TGF-beta in CAF-mediated tumor growth and metastasis.

TGF-beta signaling is one of the major pathways controlling cell and tissue behavior not only in homeostasis but also in disease. During tumorigenesis TGF-beta orchestrated processes are key due to its dual role as tumor suppressor and tumor promoter. Important functions of this pathway have been described in a context-dependent manner both in epithelial cancer cells and in the tumor microenvironment during tumor progression. Carcinoma-associated fibroblasts (CAFs) are one of the most abundant stromal cell types in virtually all solid tumors. CAFs favor malignant progression by providing cancer cells with proliferative, migratory, survival and invasive capacities. A complex network of signaling pathways underlying their tumor-promoting properties is beginning to take shape. In this review, we examine current evidence on the emerging mechanisms involving TGF-beta in CAF-mediated cancer progression, and discuss their potential as therapeutic targets.

The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells.

The adhesion protein E-cadherin plays a central part in the process of epithelial morphogenesis. Expression of this protein is downregulated during the acquisition of metastatic potential at late stages of epithelial tumour progression. There is evidence for a transcriptional blockage of E-cadherin gene expression in this process. Here we show that the transcription factor Snail, which is expressed by fibroblasts and some E-cadherin-negative epithelial tumour cell lines, binds to three E-boxes present in the human E-cadherin promoter and represses transcription of E-cadherin. Inhibition of Snail function in epithelial cancer cell lines lacking E-cadherin protein restores the expression of the E-cadherin gene.

Fibromyalgia in patients with ankylosing spondylitis: prevalence and utility of the measures of activity, function and radiological damage.

OBJECTIVES: To determine the prevalence of fibromyalgia (FM) in ankylosing spondylitis (AS). To evaluate the effect of FM on the measures of activity in AS. To analyse predictive factors in order to identify this group of patients. PATIENTS AND METHODS: A cross-sectional study based on 462 patients with definite ankylosing spondylitis included in the REGISPONSER. Sociodemographic data, clinical features, Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI), Bath AS radiology index (BASRI), Stoke modified index (Sasss-m), laboratory data, Short-Format 12 (SF-12), AS specific quality of life (ASQoL), Fibromyalgia Impact Questionnaire (FIQ) and treatments used were all documented. To diagnose FM, the ACR 1990 criteria had to be fulfilled. All statistical tests were performed using STATA. RESULTS: The prevalence of fibromyalgia in all AS was 4.11%. Among the women with AS, the prevalence of FM increased to 10.83%. The BASDAI, BASFI and total BASRI were strongly influenced by the presence of FM. The inverse relationship between BASDAI or BASFI and total BASRI was taken to generate a ratio. Accordingly, if the patient presented BASDAI/BASRI ≥1.5 or BASFI/BASRI ≥1.08, the probability of having FM was very high. CONCLUSIONS: There is an increased risk of FM in females with AS. The fact of having FM distorts the measures of activity and functional damage of AS. As a result, it is possible that some patients with AS and FM are being overtreated. The BASDAI/BASRI and BASFI/BASRI ratios are very useful to identify these patients.

Relationship between spinal mobility and disease activity, function, quality of life and radiology. A cross-sectional Spanish registry of spondyloarthropathies (REGISPONSER).

OBJECTIVE: To determine the relationship between anthropometric measurements and disease activity, functional capacity, quality of life and radiology in Spanish patients with ankylosing spondylitis (AS). PATIENTS AND METHODS: A cross-sectional study was made of 842 patients with definite ankylosing spondylitis (REGISPONSER). Sociodemographic data, spinal mobility measurements, Bath AS disease activity index (BASDAI), nocturnal pain, Bath AS radiology index (BASRI), Bath AS functional index (BASFI), the Short-Format 12 (SF-12) and the AS specific quality of life (ASQoL) questionnaire were applied. Pearson correlation coefficient analysis and regression models were constructed. RESULTS: There was moderate correlation between fingertip-to-floor distance and lateral cervical rotation with the BASFI (p<0.01). Good correlation was evident between wall-occiput distance and lateral cervical rotation with the BASRI (p<0.01). Moderate correlation was found between chest expansion, the Schober modified test and fingertip-to-floor distance with the total BASRI (p<0.01). The anthropometric measurement with the lowest correlation value was lateral lumbar flexion. Significant association was found between the Schober modified test and BASFI, BASDAI and BASRI (R(2) = 0.37; p<0.001); chest expansion and BASFI, BASDAI and BASRI (R(2) = 0.25; p<0.001); wall-occiput distance and BASFI, BASRI and ASQoL (R(2) = 0.44; p<0.001); fingertip-to-floor distance and BASFI and BASRI (R(2) = 0.30; p<0.001); and lateral cervical rotation and BASFI and BASRI (R(2) = 0.34; p<0.001). CONCLUSION: In our study, wall-occiput distance and lateral cervical rotation showed the strongest correlation to BASRI. Similarly, fingertip-to-floor distance and lateral cervical rotation exhibited the closest correlation to BASFI.

Epithelial IL-1R2 acts as a homeostatic regulator during remission of ulcerative colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease that may undergo periods of activity followed by remission. We aimed to identify the endogenous regulatory mechanisms that may promote disease remission. Transcriptional and protein analysis of the intestinal mucosa revealed that the IL-1 decoy receptor, interleukin-1 receptor type 2 (IL1R2), was upregulated in remission compared with active UC and controls. We identified epithelial cells as being responsible for increased IL-1R2 production during remission. Expression of IL1R2 was negatively regulated by Wnt/beta-catenin signals in colonic crypts or epithelial stem cell cultures; accordingly, epithelial stem cells upregulated IL-1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures of UC patients in remission and T-cell cultures stimulated with biopsy supernatant from UC patients in remission boosted IL-1ß-dependent production of inflammation-related cytokines. Finally, IL1R2 transcription was significantly lower in patients that relapsed during a 1-year follow-up period compared with those in endoscopic remission. Collectively, our results reveal that the IL-1/IL-1R2 axis is differentially regulated in the remitting intestinal mucosa of UC patients. We hypothesize that IL-1R2 in the presence of low concentrations of IL-1ß may act locally as a regulator of intestinal homeostasis.

Penetrating atherosclerotic aortic ulcer: documentation by transesophageal echocardiography.

OBJECTIVES: This study sought to describe the ability of transesophageal echocardiography (TEE) to document the presence of penetrating atherosclerotic aortic ulcers and their complications. BACKGROUND: TEE has greatly enhanced our ability to assess patients with suspected aortic disease. However, the utility of this technique in the diagnosis of penetrating atherosclerotic aortic ulcers is still undefined. METHODS: TEE was performed prospectively in 194 patients to evaluate aortic disease. Twelve patients with the diagnosis of aortic ulcers or their complications were specifically studied. The diagnosis was confirmed by pathologic studies in six patients and by an additional diagnostic technique (angiography, computed tomography or magnetic resonance imaging) in the other six. All 12 patients were hypertensive and presented with chest or back pain; the mean age was 65 years (range 56 to 79). The initial working diagnosis was acute aortic dissection in nine patients. Aortic ulcers were located in the descending thoracic aorta in eight patients, the aortic arch in two and the ascending aorta in two. RESULTS: TEE could detect aortic ulcers or their complications in 10 patients but failed to detect these lesions in the remaining 2 (1 with aortic ulcers in the distal ascending aorta and 1 with aortic ulcers in the aortic arch). In four patients, aortic ulcers were detected as a calcified focal outpouching of the aortic wall and were associated with concomitant aneurysmal dilation of the aorta in two patients and with a small localized intramural hematoma in one. TEE visualized a partially thrombosed pseudoaneurysm complicating an aortic ulcer in the descending thoracic aorta of two patients. Four patients had an aortic ulcer complicated by a "limited aortic dissection" in the descending aorta that could be detected by TEE. Five patients underwent operation, two because of aneurysmal dilation of the aorta and three because of aortic dissection; two patients died of aortic rupture; the remaining five did well (11-month follow-up) without operation. CONCLUSIONS: Aortic ulcers should be included in the differential diagnosis of chest or back pain, especially in elderly hypertensive patients. These ulcers and their complications may be recognized by TEE.

Antipeptide antibodies directed against the C-terminus of protein kinase C zeta (PKC zeta) react with a Ca(2+)- and TPA-sensitive PKC in HT-29 human intestinal epithelial cells.

We have studied the PKC isoforms present in HT-29 M6 colon cancer cells, the differentiation of which to mucus-secreting cells is blocked by TPA. In addition to a major 72 kDa band, a 77 kDa PKC isoform was recognized by two different antibodies raised against a C-terminus-specific peptide for the TPA-insensitive isoform, PKC zeta. By different criteria (association to the membrane, down-regulation, PKC activity in immunoprecipitates) we conclude that, contrary to the 72 kDa band, the 77 kDa band corresponds to a Ca(2+)- and TPA-sensitive PKC. These results suggest that antipeptide antibodies directed against the C-terminus of PKC zeta react in human cells with a member of the conventional PKC subfamily besides PKC zeta. Therefore, the data indicating that PKC zeta is sensitive to different agents in various cell lines should be carefully re-evaluated.

Supravalvular aortic stenosis in aortic dissection.

Supravalvular aortic stenosis is a rare complication of aortic dissection. We report on echocardiographic and magnetic resonance observations in 2 cases of aortic dissection with false lumen thrombosis of the ascending aorta and severe narrowing of the true lumen.

Clinical, anatomic, and echocardiographic characteristics of aneurysms of the mitral valve.

This study describes the clinical, anatomic, echocardiographic, and Doppler features of 13 patients with mitral valve aneurysms. Eleven patients had definitive criteria for infective endocarditis. Transesophageal echocardiography was superior to conventional echocardiography in detecting and assessing aneurysms. Patients with heart failure required surgery. Echocardiographic detection of this lesion should not be, by itself, an immediate surgical indication.

Clinical course, microbiologic profile, and diagnosis of periannular complications in prosthetic valve endocarditis.

Whether periannular extension of prosthetic valve endocarditis (abscesses, pseudoaneurysms, fistulas) is related to the etiologic agent, the clinical course and the prognosis is still unknown. Likewise, transesophageal echocardiographic accuracy in detecting periannular complications in prosthetic recipients remains unsettled. We retrospectively analyzed data from 87 patients with anatomically proven prosthetic valve endocarditis who underwent a transesophageal echocardiographic examination. Periannular complications (30 abscesses, 18 pseudoaneurysms, 8 fistulas; 8 with >1) were found in 46 patients; results were compared with the remaining 41 without complications. Transesophageal echocardiography correctly identified 27 abscesses (90%) and all pseudoaneurysms and fistulas. One diagnosis of pseudoaneurysm by echocardiography was not found at surgery. No statistical differences were found regarding age, sex, type of prosthesis (mechanical vs biologic), and etiologic agent. Periannular complications were more frequent in aortic location (70% vs 20% in mitral position; p <0.001) and in early (within 6 months after surgery) endocarditis (63% vs 38% in late endocarditis; p = 0.04). The same percentage of patients from both groups underwent surgery (98% with and 90% without complications). At discharge, 62% and 67% of patients were alive, respectively. Thus, periannular complications in prosthetic valve endocarditis are more frequent in aortic location and within 6 months after surgery. Neither the type of prosthesis nor the etiologic agent are related to the presence of periannular complications. Short-term prognosis in patients who underwent surgery is not affected by the presence of periannular complications.

Benzodiazepines in primary health care: a survey of general practitioners prescribing patterns.

This paper presents the results of a survey carried out to investigate the benzodiazepine (BZD) prescribing patterns of the general practitioners (GP) in the catchment area of a Drug Dependence Unit located in a general hospital in Mataro (Barcelona, Spain). The aims of the survey were: (i) to obtain descriptive information on the knowledge of the GPs about BZD and its potential for dependence; (ii) to study the frequency of their prescribing; and (iii) to examine different factors linked to their prescribing. The study was carried out using a combination of a personal interview and a self-administered questionnaire. A total of 68 doctors (88.3%) completed the questionnaire. The results show that the GPs have, in general, correct knowledge about the therapeutic indications for BZD prescribing, but are far less aware of their potential to induce dependence and how to manage withdrawal. The rate of prescribing seems to be high. Furthermore, the results of the external check of validity point out that doctors tend to underestimate the number of prescriptions. The majority of GPs express the need for alternative resources to BZD prescribing. No significant associations have been found between doctor's characteristics, such as postgraduate training and type of practice, and their knowledge about BZD and frequency of their prescribing. In our view, a more accurate knowledge about BZD and alternatives to its use, both factors closely linked to training, together with the availability of non-pharmacological resources, are likely to improve the quality of doctors prescribing habits, thus preventing risks such as dependence of BZD.

[Cardiac tamponade with the absence of a paradoxical pulse. The practical utility of echocardiography]. / Taponamiento cardíaco con ausencia de pulso paradójico. Utilidad práctica de la ecocardiografía.

A patient with cardiac tamponade but without hypotension and pulsus paradoxus is reported. In this patient, echocardiography confirmed the diagnosis of cardiac tamponade, showing diastolic collapse of the right ventricle and also the presence of an atrial septal defect (ostium secundum) that explains the absence of pulsus paradoxus. The role of echocardiography in those rare clinical situations that in the presence of cardiac tamponade showed no pulsus paradoxus are discussed.

[Comparison of dobutamine echocardiography and rest-redistribution 201-thallium SPECT in the assessment of myocardial viability taking PET as gold standard]. / Comparación entre la eco-dobutamina y talio-201 SPECT reposo-redistribución en la valoración de la viabilidad miocárdica considerando el PET como patrón oro.

BACKGROUND AND AIM: To compare Tl-201 SPECT and dobutamine stress echocardiography for the detection of myocardial viability in patients with severe left ventricular dysfunction using metabolic imaging by positron emission tomography as the standard reference. MATERIAL AND METHODS: We studied 25 consecutive patients with severe coronary artery disease and left ventricular dysfunction that underwent two different diagnostic modalities for evaluating myocardial viability: stress echocardiography with incremental doses of dobutamine from 5 up to 40 g/kg/min in 3 min stages, and 201 Tl SPECT using a rest-redistribution protocol with delayed images obtained at 4 hours. Fluorodeoxyglucose uptake by PET was used as the gold standard. Viability criteria were as follows, for 201Tl SPECT imaging: normal uptake at rest and presence of redistribution in the delayed images, for dobutamine stress echocardiography: sustained improvement and biphasic response. RESULTS: Sensitivity of thallium redistribution was 46%, for normal uptake, plus redistribution 82%, 34% for dobutamine biphasic response and 58% for sustained improvement plus biphasic response. Specificity of biphasic response was 82% and that of redistribution 67%. Stepwise logistic regression indicated that biphasic wall motion response during dobutamine stress echocardiography (2.01 CI 95%; 1.10 to 3.99) and the presence of redistribution plus normal uptake at rest with thallium imaging (2.68 CI 95%; 1.42 to 5.13) were the best predictors of viability. These results were the same when both techniques were analyzed together. CONCLUSIONS: Biphasic wall motion response during dobutamine stress echocardiography and the normal uptake plus presence of redistribution with thallium imaging were the best pre

[Identification of intramural aortic hematoma by transesophageal echocardiography]. / Identificación del hematoma intramural aórtico por ecocardiografía transesofágica.

BACKGROUND AND AIM: The usefulness of transesophageal echocardiography in the diagnosis and assessment of patients with aortic dissection has been widely demonstrated. The aim of this study was to evaluate the role of this technique in the detection of intramural aortic hematoma and in the follow-up of these patients. METHODS: The records of 51 patients with aortic dissection by transesophageal echocardiography diagnosed between May 1990 and May 1994 were reviewed. RESULTS: The diagnosis of intramural aortic hematoma was established in 6 patients by transesophageal echocardiography (11%). This diagnosis was confirmed either anatomically (3 patients) or with an additional diagnostic technique (computed tomography or magnetic resonance imaging) and on the basis of echocardiographic follow-up changes (3 patients). CONCLUSIONS: Intramural aortic hematoma represents an infrequent variant of aortic dissection that can be detected by transesophageal echocardiography and is usually unrecognized by aortography.

[Elective noninvasive test in the diagnosis of coronary disease in the aged]. / Prueba no invasiva de elección en el diagnóstico de enfermedad coronaria en el anciano.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the best noninvasive test to diagnose coronary artery disease in the elderly. PATTERNS AND METHODS: We conducted a study on 56 elderly patients (> 65 years) with chest pain and no previous history of coronary artery disease. They underwent exercise stress test, dipyridamole echocardiography (0.84 mg/kg), dobutamine echocardiography (up to a total dose of 40 microgram/kg/min and atropine when it was necessary), dobutamine MIBI-SPECT and coronary angiography. RESULTS: Angiography detected significant coronary artery disease in 41 patients. All tests used in this study had a similar sensitivity (conclusive exercise stress test 87%, dipyridamole echocardiography 83%, dobutamine echocardiography 80% and MIBI-SPECT 87%; p = NS). Coronary angiography did not identify significant lesions in 15 patients. Specificity of conclusive exercise stress test, dipyridamole and dobutamine echocardiography was similar (75%, 100% and 93% respectively; p = NS). However, the specificity of stress echocardiography was higher than that of scintigraphy (100% vs 66%; p = 0.02 for dipyridamole echocardiography and 93% vs 66%; p = 0.07 for dobutamine echocardiography). Diagnostic accuracy of each test was similar. CONCLUSIONS: Exercise stress test remains the non invasive diagnostic test of choice to detect coronary disease in the elderly. If this test is inconclusive, both stress echocardiography and isotopic studies are useful, although the specificity of stress echocardiography is higher than that of scintigraphy.

[A non-invasive test choice for the diagnosis of coronary disease in women]. / Prueba no invasiva de elección para el diagnóstico de enfermedad coronaria en mujeres.

BACKGROUND AND PURPOSE: Regarding coronary heart disease, women have often been excluded from clinical trials. Current practical recommendations are thus based on studies in men. To identify the non invasive technique of choice in detecting coronary artery disease in women, a study with different diagnostic tests has been undertaken. METHODS: Exercise stress test, dipyridamole echocardiography (0.84 mg/kg), dobutamine echocardiography (up to a total dose of 40 micrograms/kg per minute and atropine if necessary), MIBI-SPECT during dobutamine infusion and coronary angiography, were performed in 40 consecutive women with chest pain and no previous history of coronary artery disease. RESULTS: The four tests had similar sensitivity: exercise stress test (80%; CI 95%, 52-94), dipyridamole echocardiography (80%; CI 95%, 56-93), dobutamine echocardiography (80%; CI 95%, 56-93) and scintigraphy MIBI-SPECT (85%; CI 95%, 61-95). The specificity of dipyridamole echocardiography (100%; CI 95%, 83-100) and dobutamine echocardiography (90%; CI 95%, 67-98) was higher than that of exercise stress test (50%; CI 95%, 22-78) and MIBI-SPECT (65%; CI 95%, 41-84). The positive predictive values of dipyridamole and dobutamine echocardiography were 100% and 88% respectively. CONCLUSIONS: The feasibility of exercise stress test in women is inferior to that of the other techniques. The sensitivity of the four tests to diagnose coronary artery disease is similar. The specificity of dipyridamole echocardiography and dobutamine echocardiography is higher than that of exercise stress test and MIBI-SPECT. Stress echocardiography can be considered the non invasive technique of choice for diagnosing coronary artery disease in women.

[Tolerance and adverse events of treatment with acetylcholinesterase inhibitors in a clinical sample of patients with very slight and mild Alzheimer s disease over a six-month period]. / Tolerancia y acontecimientos adversos del tratamiento con inhibidores de la acetilcolinesterasa en una muestra clínica de pacientes con enfermedad de Alzheimer de gravedad mínima y leve durante un período de seis meses.

INTRODUCTION: At present acetylcholinesterase inhibitors (AChEI) are used in the treatment of the cognitive deterioration associated with Alzheimer s disease (AD). The side effects of these drugs are linked with the increase in acetylcholine, which limits their effectiveness, and must be adjusted to the patient close to the maximum tolerated dose. PATIENTS AND METHODS: We conducted a comparative retrospective study of the tolerance and the adverse events (AE) of two AChEI in a group of patients with very slight and mild probable AD over a 6 month period. RESULTS: The sample was made up of 175 patients, of which 134 began therapy with 5 10 mg/day of donepezil and 41 with 6 12 mg/day of rivastigmine. 20% of the patients presented AE and 8% abandoned the treatment. Gastrointestinal disorders (GID) were the main AE observed (57.1%). Only 6% of the patients treated with donepezil abandoned the therapy because of the AE as opposed to 14.6% of the patients treated with rivastigmine. Patients treated with rivastigmine displayed a higher incidence of GID and the relative risk of presenting GID was 4.4 times higher than in the patients treated with donepezil. CONCLUSIONS: The GID associated to therapy with AChEI are the main reason for abandoning treatment and occur more frequently in patients treated with rivastigmine.

Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis.

Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15(+) aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15(+) cell population. A large subset of the Lgr5(+) SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV-induced tumor development.