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Protein kinase C isoenzymes differentially regulate the differentiation-dependent expression of adhesion molecules in human epidermal keratinocytes

Abstract:  Epidermal expression of adhesion molecules such as desmogleins (Dsg) and cadherins is strongly affected by the differentiation status of keratinocytes. We have previously shown that certain protein kinase C (PKC) isoforms differentially alter the growth and differentiation of human epidermal HaCaT keratinocytes. In this paper, using recombinant overexpression and RNA interference, we define the specific roles of the different PKC isoenzymes in modulation of expression of adhesion molecules in HaCaT keratinocytes. The level of Dsg1, a marker of differentiating keratinocytes, was antagonistically regulated by two Ca‐independent ‘novel’ nPKC isoforms; i.e. it increased by the differentiation‐promoting nPKCδ and decreased by the growth‐promoting nPKCε. The expression of Dsg3 (highly expressed in proliferating epidermal layers) was conversely regulated by these isoenzymes, and was also inhibited by the differentiation inducer Ca‐dependent ‘conventional’ cPKCα. Finally, the expression of P‐cadherin (a marker of proliferating keratinocytes) was regulated by all of the examined PKCs, also in an antagonistic manner (inhibited by cPKCα/nPKCδ and stimulated by cPKCβ/nPKCε). Collectively, the presented results strongly argue for the marked, differential, and in some instances antagonistic roles of individual Ca‐dependent and Ca‐independent PKC isoforms in the regulation of expression of adhesion molecules of desmosomes and adherent junctions in human epidermal keratinocytes.

Protein kinase C-β and -δ isoenzymes promote arachidonic acid production and proliferation of MonoMac-6 cells

In this study, we investigated the putative roles of certain protein kinase C (PKC) isoenzymes in the regulation of proliferation and arachidonic acid (AA) release in the human monocytoid MonoMac-6 cell line. Experiments employing specific PKC inhibitors and molecular biological methods (RNA-interference, recombinant overexpression) revealed that the two dominantly expressed isozymes, i.e., the “conventional” cPKCβ and the “novel” nPKCδ, promote AA production and cellular proliferation. In addition, using different phospholipase A2 (PLA2) inhibitors, we were able to show that the calcium-independent iPLA2 as well as diacylglycerol lipase (but not the cytosolic PLA2) function as “downstream” targets of cPKCβ and nPKCδ. In addition, we have also found that, among the other existing PKC isoforms, cPKCα plays a minor inhibitory role, whereas nPKCɛ and aPKCζ apparently do not regulate these cellular processes. In conclusion, in this paper we provide the first evidence that certain PKC isoforms play pivotal, specific, and (at least partly) antagonistic roles in the regulation of AA production and cellular proliferation of human monocytoid MonoMac-6 cells.

Beyond the physico-chemical barrier: Glycerol and xylitol markedly yet differentially alter gene expression profiles and modify signalling pathways in human epidermal keratinocytes

Polyols (e.g. glycerol, xylitol) are implicated as moisturizers of the skin and other epithelial tissues. However, we lack information about their exact cellular mechanisms and their effects on the gene expression profiles. Therefore, in this study, we aimed at investigating the effects of glycerol and xylitol on human epidermal keratinocytes. The polyols (identical osmolarities; xylitol: 0.0045%‐0.45%; glycerol: 0.0027%‐0.27%) did not alter cellular viability or intracellular calcium concentration. However, they exerted differential effects on the expression of certain genes and signalling pathways. Indeed, both polyols up‐regulated the expression of filaggrin, loricrin, involucrin and occludin; yet, xylitol exerted somewhat more profound effects. Moreover, while both polyols stimulated the MAPK pathway, only xylitol induced the activation‐dependent translocation of protein kinase Cδ, a key promoter of epidermal differentiation. Finally, in various keratinocyte inflammation models, both polyols (albeit with different efficacies) exerted anti‐inflammatory effects. Taken together, these data strongly suggest that glycerol and xylitol differentially modulate expressions of multiple genes and activities of signalling pathways in epidermal keratinocytes. Thus, our findings invite clinical trials to explore the applicability and the impact of a combined glycerol‐xylitol therapy in the management of various skin conditions.

Diagnostic difficulties caused by a pulmonary infiltrate

UNLABELLED Lung infiltration still causes differential diagnostic difficulties, which may delay the start of definitive treatment. CASE REPORT The examination of a 30-year-old man began due intermittent, remittent and permanent fever. Chest X-ray confirmed infiltration in the right upper lobe, which was accompanied by elevated CRP and physiological levels of procalcitonin. Most likely atypical pneumonia, tuberculosis, Wegeners granulomatosis or a malignant process was suspected. Throughout his examination infection could not be verified, repeated CT guided transthoracic needle biopsy suggested the possibility of a malignant process. Through surgical exploration the intraoperative histology was not informative; thus, the pneumonitis-remodelled right lung was removed due to the possibility of malignant transformation. Histological examination revealed lymphocyte rich classical Hodgkin lymphoma, which was found to be stage IV/B based on the 18FDG-PET/CT scan; therefore, eight cycles of ABVD (adriablastin, bleomycin, vinblastine, and dacarbazine) therapy was administered successfully. The patient is currently (for 30 months) in a complete metabolic remission. CONCLUSION Primary pulmonary Hodgkin lymphoma is a rare disease entity (in this case it might be the original process), in which the diagnosis is often difficult. 18FDG-PET/CT may be a useful early diagnostic tool investigating fever of unknown origin.

Primary refractory and relapsed Hodgkin-lymphoma patients

Napjainkban a legtobb Hodgkin-lymphomas beteg meggyogyithato a korszerű kezelesi modszerekkel, sajnos a betegek nehany szazaleka refrakter, es kozel harmaduk relabal az elsődleges kezelest kovetően. Celkitűzes es modszer: a DEOEC III. sz. Belgyogyaszati Klinikan 1996 es 2006 kozott kezelt Hodgkin-lymphomas beteg kozott vizsgaltuk retrospektiv modszerrel a refrakter esetek es a relapszusok előfordulasat. Eredmenyek: 76 nő es 71 ferfi eseteben diagnosztizaltunk Hodgkin-lymphomat ezen idő alatt. A betegek 95,9%-a kerult remisszioba az elsődleges kezelesre. 6 nőbeteg volt primeren refrakter, 4 betegnel autolog hemopoetikus őssejttranszplantacio is tortent, de a tobbszoros kezelesek ellenere is mindannyian exitaltak. 31 betegnel alakult ki relapszus (1 even belul 16 esetben). 14 betegnel tortent autolog hemopoetikus őssejttranszplantacio, 11 beteg csak kemoterapiaban, 3 csak irradiacioban es 3 beteg kombinalt kezelesben reszesult. A relabalt betegek kozul oten alapbetegseguk progresszioja, egy beteg szekunder ...Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the fi rst-line treatment. Aim and methods: We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. Results: We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after fi rst-line therapy. 6 women were primary refracter, 4 of them had highdose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients – 13 men and 18 women – had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. Conclusions: Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.UNLABELLED Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the first-line treatment. AIM AND METHODS We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. RESULTS We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after first-line therapy. 6 women were primary refracter, 4 of them had high-dose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients - 13 men and 18 women - had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. CONCLUSIONS Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.

[Therapy for patients with primary refractory and relapsed Hodgkin-lymphoma--our experience].

Napjainkban a legtobb Hodgkin-lymphomas beteg meggyogyithato a korszerű kezelesi modszerekkel, sajnos a betegek nehany szazaleka refrakter, es kozel harmaduk relabal az elsődleges kezelest kovetően. Celkitűzes es modszer: a DEOEC III. sz. Belgyogyaszati Klinikan 1996 es 2006 kozott kezelt Hodgkin-lymphomas beteg kozott vizsgaltuk retrospektiv modszerrel a refrakter esetek es a relapszusok előfordulasat. Eredmenyek: 76 nő es 71 ferfi eseteben diagnosztizaltunk Hodgkin-lymphomat ezen idő alatt. A betegek 95,9%-a kerult remisszioba az elsődleges kezelesre. 6 nőbeteg volt primeren refrakter, 4 betegnel autolog hemopoetikus őssejttranszplantacio is tortent, de a tobbszoros kezelesek ellenere is mindannyian exitaltak. 31 betegnel alakult ki relapszus (1 even belul 16 esetben). 14 betegnel tortent autolog hemopoetikus őssejttranszplantacio, 11 beteg csak kemoterapiaban, 3 csak irradiacioban es 3 beteg kombinalt kezelesben reszesult. A relabalt betegek kozul oten alapbetegseguk progresszioja, egy beteg szekunder ...Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the fi rst-line treatment. Aim and methods: We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. Results: We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after fi rst-line therapy. 6 women were primary refracter, 4 of them had highdose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients – 13 men and 18 women – had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. Conclusions: Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.UNLABELLED Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the first-line treatment. AIM AND METHODS We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. RESULTS We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after first-line therapy. 6 women were primary refracter, 4 of them had high-dose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients - 13 men and 18 women - had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. CONCLUSIONS Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.

Uncommon Late Relapse of Angioimmunoblastic T-Cell Lymphoma after 16-Year Remission Period

Abbreviations AITL Angioimmunoblastic T-cell lymphoma EBV Epstein-Barr virus FDG-PET/ CT Fluoro-deoxy-glucose Positron Emission Tomography/Computed Tomography LDH Lactate dehydrogenase CHOP Cyclophosphamide, doxorubicine, vincristine, prednisone COPBLAM Cyclophosphamide, vincristine, prednisone, bleomycin, adriamycin and procarbazin CEVP Cyclophosphamide, vinblastine, epirubicin and prednisone DHAP Dexamethasone, cytarabin, and cisplatin TNF Tumor necrosis factor EBER Epstein-Barr early RNA

Myeloid growth factor therapy in malignant lymphomas—a 5-year retrospective study from Hungary

Myeloid growth factors help to prevent and cure neutropenic events in malignant lymphoma patients treated by chemotherapeutical regimens. Administering either filgrastim or pegfilgrastim, treatment schedule can be kept well and less dose reductions are needed, which results in better survival rates. The aim of this study was to examine the indications and the outcome of myeloid precursor therapy among our malignant lymphoma patients. Between 2003 and 2007, 249 malignant lymphoma patients received 1,655 cycles of different polychemotherapies. Myeloid growth factor therapy was administered in 138 cases by 65 patients, which meant 8.33% of all treatment cycles and 26.1% of all patients, respectively. As for the indications, prevention was more common than intervention (71.7% vs. 28.3%). By preventive usage of growths factors, two-thirds of threatening neutropenic events could be avoided. Side effects were uncommon and mild: grades I–II toxicity was observed in 31% of all treatments. Analyzing the risk factors for febrile neutropenia among patients who received myeloid growth factor therapy compared to those who did not, we found the incidence of comorbidities, hypoalbuminemia, advanced stage disease, and aggressive chemotherapies significantly different in the two groups. Interestingly, there was no significant difference regarding the median age and the incidence of low body surface area. Our observations support that myeloid precursor therapy is an effective and safe implement to prevent or treat neutropenia in high-risk malignant lymphoma patients.

Refrakter és relabált Hodgkin-lymphomás betegeink kezelésével szerzett tapasztalataink

Napjainkban a legtobb Hodgkin-lymphomas beteg meggyogyithato a korszerű kezelesi modszerekkel, sajnos a betegek nehany szazaleka refrakter, es kozel harmaduk relabal az elsődleges kezelest kovetően. Celkitűzes es modszer: a DEOEC III. sz. Belgyogyaszati Klinikan 1996 es 2006 kozott kezelt Hodgkin-lymphomas beteg kozott vizsgaltuk retrospektiv modszerrel a refrakter esetek es a relapszusok előfordulasat. Eredmenyek: 76 nő es 71 ferfi eseteben diagnosztizaltunk Hodgkin-lymphomat ezen idő alatt. A betegek 95,9%-a kerult remisszioba az elsődleges kezelesre. 6 nőbeteg volt primeren refrakter, 4 betegnel autolog hemopoetikus őssejttranszplantacio is tortent, de a tobbszoros kezelesek ellenere is mindannyian exitaltak. 31 betegnel alakult ki relapszus (1 even belul 16 esetben). 14 betegnel tortent autolog hemopoetikus őssejttranszplantacio, 11 beteg csak kemoterapiaban, 3 csak irradiacioban es 3 beteg kombinalt kezelesben reszesult. A relabalt betegek kozul oten alapbetegseguk progresszioja, egy beteg szekunder ...Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the fi rst-line treatment. Aim and methods: We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. Results: We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after fi rst-line therapy. 6 women were primary refracter, 4 of them had highdose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients – 13 men and 18 women – had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. Conclusions: Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.UNLABELLED Recovery have been achieved in the majority of Hodgkin-lymphoma patients. Unfortunately some of the patients refracter and about third of the patients relapsed after the first-line treatment. AIM AND METHODS We investigated the frequency and treatment of refracter or relapsed Hodgkin lymphoma patients between 1996 and 2006. RESULTS We examined 76 women and 71 men, who had HL in this period. 141 patients (95,9%) had remission after first-line therapy. 6 women were primary refracter, 4 of them had high-dose therapy and autolog stem cell transplantation. They died in spite of the multiple treatment. 31 patients - 13 men and 18 women - had relapse (16 cases were in one year). 14 patients had high-dose therapy and autolog stem cell transplantation, 11 patients had only chemotherapy, 3 had only radiotherapy and 3 patients were treated by combined modality treatment. 6 of the relapsed patients were died, 5 because of the progression of lymphoma and one because of secunder myelodysplasia. CONCLUSIONS Relapsed patients have a good prognosis, but refracter patients have long chance despite autolog or allogen hemopoietic stem cell transplantation. Searching for new therapeutical modalities for these patients is extremely important.