SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150.

SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Studies on the action of SPRY2 in major cancers are conflicting and its role remains unclear. Here we have dissected SPRY2 action in human colon cancer. Global transcriptomic analyses show that SPRY2 downregulates genes encoding tight junction proteins such as claudin-7 and occludin and other cell-to-cell and cell-to-matrix adhesion molecules in human SW480-ADH colon carcinoma cells. Moreover, SPRY2 represses LLGL2/HUGL2, PATJ1/INADL and ST14, main regulators of the polarized epithelial phenotype, and ESRP1, an epithelial-to-mesenchymal transition (EMT) inhibitor. A key action of SPRY2 is the upregulation of the major EMT inducer ZEB1, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEB1 in human colon tumors. Mechanistically, ZEB1 upregulation by SPRY2 results from the combined induction of ETS1 transcription factor and the repression of microRNAs (miR-200 family, miR-150) that target ZEB1 RNA. Moreover, SPRY2 increased AKT activation by epidermal growth factor, whereas AKT and also Src inhibition reduced the induction of ZEB1. Altogether, these data suggest that AKT and Src are implicated in SPRY2 action. Collectively, these results show a tumorigenic role of SPRY2 in colon cancer that is based on the dysregulation of tight junction and epithelial polarity master genes via upregulation of ZEB1. The dissection of the mechanism of action of SPRY2 in colon cancer cells is important to understand the upregulation of this gene in a subset of patients with this neoplasia that have poor prognosis.

[Laparoscopic cholecystectomy: what we can learn about]. / Colecistectomía laparoscópica en niños y adultos: lo que podemos aprender.

BACKGROUND: Laparoscopic cholecystectomy (LC) is a very usual procedure within adult population, but not as frequent in childhood. The aim of this study was to assess the outcome of LC in children compared with those performed in adulthood. MATERIALS AND METHODS: We reviewed 39 consecutive patients who underwent LC between 2003 and 2013 at our Department and a similar sample of patients from 18 to 40 years of age from the General Surgery Department. RESULTS: 39 children and 40 adults fulfilled criteria to be included in the study. The most frequent indication was cholelithiasis in both groups. The mean operating time was significantly higher among children (127 min, adults 71 min, p < 0.01) but we didn't find differences neither in conversion nor in complication rates (children 5% and 7.7%, adults 2.5% and 15% respectively). In regard to preoperative factors, only male gender was correlated to a higher complication rate (p 0.037). On the other hand we found out that, in absence of complications, both the average length of stay (children 2.1 days, adults 0.5 days) and mean time to first feeding (children 21 hours, adults 8 hours) were significantly higher among children (p < 0.01). CONCLUSIONS: 1) LC in childhood is a safe procedure that does not imply more morbidity than the same intervention in adults, even though a more prolonged operating time. 2) We believe that our longer hospital stay is due to certain lack of confidence with the technique and, in the future, the trend should be bent on encouraging a shorter time to first feeding and an earlier discharge.

Efficient in vivo microRNA targeting of liver metastasis.

Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2' sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNA-controlled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

A critical role for choline kinase-alpha in the aggressiveness of bladder carcinomas.

Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-alpha (ChoKalpha) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKalpha show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKalpha plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKalpha is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKalpha potentiate both tumor formation (P< or =0.0001) and aggressiveness of the disease on different end points (P=0.011). Accordingly, increased levels of ChoKalpha significantly reduce survival of mice with bladder cancer (P=0.05). Finally, treatment with a ChoKalpha-specific inhibitor resulted in a significant inhibition of tumor growth (P=0.02) and in a relevant increase in survival (P=0.03).

Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology.

Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.

microRNAs and cancer: role in tumorigenesis, patient classification and therapy.

MicroRNAs (miRNAs) are small non-coding RNAs that downregulate gene expression during various crucial cell processes such as apoptosis, differentiation and development. Recent work supports a role for miRNAs in the initiation and progression of human malignancies. Moreover, large high-throughput studies in patients revealed that miRNA profiling has the potential to classify tumours and predict patient outcome with high accuracy. Functional studies, some of which involve animal models, indicate that miRNAs act as tumour suppressors and oncogenes. This review examines the role of miRNAs in the pathogenesis of cancer as well as miRNA-profiling studies performed in human malignancies. Implications of these findings for the diagnosis and treatment of cancer patients are also discussed.

[Therapeutic strategy in cloacal exstrophy]. / Estrategia terapéutica en la extrofia de cloaca femenina.

Cloacal exstrophy is a complex multisistemic anomaly that involves gastrointestinal and genitourinary issues. The aim of our paper is to report our experience in dealing with genital reconstruction and faecal and urinary continence in patients with female cloacal anomalies. We reviewed the clinical records from the three patients we have achieved a final reconstruction. We recorded the surgical management and both functional and anatomic results. The three of them required a bladder neck closure associated with a continent stoma, they are dry with intermittent catheterization and free of upper urinary complications. Genital reconstruction required a unique plan for each one, according to their anatomy and their cosmetic desires. One of the patients reported satisfactory sexual intercourse. Management of patients with cloacal exstrophy has major concerns about urinary and fecal continence and about genital reconstruction and function. Knowing the long-term results may help to develop management strategies and improve counselling for patients who have under-gone reconstruction.

Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer.

During the metaphase-anaphase transition, the spindle checkpoint prevents segregation of chromosomes if the spindle assembly is perturbed. Critical components of this checkpoint are the MAD and BUB families of proteins, which prevent the proteolysis of Pds1 and B cyclins, producing mitotic arrest. In the present study, we first intended to resolve the role of the hsMAD2 gene in human cancer by determining the potential presence of hsMAD2 mutations in 44 primary bladder tumors, 42 soft-tissue sarcomas and 10 hepatocellular carcinomas. The entire coding region of the hsMAD2 gene was analyzed using PCR-SSCP and sequencing. One of the bladder tumor samples showed a point mutation consisting of a transition, ATC-->GTC (Ile-->Val) in codon 190 of hsMAD2. However, no differences were found in the mitotic arrest between cells transfected with mutant and wild-type MAD2 cDNA. We also identified mobility shifts in hsMAD2 in both normal and tumor DNA in 3 bladder tumors, 3 soft-tissue sarcomas and 1 hepatocellular carcinoma, consistent with a polymorphism at codon 143, CCA-->CCG (Pro-->Pro). Another polymorphism was identified in a hepatocellular carcinoma case at codon 22, GAG-->GAA (Glu-->Glu). In addition, a subgroup of 67 primary tumors was analyzed by Southern blot hybridization. No deletion or visible re-arrangements were detected by comparing tumor and normal DNA band signals. Two other important components of the spindle mitotic checkpoint, hBUB1 and hBUB3, were also screened for mutations: hBUB1 in 43 bladder tumors and 9 bladder cell lines and hBUB3 only in the cell lines. Two polymorphisms were found in hBUB1 at positions 144, CAG-->CAA (Gln-->Gln) in 1 primary tumor and 1 bladder cell line, and 913 (ATC-->ATT, Ile-->Ile) in 1 primary tumor. We did not find sequence alterations in hBUB3. These results suggest that mutations of the hsMAD2, hBUB1 and hBUB3 genes are very rare in bladder tumors and that hsMAD2 alterations are also infrequent in soft-tissue sarcomas and hepatocellular carcinomas.

First Spanish Trauma Registry: analysis of 1500 cases.

OBJECTIVES: To develop the first Spanish Pediatric Trauma Registry to collect and evaluate infomation concerning aspects of injuries in our pediatric population. METHODS: From January 1995 to August 1998, 35,946 children younger than 16 years were treated in our hospital for acute injury: 1500 were admitted and included in our database. Our file registry consists of 108 data points including: patient identification, type, place and mechanism of injury, pre-hospital care, transport, assessment on admission, severity scores, diagnostic studies, injuries, treatment morbidity and mortality. RESULTS: Accidents were more frequent in males (68%) than in females. The predominant age group was 12-15 years of age (34%). Accidents were more frequent in the street (35.1%) than at home (18.9%) or school (13%). Falls and traffic-related accidents were the leading cause of injury (39% and 21.2%, respectively). Two hundred and thirty-five (15.7%) had a Pediatric Trauma Score < or = 8. Fifty of these sustained multiple trauma (33%) (Injury Severity Score > or = 15). Musculoskeletal and head trauma were the most frequent injuries (48.5% and 42.0%, respectively). Surgical or orthopedic procedures were performed in 906 patients (56.5%). The average length of stay was 4.5 days (range 1-93 days). Functional impairment in children older than 4 years of age was found in 413 children (33.3%). We encountered 7 deaths in the 1500 patients, or an overall mortality of 0.5%. These 7 deaths were only seen in the I.S.S. > or = 15 group (50 patients) with 14% mortality. CONCLUSIONS: The goals of this Registry are to establish the epidemiology of our injured pediatric population, to review patient care, to develop prevention programs and to compare results with other centers so that potential deficiencies can be corrected.

Primary malignant fibrous histiocytoma of the jejunum: report of a case and review of subject.

We report a new case of primary malignant fibrous histiocytoma of the jejunum. Malignant fibrous histiocytoma (MFH) occurs most commonly in the extremities and trunk, but rarely in visceral organs. However, only eight cases of primary tumours involving the small intestine, including the present, have been described. This case report documents the appearance of malignant fibrous histiocytoma as a primary lesion of the intestinal wall in a patient with a 2-month history of dyspepsia, weight loss and unspecific abdominal pain. The final diagnosis was based on the pathological report of the surgical specimen. Emphasis is placed on the clinical signs, radiological studies and pathological findings. The literature on MFH of the jejunum is also reviewed. Malignant fibrous histiocytoma is considered an aggressive tumour, and the treatment of choice is complete surgical excision. Adjuvant chemotherapy or radiation is recommended mainly in those patients in whom there is vascular or lymphatic infiltration.

[Clinical and evolutive study of plasma cell leukemia. Apropos of 9 cases]. / Estudio clínico y evolutivo de la leucemia de células plasmáticas. A propósito de nueve casos.

Nine patients were diagnosed with plasma cell leukemia (PCL) from 1982-1995 at our hospital. Seven patients had primary PCL and the other two patients a secondary from. In this study the clinical and analytical features are reported, as well as the therapy and response obtained in these patients. Also, the karyotype findings in bone marrow of four of these patients are reported. At diagnosis, the most common symptom was bone pain which was associated with osteolytic lesions or diffuse bone demineralization. Analytical features were similar to those reported in other series of patients with PCL. Different therapeutical regimens were used, and VAD was the most commonly employed. Two patients underwent consolidation therapy with autologous transplantation of hemopoietic stem cells. The mean survival time was 5.5 months. Although PCL prognosis associated with chemotherapy is still poor, myeloablative therapy with hemopoietic support can increase the survival length in these patients.

[Simultaneous presentation of multiple myeloma and sarcoidosis]. / Mieloma múltiple y sarcoidosis de presentación simultánea.

The association between sarcoidosis and neoplasms has been described by different authors. Hodgkin's disease and non Hodgkin lymphoma are the neoplasms associated frequently with sarcoid reaction. However, the simultaneous appearance of multiple myeloma disease and sarcoidosis is very infrequent because only eleven cases have been described. The case of a 49 year old patient with simultaneous appearance of smoldering myeloma and sarcoidosis is presented. The smoldering myeloma had an aggressive evolution to multiple myeloma. The role that sarcoidosis may play in the genesis of multiple myeloma is discussed.

[Hepatic hydatidosis. Review of a series of 677 surgically treated patients]. / Hidatidosis hepática. Revisión de una serie de 677 pacientes intervenidos quirúrgicamente.

A retrospective study of 677 patients who underwent surgery for hepatic hidatidosis in the Department of Surgery A and B of the Hospital Miguel Servet in Zaragoza, Spain, over the last 21 years is presented. The frequency was analyzed in regards to sex, age, symptomatology, cyst data, surgical techniques performed and postoperative morbidity. The mean age of the patients was 39 years with the incidence being practically equal in both sexes. Dyspeptic symptoms (60%), hepatomegaly and/or palpable mass in the right hypochondria (58%) and pain (46%) were the most frequent clinical signs and symptoms observed. Radical surgery was performed in 21% of all the surgical treatments, while conservative surgery was undergone in 79%. Solitary cysts were most frequent (65.7%) with localization in the right hepatic lobe (65.4%). The most frequent postoperative complication was biliary fistula (72 cases). The rate of reintervention was 18% and operative mortality 1.6% with a mean hospitalization period of 25 days.

[Repeated cerebral embolism in a patient with papillary fibroelastoma of the mitral valve detected by two-dimensional echocardiography]. / Embolismo cerebral de repetición en una enferma portadora de fibroelastoma papilar de la válvula mitral, detectado mediante ecocardiografía bidimensional.

We report a 68 years-old woman with repeated cerebral embolism, secondary to a papillary fibroelastoma of mitral valve, located in its ventricular side. It was detected by two-dimensional echocardiography. Surgical treatment was satisfactory.

[Inhibition of expontaneous cytotoxicity and antibody dependency by rheumatoid synovial fluid]. / Inhibición de la citotoxicidad espontánea y anticuerpo-dependiente por líquido sinovial reumatoide.

A number of authors have pointed out a diminution of ADCC (Antibody dependent cellular cytotoxicity) in lymphocytes from peripheral blood of patients with rheumatoid arthritis (RA). It has also been found that the addition of rheumatoid serum inhibits ADCC and also spontaneous cellular cytotoxicity (SCC). This effect could be the result of blocking of effector cell receptors for the Fc fragment of IgG by anti-immunoglobulins and/or immune complexes, present in great quantities in rheumatoid serum. We investigated the effect of synovial fluid on the ADCC and SCC shown by purified suspensions of lymphocytes from healthy donors and RA patients towards chicken erythrocytes tagged with 51 Cr. The samples of synovial fluid from patients with RA or arthrosis did not influence per se the spontaneous release of 51 Cr, once their complement had been removed. Seven-eight of the rheumatoid synovial fluid (RSF) produced a significant decline (p less than 0.01) of SCC. Lymphocytes from the peripheral blood of RA patients showed a greater decline in SCC after the addition of RSF than those from healthy subjects (p less than 0.02). In 14/16 RSF and 5/7 samples of arthrosis synovial fluid (ASF) the ability to diminish ADCC significantly (P less than 0.01) was shown. RSF maintained this inhibitory effect in 1:40 and 1:80 dilutions, whereas in these conditions ASF had no effect on ADCC. RSF and ASF, before their complement was removed, showed an opposite effect, provoking an increase in cytotoxic activity, both SCC and ADCC, though in different proportions. These experiments show that RSF, like rheumatoid serum, inhibits ADCC and SCC, possibly by the same mechanism which blocks the Fc receptors by means of immune complexes, and coincides in its general lines with the recent findings of Díaz Jouanen et al. The pathogenetic implications of this phenomenon are difficult to clarify at present. Its occurrence in vivo would represent the establishment of a local block of cytotoxic effector cells (protector effect), which, on the other hand, would no longer be able to exercise their destructive action against cells responsible for the initiation and/or maintenance of articular damage (pathogenic effect). The non-participation of T cells, in these types of cytotoxicity, previously shown by other authors, accentuates the importance of thymus-independent regulatory systems in the mechanisms which maintain articular damage in RA.