Search

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.

The induction process of the galactose regulon has been intensively studied, but until now the nature of the inducer has remained unknown. We have analyzed a delta gal7 mutant of the yeast Kluyveromyces lactis, which lacks the galactotransferase activity and is able to express the genes of the Gal/Lac regulon also in the absence of galactose. We found that this expression is semiconstitutive and undergoes a strong induction during the stationary phase. The gal1-209 mutant, which has a reduced kinase activity but retains its positive regulatory function, also shows a constitutive expression of beta-galactosidase, suggesting that galactose is the inducer. A gal10 deletion in delta gal7 or gal1-209 mutants reduces the expression to under wild-type levels. The presence of the inducer could be demonstrated in both delta gal7 crude extracts and culture medium by means of a bioassay using the induction in gal1-209 cells. A mutation in the transporter gene LAC12 decreases the level of induction in gal7 cells, indicating that galactose is partly released into the medium and then retransported into the cells. Nuclear magnetic resonance analysis of crude extracts from delta gal7 cells revealed the presence of 50 microM galactose. We conclude that galactose is the inducer of the Gal/Lac regulon and is produced via UDP-galactose through a yet-unknown pathway.

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

Cutaneous pigmentation is regulated by a complex melanogenic network in which both keratinocytes and fibroblasts synthesize growth factors and cytokines. Solar lentigo (SL) is characterized by hyperpigmented lesions occurring on photodamaged skin areas. Despite the association of SL to ultraviolet (UV) exposure, the mechanisms underlying the development of these spots are not completely defined.To analyse the involvement of the fibroblast-derived growth factors, hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and stem cell factor (SCF) in SL hyperpigmentation; to evaluate whether the photoageing process occurring in fibroblasts could be responsible for the altered expression of these cytokines; and to investigate a new possible role of KGF in regulating pigmentation through the specific induction of melanogenic cytokines by keratinocytes.We performed immunohistochemical analysis of HGF, KGF and SCF on SL biopsies. We analysed the mRNA expression of these cytokines using an in vitro model of photoageing induced on fibroblasts. Finally, we evaluated the effects of KGF on the expression of melanogenic cytokines at the mRNA and protein levels on keratinocytes.We found positive staining for HGF, KGF and SCF in the upper dermis of SL lesions and a significant induction of the three cytokines in photoaged fibroblasts. We also demonstrated the contribution of KGF to pigmentation, showing its ability specifically to modulate the expression of SCF in keratinocytes.Fibroblasts may be persistently activated by UV exposure to release melanogenic growth factors; this inducible cytokine network acts both directly and indirectly through keratinocytes and may contribute to the hyperpigmentation of SL.

Keratinocyte growth factor (KGF) is involved in the control of proliferation and differentiation of human keratinocytes. It binds to, and activates, the tyrosine kinase KGF receptor (KGFR), a splicing transcript variant of the fibroblast growth factor receptor 2. We have previously shown (C. Marchese et al., Cell Growth Differ., 8: 989-997, 1997) that differentiation of primary cultured keratinocytes triggered by high Ca2+ concentrations in the growing medium induced up-regulation of KGFR expression, which suggested that KGFR may play a crucial role in the control of the proliferative/differentiative program during transition from basal to suprabasal cells. Here we analyzed the process of modulation of the expression of KGFRs in the human keratinocyte cell line HaCaT, widely used as a model to study keratinocyte differentiation. Western blot and double immunofluorescence for KGFR and the K1 differentiation marker showed that cell differentiation and stratification induced by confluence and high cell density correlated with an increase in KGFR expression. KGFRs, present on suprabasal differentiated cells, appeared to be efficiently tyrosine-phosphorylated by KGF, which indicated that the receptors up-regulated by differentiation can be functionally activated by ligand binding. Bromodeoxyuridine incorporation assay revealed that a significant portion of suprabasal differentiated cells expressing KGFR seemed to be still able to synthesize DNA and to proliferate in response to KGF, which suggested that increased KGFR expression may be required for retention of the proliferative activity.

This work presents a new methodology using formation testing at openhole conditions for layer fluid identification and reservoir parameters estimation. Real-time pressure and fluid identification data are obtained from the new wireline MDT* Modular Formation Dynamics Tester. The tool`s dual packer module makes zone isolation possible. Field cases from wells located in the San Jorge Gulf basin illustrate the testing methodology. The reservoir and well parameters of permeability (vertical and horizontal) and formation damage are obtained from pressure transient analysis of buildup and interference pressure data taken in several wells. The evaluation method is consistent with results obtained from testing after completion (cased hole DSTs). Evaluation results can be used to decide whether to complete or abandon the zone of interest. Fluid type is identified in real time using the OFA* Optical Fluid Analyzer module. Evaluation of anisotropy on a productive zone scale from the vertical interference test is shown.

e12051 Background: While national breast cancer mortality rates have decreased modestly among non-Hispanic White women, mortality has increased among Hispanic and Native American women, who present with later stage breast cancer, and use less screening mammography. The aims of the study were to identify barriers to mammography screening faced by Hispanic women age 40 to 64 and those faced by providers and elicit hypotheses about patient navigation interventions to increase utilization of mammography services. Methods: A socio-ecological model grounded the study. Social network, community, system design, and policy factors influence, and create barriers and facilitators to individual cancer screening behaviors among Hispanic females. The study included exploratory and confirmatory phases. The exploratory phase was informed by literature on screening barriers and facilitators. Interviews and focus groups were conducted, in five geographic regions in New Mexico, with the following groups 1) Primary care prov...

SummaryStathmokinetic agents are a class of antimitotic agents which possess the ability of arresting cell division at the metaphase stage.They are also called spindle poisons because they act by inactivating or distructing the mitotic spindle. Some new discovered stathmokinetic compounds, like vinblastine and vincristine, are effective anti-tumour agents. The mechanism of action of spindle poisons is briefly discussed.

SummaryVinblastine (VLB) and vincristine (VCR) are two alkaloids (extracted from the plant Catahranthus roseus) which possess a definite antitumor activity. The antitumor activity. The antimitotic action of these two alkaloids was studied both on normal bone marrow and leukemic cells. Comparative studies showed that they are, like colchicine, spindle poisons. They, however, differ from colchicine and its derivatives in some of their biological activities.The problem of the relationship between antitumor and antimitotic activity of VLB and VCR is discussed.

Gli AA. hanno studiato le modificazioni della reazione di Hotchkiss sul tessuto epatico di animali trattati con varie dosi di due sostanze antimitotiche : la trietilenmelamina (T.E.M.) e l'N-ossido della metil-bis(β-cloroetil)amina.E' stato dimostrato che queste sostanze determinano una riduzione del glicogeno epatico, che, negli animali trattati con le dosi piu elevate, arriva fino al di sotto della soglia di sensibilita alla reazione di Hotchkiss. Gli AA. avanzano l'ipotesi che le alterazioni osservate siano in rapporto con una inibizione enzimatica della glicogenogenesi. 188

Dopo la scoperta che i soggetti con leucemia mieloide cronica presentano una delezione del braccio lungo di uno dei cromosomi della coppia 21 (cromosoma Filadelfia o Ph1), è stata avanzata l'ipotesi (Moloney, 1961) che in questo cromosoma siano localizzati il gene, o i geni, che controllano la fosfatasi alcalina leucocitaria (FAL). Sulla base di questa ipotesi fu poi postulato che la FAL dovesse essere aumentata nella sindrome di Down, dove esiste una trisomia 21. Numerose ricerche hanno infatti dimostrato che, in questa sindrome, la FAL è spesso elevata (Trubowitz et al, 1962; King et al, 1962a, 1962b; Lennox et al, 1962; O'Sullivan e Pryles, 1963; Alter et al, 1963; Cardinali et al, 1966; Medzewski e Loesch, 1966).Indagini condotte nel nostro Istituto su un gruppo di 40 bambini affetti da sindrome di Down ci hanno permesso di dimostrare che l'aumento medio della FAL nei pazienti rispetto ai controlli era molto vicino al rapporto previsto di 3: 2 (Cardinali et al, 1966). Le nostre indagini hanno anche indicato che la FAL può essere aumentata, non solo nei casi di sindrome di Down in cui l'alterazione cromosomica è del tipo trisomia, ma anche nei casi in cui l'alterazione è del tipo traslocazione. Esiste, tuttavia, un certo numero di pazienti in cui i valori della FAL sono sovrapponibili a quelli dei soggetti normali. È noto, d'altro canto, che questa attività enzimatica può variare notevolmente sotto l'influenza di vari fattori fisiologici e patologici, quali l'età, la gravidanza, certi ormoni, le infezioni e altri stati morbosi. Resta quindi da chiarire quale sia l'importanza dei fattori genetici nel controllo della FAL.

SUMMARYRunts were observed in the offspring of mice which were injected, when newborn, with foreign bone marrow cells. The incidence of runting in the litters obtained from crosses between injected females and injected males was higher than in the litters obtained from crosses between injected females and normal males.

The bacterial flora of the skin from different anatomical sites on cancer patients and a control group of medical personnel was examined. This was done to ascertain if antineoplastic therapy was able to change the pattern of microbial flora of patients and to provide a control for possible infectious complications. The results show that in the control group bacterial flora was normal and the antineoplastic treatment did not succeed in changing the bacterial pattern in the skin of patients deeply. Gram negative bacteria were isolated more frequently from the skin of leukemia patients than from either patients with malignant melanoma or other neoplastic diseases.

Sera from 1,279 patients with various diseases were examined for the presence of antibodies to BK virus (BKV) capsid antigens. The percentage of positive sera was comparable in all the diseases except rheumatoid arthritis and chronic nephropathies, where a slightly higher prevalence was found. Sera from 952 patients with tumors were examined for the presence of antibodies to BKV tumor and capsid antigens in comparison with a matched control group of 501 blood donors. Sera from 11 tumor patients (1.15%) and from 4 normal controls (0.80%) had antibodies to BKV tumor antigen. No higher prevalence of antibodies to BKV capsid antigens was found in any cancer type except in carcinomas of the urinary bladder, where the percentage of positive sera and of sera with high titers was higher than in other groups. BKV infection is discussed in relation to its possible connection with human non-neoplastic diseases as well as with human tumors and to its activation under conditions of immunosuppressive therapy.

Adriamycin (A.) is a new antibiotic with antitumor activity recently isolated from a mutant of Streptomices Peucetius, S. Peucetius caesius, in the Research Laboratories of Farmitalia. The structural formula of A. is very close to that of daunomycin which was isolated from S. Peucetius [1].