Endre Kálmán

PIBF (PROGESTERONE INDUCED BLOCKING FACTOR) IS OVEREXPRESSED IN HIGHLY PROLIFERATING CELLS AND ASSOCIATED WITH THE CENTROSOME

PIBF was previously identified as a 34 kDa immunomodulatory molecule secreted by pregnancy lymphocytes and is thought to play a crucial role in preventing rejection of the embryo by the maternal immune response. Recent data suggested that PIBF protein was also expressed by the progesterone receptor (PR) positive MCF‐7 breast tumor cell line. Therefore our study was designed to analyze the expression of PIBF in malignant cell lines and primary tumors both at the mRNA and protein levels. RNA expression analyses of several human cell lines with different tissue origin and paired human tumor/normal tissues, as well as of several PR+ and PR− breast tumors revealed that PIBF mRNA was overexpressed in highly proliferating cells independent of the presence of PR. In addition to the full‐length PIBF mRNA encoding for a 90 kDa protein, several alternatively spliced species were detected, all resulting from perfect exon skipping. The most frequently identified splice variant is predicted to encode for an approximately 35 kDa protein. Immunofluorescence microscopy revealed a centrosomal localization for the full‐length PIBF, while the 35 kDa form showed a diffuse cytoplasmic staining. These data, together with the identification of the PIBF gene in the chromosomal region associated with breast cancer susceptibility, reveal a strong parallel with known tumor suppressor proteins, such as BRCA1 and p53 having the same centrosomal localization. Given the notion that a number of proteins shown to be involved in tumorigenesis are associated with the centrosome and disturbed centrosome function causes unequal segregation of chromosomes, studies to evaluate whether or not PIBF that is highly expressed in tumors is directly involved in tumorigenesis are thus warranted.

Large cell neuroblastoma: a distinct phenotype of neuroblastoma with aggressive clinical behavior.

Among cases of undifferentiated and poorly differentiated tumors in the neuroblastoma (Schwannian stroma–poor) category, the authors histologically identified a group of rare tumors, known as large cell neuroblastomas (LCNs), that are composed of large cells with sharply outlined nuclear membranes and 1–4 prominent nucleoli.

Alcohol-free red wine inhibits isoproterenol-induced cardiac remodeling in rats by the regulation of Akt1 and protein kinase C α/β II☆

There is increasing evidence that moderate consumption of red wine containing high amount of polyphenols and anthocyanins is associated with decreased incidence of cardiovascular morbidity and mortality. Therefore, we hypothesized that cardiac hypertrophy and fibrosis as well as Akt (protein kinase B, PKB) and protein kinase C (PKC) cascades can be beneficially influenced by an alcohol-free red wine (AFRW) extract rich in 14 types of polyphenols and 4 types of anthocyanins during cardiac remodeling. To test this assumption, rats were treated with isoproterenol (ISO) to induce postinfarction remodeling and were given tap water or AFRW ad libitum for 8 weeks. Control rats received vehicle instead of ISO. Heart mass/body mass and ventricle mass/body mass ratios, diameter of cardiomyocytes, phosphorylation of PKC alpha/beta II and protein kinase B/Akt, and deposition of collagen type III were determined from the hearts of all four groups of rats. All measured gravimetric parameters, myocyte diameters and the amount of collagen type III decreased, and the phosphorylation of PKC alpha/beta II was reduced in the ISO+AFRW group compared to the ISO group. AFRW induced activation of Akt, one of the best characterized cytoprotective pathways even without ISO treatment, and this activation was further increased in the ISO+AFRW group. These data suggest that AFRW treatment has a protective effect on hearts undergoing postinfarction remodeling by repressing hypertrophy-associated increased phosphorylation of PKC alpha/beta II and by activating Akt, providing a molecular mechanism for the cardioprotective effect of red wine polyphenols.

Estrogen Receptor Negative and Progesterone Receptor Positive Breast Carcinomas—How Frequent are they?

Estrogen receptor (ER) testing has become an important part of breast cancer reporting as the ER status is a predictor of hormonal treatment efficacy. Progesteron receptors (PR) are often tested in parallel, and the best response to hormonal manipulations can be expected in tumors positive for both receptors. The existence of breast cancers with an ER negative and PR positive phenotype is controversial. A series of cases with this phenotype were reevaluated to clarify the existence and the frequency of this entity. A total of 205/6587 (3.1%; range of the rate per department: 0.3–7.1%.) cases reported to have the ER-negative and PR-positive status by immunohistochemistry were collected from 9 Hungarian departments. After careful reevaluation of the tumor slides and control tissues with a 1% cut-off for positivity and restaining of the questionable cases, all but 1 of the reevaluable 182 cases changed their original phenotype. Most cases converted to dual positives (n = 124) or dual negatives (n = 31) or unassessable / questionable. ER-negative and PR-positive breast cancers are very rare if existing. Such a phenotype should prompt reassessment.

Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure

Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3β pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3β pathway, PKCϵ). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.

Intravascular lymphomatosis of the nervous system

Sirs: Intravascular lymphoma (IVL) is a rare and aggressive variant of diffuse large cell lymphoma [1–3]. Its rarity (one person per million), multiplicity of presentations, and absence of lymphoma cells in the reticuloendothelial system complicate early diagnosis [2– 5]. Most of IVL belong to systemic diffuse large B cell lymphomas (DLBCL), but aberrant expression of integrins prohibits extravasal migration [6]. Multifocal cortical and subcortical T2 hyperintense lesions were observed on the MRI of the brain (Fig. 1 A and Table 1). CSF showed albumino-cytological dissociation. Stereotactic brain biopsy revealed IVL. Cells displayed an activated B cell phenotype profile on immuno-staining (CD20+, MUM1+, Bcl-6+ and CD10–) (Fig. 1 B). In situ hybridiza-

Pulmonary enteric adenocarcinoma indistinguishable morphologically and immunohistologically from metastatic colorectal carcinoma

Adenocarcinoma is the most common and heterogeneous type of lung cancer. Pulmonary enteric adenocarcinoma (PEAC) is a recently described, extremely rare primary pulmonary adenocarcinoma variant, which has a histological morphology and immunohistochemical phenotype similar to metastatic colorectal carcinoma (MCC). It was described originally in 1991 by Tsao et al. as a primary pulmonary adenocarcinoma with enteric differentiation. In 2005, Inamura et al. reported a series of seven cases, and in 2008 Meada et al. described a case as pulmonary intestinal-type adenocarcinoma. Currently, there have only been 17 reported cases. PEAC was classified as a rare variant of invasive adenocarcinoma by the International Association for the Study of Lung Cancer/American Thoracic Respiratory Society in 2011. Here we describe a PEAC that developed in the postoperative scar of a 65-year-old male with a history of segmental resection and adjuvant radiotherapy for squamous cell carcinoma (SCC). Together, retrospective comparative analysis of tumour samples from the first and second surgical interventions and the autopsy findings suggest that the subsequent adenocarcinoma was PEAC rather than metastatic adenocarcinoma. The tumour was indistinguishable from MCC by histology, immunohistochemistry and EGFR/K-RAS mutation analysis.

CD99-positive undifferentiated round cell sarcoma diagnosed on fine needle aspiration cytology, later found to harbour a CIC-DUX4 translocation: a recently described entity

IntroductionPoorly differentiated, small round cell sarcomasoften represent a serious differential diagnostic prob-lem. CD99 expression was initially considered to bespecific for Ewing sarcoma (ES); however, it mayalso be seen in many histologically similar neo-plasms. The differential diagnosis of these tumoursincludes mesenchymal chondrosarcoma, poorly dif-ferentiated synovial sarcoma and lymphoblastic lym-phoma. However, rarely, CD99 expression mayappear in other neoplasms of a similar morphologysuch as the blastemal component of Wilms’ tumour,small cell osteosarcoma, rhabdomyosarcoma, smallcell carcinomas, etc., further expanding the list ofdifferentials.

Lithium Suppresses Epidermal SERCA2 and PMR1 Levels in the Rat

Autosomal dominant mutations in the genes encoding the calcium ATPases SERCA2 and PMR1/SPCA1 cause the genodermatoses Darier disease (DD) and Hailey-Hailey disease (HHD), respectively. Recent observations indicated that the level of the pathogenic proteins greatly decreases in the affected areas of the epidermis in these disorders. Here we addressed how lithium, a recognized exacerbating factor in Darier disease, affects the epidermal expression of SERCA2 and PMR1/SPCA1 in the rat as a model. Standard histologic and immunohistochemical methods were utilized in 3 lithium-treated and 3 control animals. A significant suppression of epidermal SERCA2 and PMR1 levels were observed as a result of lithium therapy in addition to marked qualitative and quantitative changes in the stratum corneum and the granular layer of the epidermis in the treated animals. Our findings suggest that exacerbating factors in calcium ATPase disorders of the skin suppress epidermal SERCA2 and PMR1 levels, further decreasing the already haploinsufficient protein expression to a potentially critical level in Darier disease and Hailey-Hailey disease, respectively. Lithium therapy should specifically be avoided not only in Darier disease, but Hailey-Hailey disease as well.

Comparison of membrane fluidity and transferrin receptor expression as proliferation markers in lymphoproliferative disorders and in mitogen induced lymphoblasts

The correlation of two proliferation related events, membrane fluidization and transferrin receptor expression was studied in different lymphoid cells. With increasing grade of malignancy the membrane microviscosity decreased. Moreover, resting lymphocytes differed significantly from chronic lymphocytic leukaemia cells in this parameter. [125I]Fe2-transferrin binding increased with increasing proliferation capacity of cells. The membrane microviscosity of mitogen induced blasts was very similar to that of acute lymphoblastic cells, whereas the [125I]Fe2-transferrin binding capacity exceeded roughly 5 times that of the blastic leukaemia cells. This dissociation indicates that these two proliferation markers do not necessarily parallel each other.