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1.
J Eur Acad Dermatol Venereol ; 35(5): 1186-1196, 2021 May.
Article in English | MEDLINE | ID: mdl-33480075

ABSTRACT

BACKGROUND: Atopic dermatitis (AD) presents with the wide spectrum of clinical phenotypes within and between various populations. Recent study showed low frequency of filaggrin loss-of-function (FLG LOF) mutations in Croatian AD patients. At present, there are no data on biomarkers of immune response in Croatian AD patients that might be useful in the selection and monitoring of novel immune therapies. OBJECTIVES: To investigate levels of cytokines of various signature in the stratum corneum (SC) collected from lesional and non-lesional skin of AD patients and healthy controls and to evaluate their relationship with the severity of disease and skin barrier function. METHODS: SC samples were collected from 100 adult patients with moderate-to-severe AD and 50 healthy controls. The levels of 21 cytokines were measured by multiplex immunoassay. We conducted machine learning analysis to assess whether a small number of cytokine measurements can discriminate between healthy controls and AD patients and can predict AD severity (SCORAD). RESULTS: The SC levels of thirteen cytokines representing innate immunity, Th-1, Th-2 and Th-17/22 immune response showed significant differences between healthy and AD skin. Our analysis demonstrated that as few as three cytokines measured in lesional skin can discriminate healthy controls and AD with an accuracy of 99% and that the predictive models for SCORAD did not achieve a high accuracy. Cytokine levels were highly correlated with the levels of filaggrin degradation products and skin barrier function. CONCLUSIONS: Stratum corneum analysis revealed aberrant levels of cytokines representing innate immunity, Th-1-, Th-2- and Th-17/22-mediated immune response in Croatian AD patients. Increased Th-2 cytokines and their strong association with natural moisturizing factor (NMF) can explain low NMF levels despite of low frequency of FLG LOF mutations in Croatian population. Predictive models for SCORAD identified cytokines associated with SCORAD but warrants further investigation.


Subject(s)
Dermatitis, Atopic , Adult , Biomarkers , Epidermis , Filaggrin Proteins , Humans , Severity of Illness Index , Skin , T-Lymphocytes, Helper-Inducer
2.
J Eur Acad Dermatol Venereol ; 34(8): 1789-1794, 2020 Aug.
Article in English | MEDLINE | ID: mdl-31989686

ABSTRACT

BACKGROUND: FLG loss-of-function mutations (FLG LOF) represent the strongest genetic risk factor for atopic dermatitis (AD) and are associated with early-onset and more severe disease. The prevalence of FLG mutations varies greatly across Europe. At present, there are no data on FLG mutation prevalence in Croatian AD patients. OBJECTIVES: To investigate the prevalence of FLG LOF mutations in adult patients with AD and healthy controls. Next to measure the stratum corneum (SC) levels of filaggrin degradation products (NMF), transepidermal water loss (TEWL) and pH in lesional and non-lesional skin. METHODS: We recruited 100 AD patients with moderate to severe disease and 50 healthy controls. They were screened for three FLG mutations (R501X, 2282del4 and R2447X). Samples of the SC for NMF analysis were collected by adhesive tapes. TEWL and skin surface pH levels were determined on the lesional and non-lesional skin. RESULTS: The combined mutation frequency was 4% in the AD group, and all patients with FLG mutations were homozygous carriers. In the control group, no mutations were found. The most common FLG mutation in AD patients was 2282del4 (3%), followed by R501X (1%). As compared to healthy controls, NMF values were strongly reduced in lesional skin; however, no significant difference was found for non-lesional skin. AD patients had elevated TEWL in both lesional and non-lesional skin. The same pattern was observed for pH. CONCLUSIONS: Our study expands understanding of the landscape of FLG mutations in the European population. The low frequency of FLG mutations and similar levels of filaggrin degradation products in healthy controls and in non-lesional skin of AD patients suggest that filaggrin deficiency does not confer a major risk for AD in the Croatian population.


Subject(s)
Dermatitis, Atopic , Intermediate Filament Proteins/genetics , Adult , Croatia , Dermatitis, Atopic/genetics , Europe , Filaggrin Proteins , Genetic Predisposition to Disease , Genotype , Humans , Loss of Function Mutation
3.
Oncogene ; 38(25): 5111-5112, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30867566

ABSTRACT

In the published version of this article, the images for cytoplasmic and nuclear FGF7 in MDA-MB-231 cells were duplicated and mistaken for total FGF7 in SKBR-3 and MDA-MB-231 cells.

5.
J Org Chem ; 82(24): 13115-13120, 2017 12 15.
Article in English | MEDLINE | ID: mdl-29131956

ABSTRACT

Selective deuteration of drugs and biologically relevant molecules is becoming increasingly important in the pharmaceutical industry. Site-selective isotopic reinforcement of polyunsaturated fatty acids (PUFAs) at their bis-allylic sites has been identified as a unique approach in preventing oxidative damage in these molecules, which had been linked to neuronal and retinal diseases, atherosclerosis, and aging. Typical methods for preparation of site-selectively deuterated PUFAs require rather long, laborious, and expensive syntheses. In this report, we disclose a very efficient catalytic protocol for site-specific deuteration of PUFAs and analogous poly-alkenes under exceptional kinetic control. Deuterium oxide (D2O) has been identified not only as a deuterium source but also as a crucial component in the overall reaction mechanism responsible for averting the formation of thermodynamically favored side-products.


Subject(s)
Alkenes/chemistry , Deuterium Oxide/chemistry , Deuterium , Fatty Acids, Unsaturated/chemistry , Models, Molecular , Radiopharmaceuticals , Substrate Specificity
6.
Dalton Trans ; 46(41): 14244-14250, 2017 Oct 24.
Article in English | MEDLINE | ID: mdl-28991293

ABSTRACT

Complex [Cp*Ru(NCMe)3][PF6], 1a, has been identified as a cis-to-trans isomerization catalyst of various non-conjugated cis-polyalkenes under exceptional kinetic control as no alkene conjugation was observed. According to the experimental and theoretical data, the cis-trans isomerization occurred via an alkene-assisted mechanism in which one cis-double bond always served as an anchoring site. Using a combination of multinuclear NMR spectroscopic evidence and mathematical methods it was possible to determine the extent of trans isomerization.

7.
Climacteric ; 20(1): 31-36, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27845859

ABSTRACT

OBJECTIVES: Visceral fat is more harmful than subcutaneous fat. Women with high amounts of visceral fat have an increased risk of metabolic syndrome (MetS), insulin resistance and low level of serum vitamin D. METHODS: This was a prospective, randomized and controlled study. Postmenopausal women (n = 101) aged 45-70 years were included. The assessed parameters were: body mass index (BMI), waist circumference (WC), 25-hydroxyvitamin D (25-OHD) status, serum insulin and HOMA-IR, bone mineral density, total fat mass, fat mass index (FMI) measured by DXA, and muscle strength. RESULTS: Significantly lower values of 25-OHD (35.26 ± 1.61 nmol/l) were found in women with MetS compared to those without MetS (47.52 ± 3.47nmol/l) (t = 3.699; p < 0.000). A significant negative correlation was observed between 25-OHD levels and: WC (rhoWC = -0.94; p < 0.004), BMI (rhoBMI = -0.80; p < 0.002), FMI (rhoFMI = -0.31; p < 0.002) and impaired fasting glucose (IFG) (rhoIFG = -0.23; p < 0.001). The percentage of body fat was statistically significantly higher in the group with insufficient 25-OHD (39.6%) and in the group with a deficit of 25-OHD (48.2%), compared with the maximum permitted percentage body fat of 35% for a female (t = -22.63; p < 0.002). The average hand grip strength of these moderately obese participants was 27.4 ± 4.7 kg. It was significantly lower than the normative grip strength for referent range groups (t = -21.65; p < 0.001). CONCLUSION: A low 25-OHD level in postmenopausal women is associated with high body fat, metabolic syndrome, low muscular strength and osteopenia.


Subject(s)
Bone Density , Hand Strength , Metabolic Syndrome/etiology , Postmenopause/physiology , Vitamin D Deficiency/etiology , Absorptiometry, Photon , Aged , Blood Glucose/analysis , Body Composition , Body Mass Index , Bone Diseases, Metabolic/etiology , Fasting/blood , Female , Humans , Insulin/blood , Insulin Resistance , Intra-Abdominal Fat/metabolism , Middle Aged , Muscle Strength/physiology , Prospective Studies , Risk Factors , Vitamin D/analogs & derivatives , Vitamin D/blood , Waist Circumference
8.
Article in English | MEDLINE | ID: mdl-27145728

ABSTRACT

The aim of this analysis was to evaluate adherence of Croatian oncologists to follow-up criteria as suggested by the current national and international guidelines for women with breast cancer receiving adjuvant endocrine therapy. The use of clinical and diagnostic methods was documented in this prospective, non-interventional, multicenter study. A total of 438 post-menopausal patients receiving adjuvant endocrine treatment with non-steroidal aromatase inhibitors were included. Average annual frequency for each clinical and diagnostic method was calculated. Median adjuvant endocrine treatment duration before study recruitment was 10.5 months (interquartile 4.7-26.6). Patients were followed up for an average 23.5 ± 4.9 months. Average number of oncological visits was 5.3. Mammograms were performed at mean annual frequency of 0.7, chest radiographs at 0.5, abdominal ultrasounds at 0.9, breast ultrasounds at 1.2, complete blood counts and chemistry panels at 1.7, carcinoembryonic antigen at 0.8, cancer antigen 15-3 at 1.6, gynaecological examination at 0.3, and densitometry at mean annual frequency of 0.3. In conclusion, among post-menopausal women with breast cancer receiving adjuvant endocrine therapy in this study, more unnecessary and unproven follow-up procedures were done compared to the guidelines' recommendations.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Neoplasms, Hormone-Dependent/drug therapy , Aftercare , Chemotherapy, Adjuvant , Croatia , Female , Guideline Adherence , Humans , Middle Aged , Oncologists/standards , Oncologists/statistics & numerical data , Postmenopause , Practice Guidelines as Topic , Practice Patterns, Physicians'/standards , Practice Patterns, Physicians'/statistics & numerical data
9.
Scand J Immunol ; 80(1): 43-9, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24684674

ABSTRACT

In humans, there are three members of type III interferon family, designated as IFN-λ1 (IL-29), IFN-λ2 (IL-28A) and IFN-λ3 (IL-28B). Bacterial infections, including Mycobacterium tuberculosis infection, trigger the expression of interferon I and II genes, but little is known about their effect on IFN-λ genes. It has been found that M. tuberculosis infection in A549 lung epithelial cells stimulate upregulation of IFN-λ2 genes in vitro. The aim of this study was to determine the IFN-λ2 levels in sputum of patients with active pulmonary tuberculosis comparing with levels in healthy persons sputum and sputum of persons with latent tuberculosis. IFN-λ2 level in the samples was quantified with sandwich enzyme-linked immunoassay kit for quantization of human IFN-λ2 (IL-28A). The IFN-λ2 level in sputum of patients with pulmonary tuberculosis was significantly higher comparing with IFN-λ2 levels in healthy group (P = 0.001) and latent tuberculosis group (P = 0.005). Logistic regression analysis has shown that IFN-λ2 level in sputum is related to culture result (OR = 4.14; 95% CI = 1.28-17.5; P = 0.019). There was the correlation between Bartlett score and IFN-λ2 levels in group with pulmonary tuberculosis (r = 0.641; P < 0.01). In conclusion, we have found that the inflammatory cells in sputum can be source of IFN-λ after receptor stimulation by M. tuberculosis components.


Subject(s)
Interleukins/analysis , Sputum/immunology , Tuberculosis, Pulmonary/immunology , Adult , Aged , Female , Humans , Logistic Models , Male , Middle Aged
10.
Phys Rev E Stat Nonlin Soft Matter Phys ; 85(6 Pt 1): 061117, 2012 Jun.
Article in English | MEDLINE | ID: mdl-23005061

ABSTRACT

The percolation aspect of random sequential adsorption of extended objects on a triangular lattice is studied by means of Monte Carlo simulations. The depositing objects are formed by self-avoiding lattice steps on the lattice. Jamming coverage θ{jam}, percolation threshold θ{p}, and their ratio θ{p}/θ{jam} are determined for objects of various shapes and sizes. We find that the percolation threshold θ{p} may decrease or increase with the object size, depending on the local geometry of the objects. We demonstrate that for various objects of the same length, the threshold θ{p} of more compact shapes exceeds the θ{p} of elongated ones. In addition, we study polydisperse mixtures in which the size of line segments making up the mixture gradually increases with the number of components. It is found that the percolation threshold decreases, while the jamming coverage increases, with the number of components in the mixture.


Subject(s)
Colloids/chemistry , Crystallization/methods , Models, Chemical , Models, Statistical , Adsorption , Computer Simulation
11.
Oncogene ; 31(14): 1845-58, 2012 Apr 05.
Article in English | MEDLINE | ID: mdl-21860419

ABSTRACT

Vascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.


Subject(s)
Breast Neoplasms/metabolism , Forkhead Transcription Factors/metabolism , Vascular Endothelial Growth Factor A/metabolism , Cell Line, Tumor , Female , Forkhead Box Protein M1 , Forkhead Box Protein O3 , Gene Expression Regulation, Neoplastic , Histone Deacetylase 2/metabolism , Humans , Lapatinib , Quinazolines/pharmacology
12.
Med Hypotheses ; 76(3): 450-2, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21195559

ABSTRACT

The postoperative period is accompanied with neuroendocrine, metabolic and immune alteration which is caused by tissue damage, anesthesia, postoperative pain and psychological stress. Postoperative pain contributes to dysfunction of immune response as a result of interaction between central nervous and immune system. The postoperatively activated hypotalamo-pituitary-adrenocortical axis, sympathic and parasympathic nerve systems are important modulators of immune response. According to bidirectional communication of immune and nervous system, appropriate postoperative pain management could affect immune response in postoperative period. Although the postoperative suppression of immune response has been reported, a very little are known about the influences of different pain management techniques on cytotoxic function of immune cells in patients with colorectal cancer in early postoperative period. Perforin is a cytotoxic molecule expressed by activated lymphocytes which has a crucial role in elimination of tumor cells and virus-infected cells, mostly during the effector's phase of immune response. Immune compromise during the postoperative period could affect the healing processes, incidence of postoperative infections and rate and size of tumor metastases disseminated during operation. The pharmacological management of postoperative pain in patients with malignancies uses very different analgesic techniques whose possible influence on cytotoxic functions of immune cells are still understood poor. For decades the most common way of treating postoperative pain after colorectal cancer surgery was intravenous analgesia with opiods. In the last decade many investigations pointed out that opiods can also contribute to postoperative suppression of immune response. Epidural analgesia is a regional anesthesia technique that acts directly on the origin of pain impulses and pain relief can be achieved with small doses of opiods combined with local anesthetics. Local anesthetics potentate analgesic properties of opiods but per se are also acting as antiinflammatory drugs. Afferent neural blockade by epidural analgesia attenuates neuroendocrine stress response. We propose that epidural analgesia could be more convenient that intravenous analgesia in maintenance of immunological homeostasis that is altered by surgical stress, tumor growth and pain.


Subject(s)
Analgesia/methods , Colorectal Neoplasms/surgery , Pain, Postoperative/drug therapy , Perforin/metabolism , Analgesia, Epidural/methods , Analgesics/therapeutic use , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/therapeutic use , Anesthesia, Local/methods , Anesthetics, Local/administration & dosage , Anesthetics, Local/therapeutic use , Colorectal Neoplasms/drug therapy , Dose-Response Relationship, Drug , Drug Therapy, Combination , Humans , Pain/drug therapy , Postoperative Period
13.
Autoimmun Rev ; 10(4): 235-7, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21095242

ABSTRACT

Antiphospholipid syndrome (APS) is an autoimmune disease which is characterized by arterial and venous thromboses, fetal loss, and the presence of antiphospholipid antibodies in the serum (aPL). It is characterized by accelerated atherosclerosis and that together with an increased tendency towards thrombosis leading to the occurrence of various vascular events. Timely diagnosis of vascular changes, preferably in subclinical phase, is required due both to their severity and to the high mortality rate. Detection of arterial and venous changes nowadays is performed through diversity of invasive and non invasive diagnostic methods. 64-multi slice computed tomographic angiography (64-MSCT) seems to be the most precise method with low exposure time, giving the opportunity for clinicians to early diagnose and timely treat APS patients.


Subject(s)
Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/diagnosis , Vascular Diseases/diagnosis , Vascular Diseases/etiology , Humans
14.
West Indian med. j ; 59(5): 518-522, Oct. 2010. ilus, tab
Article in English | LILACS | ID: lil-672668

ABSTRACT

OBJECTIVE: To assess the oncologic and cosmetic outcomes in women with multifocal breast cancers or T2 tumours with diameters larger than 3 cm situated in the upper outer quadrant who were treated with "V"-technique. METHODS: From July 1999 till June 2003, 44 conserving surgeries with "V"-technique using a local rotational flap were performed. Localization of tumours was in the upper outer quadrant. All solid tumours were larger than 3 cm in diameter. In all patients, axillary lymph node dissection was performed. All the patients received postoperative radiotherapy. Mean follow-up was 58 months. RESULTS: Out of 44 conserving surgeries with "V"-technique, an adequate distance of tumour from the margins was obtained in 84.1% (37/44). Out of 37patients who underwent conserving surgery with this technique, the cosmetic result was favourable in 83.78% (31/37). None of these patients had a corrective surgery such as reduction mammaplasty or mastopexy. Mean weight of excised tissue was 215 g. The 5-year local recurrence rate was 10.8%. The 5-year metastasis-free survival rate was 81,1%. The 5-year overall survival rate was 86.5 %. CONCLUSIONS: Surgical treatment of multifocal and T2 breast cancers larger than 3 cm in diameter situated in the upper outer quadrant and performed with "V"-technique gives a good aesthetic result and enables a wide resection of breast tissue around the tumour.


OBJETIVO: Evaluar los resultados oncológicos y cosméticos en las mujeres con cánceres multifocales de mama o tumores T2 de diámetro mayor de 3 cm, situados en el cuadrante superior externo, en pacientes tratadas con la técnica "V". MÉTODOS: De julio 1999 hasta junio de 2003, se realizaron 44 cirugías conservadoras usando la técnica "V" con colgajo local de rotación. Los tumores se hallaban localizados en el cuadrante superior. Todos los tumores sólidos tenían más de 3 centímetros de diámetro. A todas las pacientes se les practicó la disección del ganglio linfático axilar. Todas las pacientes recibieron radioterapia postoperatoria. El seguimiento promedio fue de 58 meses. RESULTADOS: De las 44 cirugías conservadoras con la técnica "V", se obtuvo una distancia adecuada del tumor en 84.1% (37/44) desde los márgenes. De 37 pacientes que tuvieron cirugía conservadora con esta técnica, el resultado cosmético fue favorable en 83.78% (31/37). A ninguna de estas pacientes se les realizó cirugías correctivas tales como mamoplastia de reducción, o mastopexia. El peso promedio del tejido extirpado fue 215 g. La tasa de recurrencia local quinquenal fue de 10.8%. La tasa de supervivencia quinquenal libre de metástasis fue 81, 1%. La tasa general de supervivencia fue de 86.5%. CONCLUSIONES: El tratamiento quirúrgico de los cánceres de mama T2 y multifocales mayores de 3 cm. de diámetro situados en el cuadrante superior externo y realizado con la técnica "V" produce un buen resultado estético y permite una resección amplia del tejido mamario alrededor del tumor.


Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Mastectomy, Segmental/methods , Axilla/surgery , Breast Neoplasms/mortality , Breast Neoplasms/radiotherapy , Lymph Node Excision , Recurrence , Survival Rate , Treatment Outcome , Tumor Burden
15.
West Indian Med J ; 59(5): 518-22, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21473399

ABSTRACT

OBJECTIVE: To assess the oncologic and cosmetic outcomes in women with multifocal breast cancers or T2 tumours with diameters larger than 3 cm situated in the upper outer quadrant who were treated with "V"-technique. METHODS: From July 1999 till June 2003, 44 conserving surgeries with "V"-technique using a local rotational flap were performed. Localization of tumours was in the upper outer quadrant. All solid tumours were larger than 3 cm in diameter In all patients, axillary lymph node dissection was performed. All the patients received postoperative radiotherapy. Mean follow-up was 58 months. RESULTS: Out of 44 conserving surgeries with "V"-technique, an adequate distance of tumour from the margins was obtained in 84.1% (37/44). Out of 37 patients who underwent conserving surgery with this technique, the cosmetic result was favourable in 83.78% (31/37). None of these patients had a corrective surgery such as reduction mammaplasty or mastopexy. Mean weight of excised tissue was 215 g. The 5-year local recurrence rate was 10.8%. The 5-year metastasis-free survival rate was 81.1%. The 5-year overall survival rate was 86.5%. CONCLUSIONS: Surgical treatment of multifocal and T2 breast cancers larger than 3 cm in diameter situated in the upper outer quadrant and performed with "V"-technique gives a good aesthetic result and enables a wide resection of breast tissue around the tumour


Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/surgery , Mastectomy, Segmental/methods , Adult , Aged , Aged, 80 and over , Axilla/surgery , Breast Neoplasms/mortality , Breast Neoplasms/radiotherapy , Female , Humans , Lymph Node Excision , Middle Aged , Recurrence , Survival Rate , Treatment Outcome , Tumor Burden
16.
Clin Oncol (R Coll Radiol) ; 21(1): 43-8, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18976894

ABSTRACT

AIMS: To identify independent prognostic factors in patients with cancer of unknown primary site (CUP) who do not belong to prognostically favourable subsets, and to develop a prognostic index for predicting survival in these patients. MATERIALS AND METHODS: In this prospective study, univariate and multivariate analyses of prognostic factors were conducted in a population of 145 patients with CUP in two clinical institutions. Subsets of patients with favourable prognostic features and those requiring well-defined treatment were excluded. RESULTS: The 1-year overall survival rate for all patients was 42% and the median overall survival was 330 days. Overall survival was significantly related to the following pre-treatment prognostic factors: poor Eastern Cooperative Oncology Group performance status (ECOG PS)>or=2, presence of liver metastasis, elevated serum lactate dehydrogenase (LDH), high white blood cell count, anaemia, age>or=63 years, and prolonged QTc interval in electrocardiography (ECG). In multivariate analysis, four independent adverse prognostic parameters were retained: elevated LDH (hazard ratio 2.21; 95% confidence interval 1.41-3.47; P=0.001), prolonged QTc interval (hazard ratio 2.10; 95% confidence interval 1.28-3.44; P=0.003), liver metastasis (hazard ratio 1.77; 95% confidence interval 1.11-2.81; P=0.016) and ECOG PS>or=2 (hazard ratio 1.69; 95% confidence interval 1.05-2.73; P=0.03). We developed a prognostic index for overall survival based on the following subgroups: good prognosis (no or one adverse factor), intermediate prognosis (two adverse factors) and poor prognosis (three or four adverse factors). The median overall survival for the three subgroups was 420, 152 and 60 days, respectively, P<0.0001. CONCLUSIONS: This study validated previously identified important prognostic factors for survival in patients with CUP. Prolonged QTc was additionally identified as a strong adverse prognostic factor. We developed a simple prognostic index using performance status, LDH, presence of liver metastasis and QTc interval in ECG, which allowed assignment of patients into three subgroups with divergent outcome.


Subject(s)
Neoplasms, Unknown Primary/mortality , Activities of Daily Living , Adult , Aged , Aged, 80 and over , Electrocardiography , Female , Humans , L-Lactate Dehydrogenase/blood , Liver Neoplasms/secondary , Male , Middle Aged , Prognosis , Proportional Hazards Models , Survival Analysis , Survival Rate
17.
Neoplasma ; 54(1): 37-45, 2007.
Article in English | MEDLINE | ID: mdl-17233550

ABSTRACT

The role of heat shock protein 70 (HSP70) expression has been investigated in various types of tumors. There are only little and controversial data about its clinical relevance in colorectal carcinoma, one of the most common carcinomas observed in humans. In this study we investigated expression of HSP70 in human colonic carcinoma and possible correlation with clinicopathology. To assess patterns (cytosolic and membrane) of HSP70 expression, the 48 surgically removed colorectal adenocarcinomas and 12 normal colonic and rectal mucosal samples were examined by immunohistochemistry and Western-blot. According to results of immunohistochemistry, expression of cytoplasmic HSP72 was significantly higher in colorectal carcinoma compared with normal and adjacent mucosa (p<0.01). In addition, there was significant increase in HSP72 expression in lymph node-positive compared to node-negative group (p<0.001). Dukes C2 stage of colonic cancer showed significantly higher immunohistochemical score than Dukes B2 and B1 stage groups (p< 0.05 i.e. p< 0.02). There was no relation between expression of HSP72 and degree of tumor differentiation. Using Western blot analyses, we noticed elevated levels of cytosolic HSP70 in colorectal cancer cells compared to normal. Densitometric analysis of blots of plasma membrane HSP70 expression has shown decrease in colorectal cancer cells compared to normal mucosa. According to our results, overexpression of HSP72 in malignant tissues of patients with colorectal carcinoma is related to tumor progression, suggesting that these proteins could play an important role not only in tumorigenesis but also in the development of drug resistance. Further research is necessary to clarify the mechanisms responsible for differential HSP70 expression as well as its definitive role in colorectal cancer.


Subject(s)
Adenocarcinoma/pathology , Colorectal Neoplasms/pathology , HSP70 Heat-Shock Proteins/metabolism , Adenocarcinoma/metabolism , Adult , Aged , Aged, 80 and over , Blotting, Western , Cell Membrane/metabolism , Colorectal Neoplasms/metabolism , Cytoplasm/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Staging
18.
Biochem Soc Trans ; 34(Pt 5): 722-6, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17052182

ABSTRACT

FOXO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FOXO proteins relies on their ability to control diverse and at times, opposing cellular functions, such as proliferation, differentiation, DNA repair, defence against oxidative stress damage and apoptosis, in response to hormones, growth factors and other environmental cues. This review discusses our current understanding of the regulation and role of FOXO transcription factors in determining cell fate and highlights their relevance to tumorigenesis and drug resistance.


Subject(s)
Cell Cycle/physiology , Cell Physiological Phenomena , Forkhead Transcription Factors/physiology , Cell Nucleus/physiology , Cell Survival/physiology , Cytoplasm/physiology , Homeostasis , Humans , Proto-Oncogene Proteins c-akt/metabolism , Transcription Factors/metabolism
19.
Andrologia ; 38(2): 69-75, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16529578

ABSTRACT

Phospholipase A(2) controls the phospholipid composition in spermatozoal membranes and is released from the acrosome of human spermatozoa. The extracellular phospholipase A(2) activity of human spermatozoa was determined by matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry after destabilization of acrosome by the calcium-ionophore calcimycin. MALDI-TOF mass spectrometry allowed the monitoring of changes in both substrate and products of spermatozoal phospholipase A(2) (PLA(2)) without the use of labelled phospholipids. The spermatozoal PLA(2) was characterized as a secretory one (sPLA(2)). Secretory PLA(2) exhibited a high substrate specificity for 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC), the most abundant spermatozoal phospholipid. A time- and cell number-dependent formation of the lysophospholipid PDPC was observed following incubation of extracellular medium of calcimycin-treated spermatozoa (CTS) with PDPC. Antibodies against sPLA(2), specific inhibitors of sPLA(2) and Ca(2+)-chelators could inhibit its generation. An antibody against lysophospholipase enhanced the lysoproduct concentration in the extracellular medium of CTS containing sPLA(2) because further metabolization of these products was blocked. The results demonstrated that destabilization of the acrosome is able to induce a release of secretory phospholipase A(2) from human spermatozoa with subsequent generation of lysophosphocholine in the surrounding of spermatozoa.


Subject(s)
Acrosome/enzymology , Lysophospholipids/biosynthesis , Phospholipases A/metabolism , Animals , Calcimycin , Humans , Male , Mice , Phospholipases A/antagonists & inhibitors , Phospholipases A2 , Spermatozoa , Substrate Specificity , Time Factors
20.
Phys Rev E Stat Nonlin Soft Matter Phys ; 72(4 Pt 2): 046118, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16383479

ABSTRACT

Reversible random sequential adsorption of objects of various shapes on a two-dimensional triangular lattice is studied numerically by means of Monte Carlo simulations. The growth of the coverage rho(t) above the jamming limit to its steady-state value rho(infinity) is described by a pattern rho(t) = rho(infinity - deltarhoE(beta)[-(t/tau)beta], where E(beta) denotes the Mittag-Leffler function of order beta element of (0, 1). The parameter tau is found to decay with the desorption probability P_ according to a power law tau = AP_(-gamma). The exponent gamma is the same for all shapes, gamma = 1.29 +/- 0.01, but the parameter A depends only on the order of symmetry axis of the shape. Finally, we present the possible relevance of the model to the compaction of granular objects of various shapes.

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