostasis. Despite their connection to serious human diseases, the repertoire of identified cargoes of mammalian cornichons is much more limited. The majority of current information is about the structure and functioning of CNIH2 and CNIH3 as auxiliary subunits of AMPAR multi-protein complexes. Based on their unique properties and easy genetic manipulation, we propose yeast cells to be a useful tool for uncovering a broader spectrum of human cornichons´ cargoes.

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Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer) is the most com-mon hereditary colorectal cancer syndrome. The syndrome is caused by a germline mutation of one of the mismatch repair (MMR) genes responsible for DNA replication error repair. Impaired function of the proteins encoded by these genes leads to microsatellite instability (MSI), which is associated with increased incidence of neoplasms: mainly colorectal cancer. According to recent estimates, up to 5% of all colorectal cancers are associated with Lynch syndrome. Due to this relatively high frequency, familial occurence, absence of premorbid phenotype, and development of malignant tumors at a reproductive age, a correct diagnosis is important not only from an ethical but also from an economical point of view. Unfortunately, clinical means of diagnosis, namely, the revised Bethesda guidelines designed to detect patients suitable for genetic testing for Lynch syndrome, lack sufficient sensitivity. The methods associated with modern pathology are more sensitive than the clinical criteria used to detect patients suspected of having Lynch syndrome. Pathological diagnostics are based on direct or indirect detection of MSI. Indirect methods include analysis of morphological signs associated with MSI in histological samples from colorectal carcinoma patients and immunohistochemical investigation of MMR protein expression. To rule out sporadic cases caused by epigenetic inactivation of an MMR gene, molecular genetic investigation of the BRAF gene and methylation analysis of the MLH1 promoter are performed during diagnostic workup. A suspicion of Lynch syndrome based on the results of the methods mentioned above should be proven by detection of a germline mutation in an MMR gene in peripheral blood leukocytes.

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INTRODUCTION: Nowadays, the prognosis of newly diagnosed colorectal cancer patients relies mostly on the tumour-node-metastasis (TNM) classification which is also a determining criterion for the indication of adjuvant oncological treatment. Currently, new prognostic and predictive biomarkers are sought after in order to more precisely define prognosis and better predict the benefits of adjuvant treatment in colorectal cancer. Besides several molecular biomarkers, such as mutations in the proto-oncogene K-ras, analyses of tumour-infiltrating lymphocytes have shown promising prognostic value. The aim of the study is to examine the correlations between K-ras mutational status and tumour-infiltrating immune cells in colon cancer patients with respect to colon cancer recurrence. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded specimens were obtained from 44 patients with surgically resected colon cancer (R0 resection) treated between 2004 and 2009. K-ras mutational status was detected using PCR amplification of exon 1 followed by direct sequencing and K-ras StripAssay. Tumour-infiltrating immune cells were detected by immunofluorescence staining using monoclonal antibodies against CD3, CD8, FoxP3, CD1a and DC-LAMP. RESULTS: All 44 patients in our cohort underwent radical resection of colon cancer. In 16 patients the tumour relapsed (36.4%). K-ras mutations were found in 45.5% (n=20) of the primary carcinomas: 65% in codon 12 and 35% in codon 13. Although codon 13 K-ras mutations were associated with disease relapse, they were present in both disease-free and relapsed patients. However, disease-free and relapsed patients differed markedly in their patterns of tumour-infiltrating immune cells. There was a trend towards decreased density of tumour-infiltrating lymphocytes within the group of relapsed patients. In addition, relapsed patients with codon 13 mutations had markedly lower levels of tumour-infiltrating mature DC-LAMP+ dendritic cells and higher frequency of CD1a+ cells compared to disease-free patients. CONCLUSION: Colon cancer patients with low levels of tumour-infiltrating lymphocytes, a high CD1a+/DC-LAMP+ tumour-infiltrating DC ratio and a K-ras mutation in codon 13 are at a high risk of disease recurrence.

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Muir-Torre syndrome (MTS) represents an autosomal dominantly inherited condition and is considered a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), or Lynch syndrome. MTS combines at least one cutaneous neoplasm with sebaceous differentiation (e.g. sebaceoma, sebaceous adenoma, and sebaceous carcinoma), and at least one visceral malignancy. MTS is a genetic disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors in MTS patients are characteristically associated with the loss of MMR protein expression and/or microsatellite instability (70%). Patients who are suspected to have MTS/Lynch syndrome are often identified by dermatologists, dermatopathologists/pathologists, gastroenterologists and gynecologists. If MTS is suspected on a clinicopathological ground, necessary additional laboratory investigations should be performed only in specialized pathological departments providing immunohistochemistry and molecular biologic analysis service.

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UNLABELLED: The objective of the work was to evaluate the frequency and time of incidence of cytomegaloviral (CMV) infection and disease in patients after allogeneic bone marrow transplantation (BMT). One hundred patients were followed up (70 with a related and 30 with an unrelated donor), who had transplantations during the period between XI/1996-XI/2000. METHODS USED: nested-PCR (MIE-gene) and antigenaemia (antigen pp65). Active CMV infection was proved in antigenaemia > or = 5 positive cells or in two consecutive positive PCR. The CMV syndrome was assessed in confirmed CMV infection and otherwise inexplicable febrile conditions and/or a drop of haemogram values. For the diagnosis of CMV pneumonia the clinical picture was needed, evidence of active CMV infection and on the X-ray of the lungs interstitial pneumonia. In 33 patients both methods were used, in 67 only PCR. The first positive test appeared 6-321 days after BMT (median +/- 49 days). CMV infection was proved in 44% cases, CMV syndrome in 30% and CMV pneumonia in 4%. In patients with a related donor CMV infection was found in 34.3%, CMV syndrome in 22.9%, CMV pneumonia in 1.4%. After unrelated donor BMT CMV infection was recorded in 66.7%, CMV syndrome in 46.7% and CMV pneumonia in 10% patients. Two patients died from CMV pneumonia. CMV pneumonia was diagnosed 57-115 days after BMT (median +/- 68 days. The risk of CMV infection is high in both groups of patients, in particular in patients after unrelated donor BMT (66.7%). As far as the development of CMV pneumonia was concerned, the mortality in the authors' group was 50%.

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The authors compare the results of allogenic bone marrow transplantations of relatives in patients with chronic myeloid leukaemia during the initial years of the transplantation programme 1991-1995 (group 1, 15 patients) with results achieved in 1996-1998 (group 2, 30 patients) and evaluate the effect of changes concerning supportive treatment and new diagnostic methods. The age median of group 1 was 35 years, the median age of group 2 46 years. In other parameters the groups were comparable. In 1991-1995 a high transplantation mortality by the 100th day was recorded (40% as compared with 17%) and a higher incidence of stage III and IV of the acute reaction of the graft against the host (GVHD) in group 1 (20% vs. 6%). In group 2 there was a higher transplantation mortality after day 100 associated with a more frequent chronic GVHD (0% vs. 16.5%). The total survival is insignificantly better in group 2 (60% in group 1 survive with a median of 58 months follow up and 67% of group 2 with a median follow up of 33 months). Group 2 comprises however older patients. In the improved early transplantation mortality participated new methods, a change of the posttransplantation immunosuppression, experience with care of transplanted patients and better collaboration with other medical disciplines. The authors did not observe a substantial effect of changes in the basic supportive treatment on results of transplantation. Late transplantation mortality associated in particular with a higher incidence of chronic GVHD could be in the authors' opinion reduced by longer administration of immunosuppression after transplantation, in particular in older patients.

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Increasing age has been reported to be associated with worse outcome and higher occurrence of complication after allogeneic bone marrow transplantation. We analysed a cohort of 39 patients between the ages of 45 and 57 (median 49 years) with different hematologic malignancies who had undergone BMT in our institution over the preceding 4 years. Pretransplant conditioning consisted of Bu/CY2, GVHD prophylaxis of a combination of cyclosporine and "short" methotrexate. At present 54% of patients remain alive (with a median follow-up 44 months), the probability of survival at 5 years is 53% (5-year DFS 78%). The 5-year survival probability in the control group of younger patients is 53% (P = 0.8003). Main causes of death were GVHD (4 patients, 10%), relapse (5 patients, 13%) and infection (6 patients, 15%). The incidence of acute GVHD grade II-IV was 51% (grade III-IV 0% patients), the incidence of chronic GVHD 49% (limited 18% and extensive 31% patients). Our results suggest that allogeneic BMT can be performed in patients above the age of 45 years with acceptable morbidity and mortality, especially if a family HLA matched donor is available.

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