Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Thyrotrophin-Releasing Hormone Raises Cytosolic Free Calcium Concentration in Human Adenomatous Somatotrophs and Corticotrophs; Comparison with in vivo Responsiveness to Thyrotrophin-Releasing Hormone in Patients with Acromegaly or Cushing's Disease

The effect of thyrotrophin-releasing hormone (TRH) on intracellular free Ca²⁺ concentration, [Ca²⁺)i, was investigated with the fluorescent dye fura-2 in cell suspensions obtained from 13 human growth hormone-secreting adenomas and 6 adrenocorticotrophin-secreting adenomas. Preoperatively, 9 out of 13 acromegalic patients showed a positive growth hormone response to TRH administration while none of the 6 patients with Cushing's disease had a plasma adrenocorticotrophin increase after TRH injection. In all the growth hormone-secreting adenomas the addition of TRH (100 nM) caused a significant rise in [Ca²⁺]i (from a resting level of 133±40 (±SD) to a value of 284±119 nM at 100 nM TRH, n = 42; P<0.001). The transient induced by TRH was found to have a dual origin, one due to Ca²⁺ mobilization from intracellular stores which was maintained in presence of EGTA (3mM) and verapamil (10 μM) and a plateau phase due to Ca²⁺ influx from the extracellular media. Somatostatin (0.1 μM) lowered both resting [Ca²⁺]i and TRH-induced transients. The effect of gonadotrophin-releasing hormone on [Ca²⁺]i was evaluated on cell suspensions obtained from 6 growth hormone-secreting adenomas. Gonadotrophin-releasing hormone (100 nM) caused a marked rise in [Ca²⁺]i (from 179±25 to 283±15nM) on the cell suspension obtained from the only in vivo responsive adenoma while it was ineffective in the remaining 5. Although TRH was ineffective in modifying plasma adrenocorticotrophin levels in all patients with Cushing's disease, in 5 out of 6 tumors the addition of 100 nM TRH caused a significant rise in [Ca²⁺]i (from 102.5 ± 36 to 163±66 nM, n = 22; P < 0.005). However, the effect of TRH on [Ca²⁺]i was significantly lower than that caused by arginine vasopressin, a physiological stimulator of adrenocorticotrophin release ([Ca²⁺]i values; 145±78 nM at 100 nM TRH versus 300±140 at 10 nM arginine vasopressin, n = 15; P<0.05). Moreover, the effect of arginine vasopressin on [Ca²⁺]i was detectable at concentrations as low as 0.1 nM while TRH was effective at concentrations higher than 1 nM. By contrast, gonadotrophin-releasing hormone was ineffective in increasing [Ca²]i in all the adrenocorticotrophin-secreting adenomas studied. Collectively, these data indicate that sensitivity to TRH is present in almost all the growth hormone- and adrenocorticotrophin-secreting adenomas independently of the responsiveness of the individual patients to the peptide.     

New advances in treating osteoporotic compression fractures.

Osteoporosis is a chronic and potentially debilitating disease. A painful consequence of osteoporosis is a compression fracture of a vertebral body of the spine. These fractures can lead to physical deformities and emotional trauma. Treatment options for these fractures are limited and occasionally ineffective. New surgical advances in treating vertebro-compression fractures are evolving. Kyphoplasty is a new surgical procedure now being used to treat the painful compression fracture.     

Cast syndrome

The term cast syndrome is used to denote duodenal obstruction occurring after application of a corrective plaster cast to patients with scoliosis. We report a classical case in a 14-year-old female who required surgical intervention after conservative treatment failed. Six months later the patient had no further gastrointestinal symptoms. Clinical, radiological, and pathological details as well as the surgical treatment are described and discussed. Offprint requests to: M. E. Martín Hortigüela     

Porphyrins and pentachlorophenol in rat-liver mitochondria in hexachlorobenzene-induced porphyria

This study investigated the extent of impairment in functional parameters of liver mitochondria from rats treated for 60 days with hexachlorobenzene (HCB). A constant amount of mitochondrial uncoupling was found throughout the treatment period. At the same time a nearly constant amount of pentachlorophenol was detected in these mitochondria. In contrast, the level of mitochondrial porphyrins increased progressively. There was good correlation between the concentration of mitochondrial pentachlorophenol and the degree of uncoupling of oxidative phosphorylation.     

Phylogenetic relationships of snake venom toxic proteins

Two kinds of distance matrices have been formed from minimum mutational distances and absolute hydrophobicity differences obtained by comparison of aligned homologous sequences of 56 toxins from venom of snakes belonging to 7 genera. Phylogenetic trees were constructed from these distance matrices, employing the unweighted pair-group method using arithmetic averages (UPGMA). The Pearson product-moment correlation coefficient has been used to estimate the agreement between the original distance matrix and that obtained directly from the dendrogram. For all these procedures the set of computer programs PHYTREE (written in BASIC for micro-computer, and available from the author) has been used.     

The magnetic resonance of small hepatocarcinoma. A comparison with echography, computed tomography, digital angiography and computed tomography with lipiodol]

Diagnostic techniques as a whole and periodic ultrasonography (US) in particular frequently allows tumors < 3 cm (small hepatocellular carcinomas) to be detected in patients suffering from liver cirrhosis. Multifocal diseases are a major limitation to surgery. Recently, MR imaging has shown its capabilities in the diagnosis of small hepatocellular carcinomas. In our study the diagnostic value of MR imaging was compared with that of US, of pre- and post-contrast CT, of digital angiography and of CT after lipiodol injection (Lipiodol CT). The morphologic and signal intensity MR features of small hepatocellular carcinomas were investigated. Fifteen cirrhotic patients with 31 nodules of hepatocellular carcinoma < 3 cm were examined. All patients were studied with US, MR imaging, angiography and Lipiodol CT; 12/15 patients underwent CT. Histologic confirmation was obtained in 12 nodules (2 at surgery and 10 by means of percutaneous biopsy); in the extant 19 cases the diagnosis was made by combining US, CT, MR, angiographic and lipiodol-CT findings; in 9 tumors < 1 cm Lipiodol retention one month after angiography was considered as diagnostic. MR imaging detected 21/31 nodules (63%), US 22/31 (66.6%), CT 12/24 (50%), angiography 24/31 (74%), lipiodol CT 29/31 (92.5%). Mc Nemar test showed no difference in sensitivity between MR imaging and CT, MR and angiography, MR and US, lipiodol CT and angiography; however, the differences between the detection rates of MR imaging and Lipiodol CT and CT and lipiodol CT and US were statistically significant (p < 0.05). The difference in sensitivity between the detection rates of lipiodol CT and US was just above the threshold value which is usually considered significant (p = 0.065). One false positive was observed on US and none with MR, CT, angiography and lipiodol CT. On Se T1-weighted images 18 nodules were hyperintense, 2 isointense and 2 hypointense; on proton-density images 14 nodules were hyperintense, 7 isointense and none hypointense. On SE T2-weighted images 18 nodules were hyperintense, 3 isointense and none hypointense. A pseudocapsule was seen in 10/17 nodules (58%), especially on T1-weighted images. Accuracy and limitations of each technique and morphologic and signal intensity MR findings of small hepatocellular carcinoma are discussed. We believe that US is still the best diagnostic technique for the screening of hepatocellular carcinomas in cirrhotic livers.(ABSTRACT TRUNCATED AT 400 WORDS)