VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma

The von Hippel-Lindau tumor-suppressor gene (VHL) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Of note, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF-regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor-suppressing regulator of autophagic programs.     

Synergistic cytotoxic effect of sulindac and pyrrolidine dithiocarbamate against ovarian cancer cells

Sulindac, a non-steroidal anti-inflammatory drug, suppresses carcinogenesis and inhibits growth of tumor cells. Pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, has been also identified as a potential anti-neoplastic agent. We hypothesized that combination of sulindac and PDTC could result in augmentation of cytotoxicity against ovarian cancer cells. The effect of sulindac and PDTC was examined on several ovarian cancer lines. Tumor cell viability was assessed using the MTT assay. Annexin-V/PI staining was used to detect apoptosis, cell cycle distribution was analyzed in FACS, and expression of cellular proteins was detected by western blotting. Incubation of OVA-14, OVP-10 and CAOV-1 ovarian cancer cells with sulindac and PDTC resulted in significantly greater inhibition of cell viability compared to either compound alone. In a model of OVA-14 cells it was evident that this effect was not related to the expression of COX enzymes since both active (sulindac sulfide) and inactive (sulindac) in vitro compounds affected the growth of tumor cells to a similar extent and synergized in cytotoxicity with PDTC. Combination of sulindac and PDTC lead to G0 arrest and massive apoptosis in co-treated cultures. Western blotting analysis argued for induction of the mitochondrial apoptotic pathway. These data demonstrate the synergistic cytotoxic effect of sulindac and PDTC on ovarian cancer cells through apoptosis and cell cycle arrest and prompt to test the efficacy of this combination in animal models.     

Expression of Metallothioneins in Cutaneous Squamous Cell Carcinoma and Actinic Keratosis

Metallothioneins (MT) are low-molecular weight proteins implicated in heavy metal detoxification, zinc and cooper homeostasis and cell protection against free radicals. In variety of cancers MT-overexpression was shown, but there are just a few studies on the role of MT in skin carcinogenesis. Current study was undertaken to evaluate MT and Ki-67 expression in pre-cancerous skin lesions as well as in fully developed skin cancers. 73 squamous cell carcinomas (SCC), 23 actinic keratoses (AK) and 20 normal skin samples were included in the study. In obtained paraffin sections immunohistochemical reactions were performed. MT-expression in SCC (mean 2.89?±?1.83) was significantly higher than in AK (mean 1.69?±?1.26)(p?=?0.006) and higher than in normal skin (mean 2?±?0.79) (p?=?0.0075). The MT-expression positively correlated with Ki-67 expression (R?=?0.28; p?=?0.017) in SCC and in AK (R?=?0.49; p?=?0.018). Various clinico-pathological variables, e.g. morphology, size of lesions and the depth of neoplastic infiltration were not associated to MT-expression in both SCC and AK. The grade of histological differentiation of SCC correlated positively with Ki-67 antigen (p?相似文献   

Hemostatic changes after 1?month of thalidomide and dexamethasone therapy in patients with multiple myeloma

Thromboembolic events (TEE) are a serious clinical problem in multiple myeloma (MM) patients receiving thalidomide (T). Thirty-one MM patients were tested on diagnosis and after 2 and 4?weeks of therapy with T alone, or T in combination with dexamethasone (TD). Closure time (CT) in PFA-100 and P-selectin expression were assessed, as well as plasma levels of thrombin-antithrombin complexes (TAT), D-dimer (DD), soluble thrombomodulin (sTM) and von Willebrand factor antigen (vWF:Ag), along with the activity of coagulation factor VII and factor VIII. The concentration of vascular endothelial growth factor and its type 1 and 2 receptors were also assayed. On diagnosis, significantly prolonged median CT with both used cartridges, elevated P-selectin expression, DD concentration, TAT, vWF:Ag and factor VIII and factor VII activity were seen in the patient group as compared to controls. Therapy with these regimens caused marked shortening of CT with both cartridges. Treatment with TD leads to the significant increase in CD62P expression on platelets. Median TAT value increased significantly in relation to baseline after therapy with both regimens. Factor VIII activity exceeded 150?% in all patients after 2?weeks of TD therapy and was markedly elevated compared to baseline. One month of TD therapy significantly increased sTM concentration. These results demonstrate the enhanced platelet and coagulation system activation already present in MM patients on diagnosis, which is further increased by antimyeloma therapy. These changes are more pronounced after TD therapy and may promote TEE. Tested angiogenesis marker levels are elevated already on diagnosis, do not change after therapy and have no significant impact on the coagulation system in patients with MM.     

Amelanotic malignant melanoma in an acral location

We present the case of a 74-year-old white female admitted to the Department of Dermatology because of a tumor in the IV-V interdigital area of her right foot. A crimson, dome-shaped tumor with a granular, spongy surface (diameter 4 cm) had developed over a period of about 3 months. The biopsy, stained with H and E, revealed an anaplastic malignant tumor. Additional immunochemical staining with Melan A allowed us to make the final diagnosis: amelanotic malignant melanoma (MM). The melanoma was removed by amputation of digits IV and V, with partial removal of the metatarsal bones (Clark degree 5, Breslow thickness 9 mm). Sentinel node biopsy was done using Tc99; it revealed no neoplastic alteration. The patient is still under oncological observation.     

Vulvar pruritus and burning sensation in women with psoriasis

Approximately 80% of psoriatic individuals experience pruritus, of varying intensity. This study evaluated the frequency of vulvar itching and burning and its influence on well-being in women with psoriasis. A total of 93 women were included in the study. Psoriasis severity was assessed according to the Psoriasis Area and Severity Index, the intensity of vulvar discomfort by visual analogue scale and depressive symptoms by Beck's Depression Inventory. On admission 41 (44.1%) women experienced vulvar discomfort, 18 (19.4%) itching, 10 (10.8%) burning and 13 (14.0%) both itching and burning sensations. Psoriatic lesions on the vulva were found in 22 (23.7%) women. No significant correlation was found between burning or itching intensity and global psoriasis severity (r = 0.19, p = 0.26). Patients with vulvar discomfort had psoriatic lesions on the vulva more often than women without discomfort (43.6% vs. 8.2%, p < 0.001). In addition, patients with vulvar discomfort more frequently demonstrated depressive symptoms (p < 0.05). We conclude that vulvar discomfort is an important clinical problem in women with psoriasis and should be taken into consideration during treatment.     

Analyses of volatile organic compounds from human skin

Background Human skin emits a variety of volatile metabolites, many of them odorous. Much previous work has focused upon chemical structure and biogenesis of metabolites produced in the axillae (underarms), which are a primary source of human body odour. Nonaxillary skin also harbours volatile metabolites, possibly with different biological origins than axillary odorants. Objectives To take inventory of the volatile organic compounds (VOCs) from the upper back and forearm skin, and assess their relative quantitative variation across 25 healthy subjects. Methods Two complementary sampling techniques were used to obtain comprehensive VOC profiles, viz., solid‐phase microextraction and solvent extraction. Analyses were performed using both gas chromatography/mass spectrometry and gas chromatography with flame photometric detection. Results Nearly 100 compounds were identified, some of which varied with age. The VOC profiles of the upper back and forearm within a subject were, for the most part, similar, although there were notable differences. Conclusions The natural variation in nonaxillary skin odorants described in this study provides a baseline of compounds we have identified from both endogenous and exogenous sources. Although complex, the profiles of volatile constituents suggest that the two body locations share a considerable number of compounds, but both quantitative and qualitative differences are present. In addition, quantitative changes due to ageing are also present. These data may provide future investigators of skin VOCs with a baseline against which any abnormalities can be viewed in searching for biomarkers of skin diseases.     

Demodex infections in general Polish population, in patients suffering from blepharitis, and among people who work with microscopes

In this study we examined 264 people to estimate the prevalence of Demodex infection. The subjects were divided into 4 groups. First two groups consisted of young people (mean age 22 years) and seniors (mean age 66 years) respectively. The third group included people who work with microscopes (mean age 44 years). Forth group consisted of patients with diagnosed blepharitis (mean age 65 years). From every individual 3-4 lashes were epilated from the eyelids of both eyes and examined under the microscope for Demodex mites. The statistical analysis based on logistic regression was used to estimate the probability of infection. Age was independent variable significant for this model (p < 0.001). Significant relation between age and probability of Demodex infection was showed. The lowest number of infected individuals was observed in the group of young subjects (only 5%), the highest in the blepharitis patients (74% infected). Among microscope users 30% were infected, in the group of seniors 34% were infected.