Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation.

We have isolated murine cDNAs encoding two isoforms of a putative protein-serine/threonine kinase, designated Sak-a and Sak-b, which differ in their noncatalytic C-terminal ends. The kinase domain of Sak is related to the catalytic domains of the Drosophila polo, Saccharomyces cerevisiae CDC5, and murine Snk and Plk kinases, a family of proteins for which a role in controlling cell proliferation has been established (polo, CDC5) or implicated (Snk, Plk). Northern and in situ RNA analyses of Sak gene expression in mouse embryos and adult tissues revealed that expression was associated with mitotic and meiotic cell division. In addition, during embryogenesis, Sak expression was prominent in the respiratory and olfactory mucosa. The pattern of Sak expression and its sequence homology with the polo gene family suggest that the Sak kinase may play a role in cell proliferation. In support of this, cell growth was suppressed by expression of a Sak-a-antisense fragment in CHO cells.     

Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment

BACKGROUND: In several clinical studies, topical calcineurin inhibitors have been shown to be effective in the treatment of atopic dermatitis (AD). They target signaling pathways that control gene expression, particularly the expression of cytokines. OBJECTIVE: We examined the cellular infiltrate in skin lesions of 10 patients with AD and characterized the cytokine pattern expressed by the infiltrating cells before and after short-term topical therapy with tacrolimus 1% ointment. METHODS: Skin biopsies were examined for histologic alterations (hematoxylin and eosin staining), composition of the cellular inflammatory infiltrate (immunofluorescence), and cytokine expression (ribonuclease protection assay, ELISA, immunofluorescence) before as well as 1 and 3 weeks after initiation of tacrolimus therapy. For comparison, biopsies from nonlesional AD and normal skin were analyzed. Systemic immunologic effects were assessed by analyzing peripheral blood leukocytes (immunofluorescence) as well as in vitro stimulated pan-T-cell cytokine production (ELISA). RESULTS: All patients showed a significant improvement of their skin lesions associated with a marked regression of spongiosis, acanthosis, and density of the cellular infiltrate in the dermis. The last was a result of reduced infiltration of T cells, B cells, and eosinophils. In contrast, the numbers of mast cells did not change. Moreover, the expression of the T H 2 cytokines IL-5, IL-10, and IL-13 in CD4 + T cells was reduced after therapy. Interestingly, tacrolimus therapy was also associated with a reduction of CD8 + T cells expressing the T H 1 cytokine IFN-gamma. Furthermore, the numbers of epidermal CD1a + dendritic cells increased after treatment. In the peripheral blood, a decrease of granulocytes (eosinophils and neutrophils) but no changes in the distribution of lymphocyte subpopulations were noticed. CONCLUSION: Topical tacrolimus treatment has anti-inflammatory effects on AD skin as indicated by reduced infiltration of cytokine expressing inflammatory cells. No evidence for drug-induced systemic immunosuppression was obtained.     

Genetic and biochemical characterization of Malassezia pachydermatis with particular attention to pigment-producing subgroups.

The aim of the study was the characterization of Malassezia pachydermatis and its pigment-producing subgroup using biochemical tests and RAPD. It was of interest to determine whether particular RAPD patterns could be used to indicate pigment production, as well as a close genetic relatedness to Malassezia furfur. Therefore, 210 strains of M. pachydermatis were examined for morphology, catalase and ss-glucosidase activity, lipid and carbohydrate assimilation and the tryptophan-dependent synthesis of pigments. Of these, 114 strains were subjected to RAPD analyses. A multivariate logistic regression model was applied to classify M. pachydermatis isolates regarding their pigment production by using genetic and biological parameters. Biological and RAPD findings showed a high biological and genetic diversity within the species M. pachydermatis and within pigment producers. RAPD analysis revealed 28 genotypes within 114 strains tested. Pigment producing strains could not be assigned to a common RAPD profile, but a genetic relatedness of pigment-producing M. pachydermatis with M. furfur can be assumed. A particular RAPD pattern allowed statistically significant probability of pigment production (P<0.001) and might be used as a tool to rapidly detect pigment producing M. pachydermatis, e.g. in Malassezia-associated pityriasis versicolor. The reported method is useful for identification of pigment producing M. pachydermatis isolates and has advantages over established tests.     

Immunotherapeutic targets in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5-year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in-depth profiling of the tumour microenvironment (TME) is required. The TME is a complex network of cell types that form an interconnected network, promoting tumour cell initiation, growth and dissemination. The stroma, immune cells and endothelial cells that comprise the TME generate a plethora of cytotoxic or cytoprotective signalling pathways. In this review, we discuss immunotherapeutic targets in NSCLC tumours and how the TME may influence patients' response to immunotherapy.     

Are seizures more frequent in asthmatic children?

Asthma and epilepsy have been suspected to be related to each other for a long time. To determine the frequency of seizures occurring in all asthmatic children referred to the teaching hospitals affiliated to Tehran University of Medical Sciences (TUMS) for two consecutive years, we conducted the following study. 16 out of 202 cases had previous history of non-febrile seizures (7.9%). Five patients (2.5%) had only a single seizure, and the remaining (5.4%) had recurrent attacks. All cases had generalized tonic-clonic type of seizures. One of the cases had a prolonged seizure (status epilepticus) lasting for more than 30 minutes. We concluded that the occurrence of seizure in our asthmatic patients was far more frequent than that in the general population.     

Acetyl Salicylic Acid Locally Enhances Functional Recovery after Sciatic Nerve Transection in Rat

Local effect of acetyl salicylic acid (ASA) on peripheral nerve regeneration was studied using a rat sciatic nerve transection model. Forty-five male healthy White Wistar rats were divided into three experimental groups (n = 15), randomly: Sham-operation (SHAM), control (SIL), and ASA-treated (SIL/ASA) groups. In SHAM group after anesthesia left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis the muscle was sutured. In SIL group the left sciatic nerve was exposed the same way and transected proximal to tibio-peroneal bifurcation leaving a 10-mm gap. Proximal and distal stumps were each inserted into a silicone tube and filled with 10 μl phosphate buffered solution. In SIL/ASA group defect was bridged using a silicone tube filled with 10 μl acetyl salisylic acid (0.1 mg/ml). Each group was subdivided into three subgroups of five animals each and were studied 4, 8, and 12 weeks after surgery. Data were analyzed statistically by factorial analysis of variance (ANOVA) and the Bonferroni test for pair-wise comparisons. Functional study confirmed faster and better recovery of regenerated axons in SIL/ASA than in SIL group (p < 0.05). Gastrocnemius muscle mass in SIL/ASA was significantly more than in SIL group. Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers in SIL/ASA were significantly higher than in control group. In immuohistochemistry, location of reactions to S-100 in SIL/ASA was clearly more positive than in SIL group. Response to local treatment of ASA demonstrates that it influences and improves functional recovery of peripheral nerve regeneration.     

Breast tumor stroma: A driving force in the development of resistance to therapies

Breast cancer is the most common cancer and the second leading cause of cancer‐related death in women worldwide. In spite of huge advancements in early detection and ever‐increasing knowledge of breast cancer biology, approximately 30% of patients with early‐stage breast cancer experience disease recurrence. Most patients are chemosensitive and cancer free immediately after the treatment. About 50% to 70% of breast cancer patients, however, will relapse within 1 year. Such a relapse is usually concomitant with adenocarcinoma cells acquiring a chemoresistant phenotype. Both de novo and acquired chemoresistance are poorly understood and present a major burden in the treatment of breast cancer. Although, previously, chemoresistance was largely linked to genetic alterations within the cancer cells, recent investigations are indicating that chemoresistance can also be associated with the tumor microenvironment. Nowadays, it is widely believed that tumor microenvironment is a key player in tumor progression and response to treatment. In this study, we will review the interactions of breast tumor cells with their microenvironment, present the latest research on the resistance mediated by the stromal component in breast cancer, and discuss the potential therapeutic strategies that can be exploited to treat breast cancers by targeting tumor microenvironment.