Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis.

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease.

Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma: Association with Metabolic Tumor Burden Determined with FDG-PET/CT.

BACKGROUND: The detection of circulating tumor DNA (ctDNA) with next-generation sequencing (NGS) in venous blood is a promising tool for the genomic profiling of head and neck squamous cell carcinoma (HNSCC). The association between ctDNA findings and metabolic tumor burden detected with FDG-PET/CT imaging is of particular interest for developing prognostic and predictive algorithms in HNSCC. METHODS: Twenty-six prospectively enrolled HNSCC patients were eligible for further analysis. All patients underwent tumor tissue and venous liquid biopsy sampling and FDG-PET/CT before definitive oncologic treatment. An NGS-based commercial panel was used for a genomic analysis of the samples. RESULTS: Maximum variant allele frequency (VAF) in blood correlated positively with whole-body (WB) metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (r = 0.510, p = 0.008 and r = 0.584, p = 0.002, respectively). A positive liquid biopsy was associated with high WB-TLG using VAF ≥ 1.00% or ≥5.00% as a cut-off value (p = 0.006 or p = 0.003, respectively). Additionally, ctDNA detection was associated with WB-TLG when only concordant variants detected in both ctDNA and tissue samples were considered. CONCLUSIONS: A high metabolic tumor burden based on FDG imaging is associated with a positive liquid biopsy and high maximum VAF. Our findings suggest a complementary role of metabolic and genomic signatures in the pre-treatment evaluation of HNSCC.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Increased Liver Fatty Acid Uptake Is Partly Reversed and Liver Fat Content Normalized After Bariatric Surgery.

OBJECTIVE: Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery. RESEARCH DESIGN AND METHODS: Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects. RESULTS: The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased. CONCLUSIONS: The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively.

Novel COL1A1 Mutation c.3290G>T Associated With Severe Form of Osteogenesis Imperfecta in a Fetus.

Osteogenesis imperfecta is a genetically and clinically heterogenous group of skeletal dysplasias characterized by bone fragility. Its severity ranges from nearly asymptomatic individuals to perinatal lethality. The majority of cases are caused by mutations in either the COL1A1 or the COL1A2 gene coding for alpha 1 and alpha 2 chains of collagen type 1, respectively, and a large number of pathogenic variants of these genes has been identified. We describe a novel COL1A1 mutation associated with prenatally diagnosed severe form of osteogenesis imperfecta.

Causes of Stillbirth in Turku, Finland, 2001-2011.

The objective of the study was to examine the causes of stillbirth in the district of Southwest Finland and to assess the importance of postmortem examination and the selection of a suitable classification system for classifying stillbirths. This study is a cohort study where the fetal autopsies were performed in the Department of Pathology at Turku University Hospital, Finland, 2001-2011. Stillbirths from singleton pregnancies at the gestational age of ≥ 24 + 0 weeks (if unknown, gestational weight ≥ 500 g) (n = 98) were selected. In addition, stillbirths from multiple gestations (n = 6) were also analyzed. The causes of stillbirths were classified according to the Relevant Condition at Death classification system. Maternal risk factors and the role of fetal gestational age and weight for the causes of stillbirth were assessed. The most common causes of singleton stillbirth were lethal congenital anomalies, placental insufficiencies, and constricting loops and knots of the umbilical cord. The cause of singleton stillbirth could be determined for 78% of the cases, leaving 22% unclassified. There were no significant differences in the causes of stillbirth by gestational age or weight. Smoking may increase the incidence of placental abruption ( P < 0.01). The most common causes of stillbirth in Turku, Finland, are consistent with findings from other high-income countries. With careful postmortem examination and ancillary studies, it is possible to find the cause of stillbirth for most of the cases. Even if the stillbirth is left unexplained, many other harmful conditions can be excluded thus benefiting both the parents and the health care unit.

Gestational hyperglycemia reprograms cardiac gene expression in rat offspring.

BackgroundRat fetuses with maternal pregestational hyperglycemia develop cardiac dysfunction, and their cardiac gene expression differs from that of healthy control fetuses near term. We hypothesized that cardiac gene expression and morphologic abnormalities of rat fetuses with maternal pregestational hyperglycemia become normal after birth.MethodsNine rats were preconceptually injected with streptozotocin to induce maternal hyperglycemia and nine rats served as controls. The hyperglycemia group comprised 82 mice and the control group 74 offspring fed by euglycemic dams. Hearts of the offspring were collected on postnatal days 0, 7, and 14, and processed for histologic and gene expression analyses.ResultsOn day 0, heart weight was increased, and expression of cardiac genes involved in contractility, growth, and metabolism was decreased in the hyperglycemia group. On day 7, although cardiomyocyte apoptosis was enhanced, most of the changes in gene expression had normalized in the hyperglycemia group. By day 14, the expression of genes important for myocardial growth, function, and metabolism was again abnormal in the hyperglycemia group.ConclusionMost cardiac gene expression abnormalities become transiently normal during the first week of life of offspring to hyperglycemic rats. However, by day 14, cardiac expressions of genes involved in growth, function, and metabolism are again abnormal in relation to control offspring.

Placental structural abnormalities have detrimental hemodynamic consequences in a rat model of maternal hyperglycemia.

INTRODUCTION: Human type 1 diabetic pregnancy is associated with placental structural and hemodynamic abnormalities. We hypothesized that in rat fetuses of hyperglycemic dams, placental and fetal blood flow velocity waveforms demonstrate compromised hemodynamics when compared to control fetuses, and these hemodynamic parameters correlate with placental structural abnormalities at near term gestation. METHODS: Streptozotocin-induced maternal hyperglycemia group comprised 10 dams with 107 fetuses and the control group 20 dams with 219 fetuses. Doppler-ultrasonographic examinations were performed at gestational days 13-14, 16-17, and 19-21. After the last examination, placentas were collected for morphologic, gene expression, and cytokine analysis. RESULTS: Umbilical artery (UA), descending aorta (DAO), and ductus venosus (DV) pulsatility indices (PI) were significantly higher at each study point in maternal hyperglycemia compared to controls. Placental size, glycogen storages, venous thrombosis formation, and fluid accumulation were increased in maternal hyperglycemia. Epidermal growth factor receptor (Edgfrb), platelet derived growth factor receptor beta polypeptide (Pdgfrb), and tumor necrosis factor receptor superfamily, member 12α (Tnfrsf12α) expressions were decreased. Interleukin (IL) -2 and -4 concentrations were decreased, and IL-1beta levels were increased in maternal hyperglycemia. UA PIs correlated positively with DV PIV, DAO PI, fluid accumulation, and glycogen storages. UA PIs correlated negatively with IL-4, Edgfrb, and Pdgfrb. DISCUSSION: In maternal hyperglycemia, placental and fetal hemodynamics were compromised during the last trimester of pregnancy compared to normoglycemic pregnancies. Placental structural, metabolic, and growth related gene expression, and inflammatory marker abnormalities were associated with hemodynamic compromise.

Cathepsin K overexpression modifies lung development in newborn mice.

Cathepsin K (CatK), contributes to the development of chronic lung disease in newborn infants, but the impact of CatK for the lungs may be multifaceted. We have previously demonstrated that low level of CatK is associated with newborn lung injury and CatK deficiency aggravates lung injury in hyperoxia-exposed newborn mice. Thus, we hypothesized that sustained/higher expression of CatK could ameliorate hyperoxia-induced injury and restrain the development of pulmonary fibrosis. We studied the lungs of newborn wild-type (WT) and CatK overexpressing transgenic mice (TG) that were exposed to hyperoxia or room air for 7 or 14 days after birth. Fourfold pulmonary overexpression of CatK did not affect the growth or lung weight in room-air bred TG mice. The distal airspaces in TG mice were, however, enlarged on postnatal days (PN) 7 and 14, the latter together with increased apoptosis, compared with WT controls. Survival rate was normal and no respiratory distress was observed in air-bred TG mice. Hyperoxia inhibited alveolarization and increased collagen accumulation in WT mice. In TG mice, hyperoxia for 1 week did not aggravate the lung injury, and the lung morphology and already enlarged alveoli remained unchanged in TG mice at PN7. Prolonged hyperoxic exposure caused significant lung injury and mortality similarly in both group of mice, and only few mice survived until PN14. In summary, CatK overexpression slightly enlarges distal airways in infant mice, but hyperoxic environment is initially better tolerated when compared to WT mice. These findings suggest multifaceted role for CatK in lung development and newborn lung injury.

Hypoxia, blood flow and metabolism in squamous-cell carcinoma of the head and neck: correlations between multiple immunohistochemical parameters and PET.

BACKGROUND: The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). METHODS: [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome. RESULTS: None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = -618, p =0.019) and apoptosis with Ki-67 (rs = -638, p =0.014). CONCLUSIONS: A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.

Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy.

OBJECTIVE: We report novel defects of mitochondrial translation elongation factor Ts (EFTs), with high carrier frequency in Finland and expand the manifestations of this disease group from infantile cardiomyopathy to juvenile neuropathy/encephalopathy disorders. METHODS: DNA analysis, whole-exome analysis, protein biochemistry, and protein modeling. RESULTS: We used whole-exome sequencing to find the genetic cause of infantile-onset mitochondrial cardiomyopathy, progressing to juvenile-onset Leigh syndrome, neuropathy, and optic atrophy in 2 siblings. We found novel compound heterozygous mutations, c.944G>A [p.C315Y] and c.856C>T [p.Q286X], in the TSFM gene encoding mitochondrial EFTs. The same p.Q286X variant was found as compound heterozygous with a splice site change in a patient from a second family, with juvenile-onset optic atrophy, peripheral neuropathy, and ataxia. Our molecular modeling predicted the coding-region mutations to cause protein instability, which was experimentally confirmed in cultured patient cells, with mitochondrial translation defect and lacking EFTs. Only a single TSFM mutation has been previously described in different populations, leading to an infantile fatal multisystem disorder with cardiomyopathy. Sequence data from 35,000 Finnish population controls indicated that the heterozygous carrier frequency of p.Q286X change was exceptionally high in Finland, 1:80, but no homozygotes were found in the population, in our mitochondrial disease patient collection, or in an intrauterine fetal death material, suggesting early developmental lethality of the homozygotes. CONCLUSIONS: We show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease.

Delay in rat lung alveolarization after the combined exposure of maternal hyperglycemia and postnatal hyperoxia.

BACKGROUND: Maternal diabetes interferes with fetal lung development and postnatal treatments may further disturb pulmonary growth. Therefore, we investigated the effect of postnatal oxygen exposure on alveolar development in neonatal rat lungs pre-exposed to intrauterine hyperglycemia. METHODS: Diabetes was induced in Sprague-Dawley rats with streptozotocin injection before pregnancy. Hyperglycemia-exposed and control litters were randomized to breath room air or 85% oxygen for 7 days after birth. Lungs were analyzed on postnatal d7 for weight, morphology, apoptosis, proliferation, and biomarkers of oxidative stress. RESULTS: Maternal hyperglycemia accelerated lung development as demonstrated by thinner alveolar walls and slightly increased secondary septation when compared to room air bred rats. Hyperoxia alone caused thin-walled and enlarged alveoli with few secondary septa. Interestingly, the dual exposure inhibited the thinning of alveolar walls and the disappearance of mesenchymal cells from the alveolar walls together with the delay in the formation of alveoli and secondary crests. While the lungs' oxidative stress was similar in all groups, pulmonary apoptosis and proliferation were altered. CONCLUSION: Our results thus indicate that the hyperglycemic priming of the fetal lung modifies the deleterious effect of hyperoxia on alveolarization in neonatal rats.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients.

BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation.

Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non-transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype.

Measurement of brown adipose tissue mass using a novel dual-echo magnetic resonance imaging approach: a validation study.

OBJECTIVE: The aim of this study was to evaluate and validate magnetic resonance imaging (MRI) for the visualization and quantification of brown adipose tissue (BAT) in vivo in a rat model. We hypothesized that, based on differences in tissue water and lipid content, MRI could reliably differentiate between BAT and white adipose tissue (WAT) and could therefore be a possible alternative for (18)F-Fluorodeoxyglucose Positron Emission Tomography ((18)FDG-PET), the current gold standard for non-invasive BAT quantification. MATERIALS/METHODS: Eleven rats were studied using both (18)FDG-PET/CT and MRI (1.5 T). A dual echo (in-and-out-of-phase) sequence was used, both with and without spectral presaturation inversion recovery (SPIR) fat suppression (DUAL-SPIR) to visualize BAT, after which all BAT was surgically excised. The BAT volume measurements obtained via (18)FDG-PET/CT and DUAL-SPIR MR were quantitatively compared with the histological findings. All study protocols were reviewed and approved by the local ethics committee. RESULTS: The BAT mass measurements that were obtained using DUAL-SPIR MR subtraction images correlated better with the histological findings (P=0.017, R=0.89) than did the measurements obtained using (18)FDG-PET/CT (P=0.78, R=0.15), regardless of the BAT metabolic activation state. Additionally, the basic feasibility of the DUAL-SPIR method was demonstrated in three human pilot subjects. CONCLUSIONS: This study demonstrates the potential for MRI to reliably detect and quantify BAT in vivo. MRI can provide information beyond that provided by (18)FDG-PET imaging, and its ability to detect BAT is independent of its metabolic activation state. Additionally, MRI is a low-cost alternative that does not require radiation.

Metagenes associated with survival in non-small cell lung cancer.

NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%-55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies.A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR.Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified.Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients.

Environmental services provided from riparian forests in the Nordic countries.

Riparian forests (RF) growing along streams, rivers and lakes comprise more than 2% of the forest area in the Nordic countries (considering a 10 m wide zone from the water body). They have special ecological functions in the landscape. They receive water and nutrients from the upslope areas, are important habitats for biodiversity, have large soil carbon stores, but may emit more greenhouse gases (GHG) than the uplands. In this article, we present a review of the environmental services related to water protection, terrestrial biodiversity, carbon storage and greenhouse gas dynamics provided by RF in the Nordic countries. We discuss the benefits and trade-offs when leaving the RF as a buffer against the impacts from upland forest management, in particular the impacts of clear cutting. Forest buffers are effective in protecting water quality and aquatic life, and have positive effects on terrestrial biodiversity, particularly when broader than 40 m, whereas the effect on the greenhouse gas exchange is unclear.

The expression and distribution of group IIA phospholipase A2 in human colorectal tumours.

Secretory phospholipase A2 group IIA (IIA PLA2) is a protein shown to be increased in various human malignancies. The expression profile of this protein, however, is controversial in colorectal carcinoma. The aim of this study was to examine the distribution and expression of IIA PLA2 protein in benign, premalignant and malignant colorectal tumours as well as in peritumoural mucosa. Seven hyperplastic polyps, 24 adenomas and 83 colorectal carcinomas were stained with immunohistochemistry (IHC) for IIA PLA2. Four hyperplastic polyps, 12 adenomas and nine carcinomas were also evaluated for the sites of IIA PLA2 expression using mRNA in situ hybridisation (ISH). There was no immunoreactivity for IIA PLA2 in hyperplastic polyps. A total of 79% of adenomas and 31% of carcinomas showed IIA PLA2-immunopositive tumour cells in IHC, and the expression was localised to epithelial cells with ISH. In carcinomas, IIA PLA2-immunopositive apoptotic cells and necrosis were also found. The epithelial cells in the peritumoural mucosa showed immunopositivity for IIA PLA2 in 96% of cases, with considerably stronger intensity adjacent to carcinoma than in the more distal mucosa. Moreover, IIA PLA2-immunopositive malignant epithelial cells were found in 44% of cases in the invasive front of carcinomas. Our results suggest that the IIA PLA2 protein content is dramatically decreased in malignant colorectal tumours as compared with adenomas. The protein is also found in the apoptotic cells, necrosis, peritumoural mucosa and in the invasive front of carcinomas.

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis.

BACKGROUND: Medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumours (PNETs) are the most common highly aggressive paediatric brain tumours. In spite of extensive research on these tumours, there are only few known biomarkers or therapeutic target proteins, and the prognosis of patients with these tumours remains poor. Our aim was to investigate whether carbonic anhydrases (CAs), enzymes commonly overexpressed in various tumours including glioblastomas and oligodendrogliomas, are present in MBs and PNETs, and whether their expression can be correlated with patient prognosis. METHODS: We determined the expression of the tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a series of MB/PNET specimens (n = 39) using immunohistochemistry. RESULTS: Endothelial CA II, cytoplasmic CA II, CA IX and CA XII were expressed in 49%, 73%, 23% and 11% of the tumours, respectively. CA II was detected in the neovessel endothelium and the tumour cell cytoplasm. CA IX was mainly expressed in the tumour cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumours. Importantly, CA IX expression predicted poor prognosis in both univariate (p = 0.041) and multivariate analyses (p = 0.016). CONCLUSIONS: We suggest that CA IX should be considered a potential prognostic and therapeutic target in MBs and PNETs.