Functional significance of the hepaCAM gene in bladder cancer

<p>Abstract</p> <p>Background</p> <p>The hepaCAM gene encodes a new immunoglobulin-like cell adhesion molecule, and its expression is suppressed in a variety of human cancers. Additionally, hepaCAM possesses properties often observed in tumor suppressor genes. However, the expression and biological function of hepaCAM has not been investigated in bladder cancer. Therefore we sought to examine hepaCAM expression and the relationship between its structure and function in human transitional cell carcinoma of bladder (TCCB).</p> <p>Materials and methods</p> <p>HepaCAM expression was evaluated in 28 normal and 34 TCCB bladder specimens and 2 TCCB cell lines using semi-quantitative RT-PCR. The wild-type hepaCAM and the extracellular domain-truncated mutant gene were transfected into the TCCB cell line T24, and the biological properties of both the wild-type gene and the domain-truncated mutant were then assessed.</p> <p>Results</p> <p>HepaCAM expression was down-regulated in 82% (28/34) of TCCB specimens and undetectable in the 2 TCCB cell lines tested. The localization of hepaCAM appeared to be dependent on cell density in T24 cells. In widely spread cells, hepaCAM accumulated on the perinuclear membrane and the cell surface protrusions, whereas in confluent cells, hepaCAM was predominantly localized at the sites of cell-cell contacts on the cell membrane. Functionally, hepaCAM expressed not only increased cell spreading, delayed cell detachment, enhanced wound healing and increased cell invasion; it also inhibited cell growth (P < 0.01). When the extracellular domain was deleted, the localization of hepaCAM was significantly altered, and it lost both its adhesive function and its influence on cell growth.</p> <p>Conclusions</p> <p>HepaCAM is involved in cell adhesion and growth control, and its expression is frequently silenced in TCCB. The extracellular domain of hepaCAM is essential to its physiological and biological functions.</p

Grootschalige concentratie- en depositiekaarten Nederland : Rapportage 2014

Nieuwe concentratie- en depositiekaarten voor NSL en PAS Het RIVM heeft kaarten opgesteld waarop staat aangegeven wat in 2013 in Nederland de concentraties in de lucht waren van onder andere stikstofdioxide en fijn stof. Ook is op een kaart aangegeven in welke mate stikstof op de bodem neerslaat. Daarnaast zijn toekomstberekeningen voor deze stoffen gemaakt voor de periode 2015- 2030. De kaarten worden gebruikt voor de monitoring van het Nationaal Samenwerkingsprogramma Luchtkwaliteit (NSL) en de Programmatische Aanpak Stikstof (PAS). Hiermee worden onder andere de effecten van ruimtelijke plannen getoetst Stikstofdioxideconcentraties voor 2015 veelal lager De gemeten concentraties stikstofdioxide waren in 2013 lager dan in 2012. De concentraties die voor 2015 zijn berekend, zijn op de meeste locaties lager dan vorig jaar was geraamd. Toch blijven er een aantal probleemgebieden bestaan waarin de verwachte concentraties hoger zijn dan vorig jaar geraamd, vooral in de regio's Rotterdam en Den Haag. Wat de verwachte overschrijdingen van de normen in 2015 betreft, zal dat in Amsterdam en Utrecht op minder locaties aan de orde zijn dan eerder was ingeschat, en in Rotterdam op meer locaties Drie oorzaken voor deze aangepaste verwachting zijn het belangrijkst. Als eerste is bij de ramingen een correctie aangebracht voor systematische verschillen tussen gemeten en berekende stikstofdioxideconcentraties. Ten tweede stoten de nieuwste modellen vrachtauto's minder stikstofoxiden uit dan eerder was ingeschat. Ten derde zijn effecten meegenomen van het SER-energieakkoord uit 2013. Hierin zijn afspraken gemaakt om energie te besparen bij huishoudens, industrie en landbouw en het aandeel alternatieve energiebronnen als wind- en zonne-energie te vergroten Roetconcentraties dalen naar verwachting verder Steeds meer dieselauto's hebben een filter, waarmee roet effectief wordt afgevangen. Op basis van het huidige beleid wordt geschat dat de roetconcentratie de komende jaren verder daalt, en in 2020 bijna zal zijn gehalveerd ten opzicht van het huidige niveau Daling stikstofdepositie onveranderd De neerslag van stikstof op de bodem in Nederland daalt naar verwachting de komende jaren in ongeveer dezelfde mate als vorig jaar was geraamd. Een dalende stikstofdepositie is een voorwaarde voor natuurbehoudNew maps of concentrations and depositions for NSL and PAS In this report, the National Institute for Public Health and the Environment (RIVM) presents the latest maps of air concentrations in the Netherlands for several substances, including nitrogen dioxide and particulate matter for 2013. It also presents the maps for the deposition of nitrogen compounds to the soil for that year. Calculations for the future (2015-2030) have also been made. The maps are being used in the national air quality collaboration programme (NSL) and for the programmatic approach to nitrogen (PAS) for monitoring new spatial planning projects Nitrogen dioxide concentrations mostly lower for 2015 The measured concentrations of nitrogen dioxide were in 2013 lower than in 2012. Concentrations calculated for 2015 are at most locations below last year's estimates. Yet, there remain a number of areas where the expected concentrations are higher than last year's estimates, especially in the vicinity of Rotterdam and The Hague. The limit value for the nitrogen dioxide concentration will probably be exceeded in fewer locations in Amsterdam and Utrecht than was estimated earlier and in more locations in Rotterdam in 2015 There are three main reasons for these adjusted expectations of future concentrations. First, a correction is applied to projections of nitrogen dioxide concentrations for systematic differences between measured and calculated concentrations. Second, the latest truck models emit less nitrogen oxides than was previously expected. Third, the effects of the SER energy agreement from 2013 have been taken into account. Arrangements have been made in the agreement to save energy in households, industry and agriculture, and to increase the share of alternative energy sources, such as, wind and solar energy Soot concentrations are expected to decrease further More and more diesel cars have a filter, which is effective in capturing soot. It is expected that, based on the current policies, the soot concentrations will continue to decrease in the coming years and will be reduced by almost 50 percent by 2020 compared to current levels Decrease in nitrogen deposition unchanged The deposition of nitrogen to the soil in the Netherlands is expected to decrease in the coming years by approximately the same amount as was estimated last year. A reduction in nitrogen deposition is a prerequisite for nature conservationMinisterie van I&

Response of different PTH assays to therapy with sevelamer or CaCO3 and active vitamin D sterols

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO3) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO3 therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO3 and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 ± 75 and 932 ± 89 pg/ml, and levels declined to 491 ± 55 and 543 ± 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO3. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels

LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial

Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-2

The Relevance of Breast Cancer Subtypes in the Outcome of Neoadjuvant Chemotherapy

BACKGROUND: Breast cancer is increasingly considered a heterogeneous disease. The aim of this study was to assess the differences between histological and receptor-based subtypes in breast-conserving surgery and pathological complete response (pCR) after neoadjuvant chemotherapy. METHOD: A consecutive series of 254 patients with operable breast cancer treated with neoadjuvant chemotherapy was analyzed. Tumors were classified according to their receptor status in estrogen receptor (ER)-positive tumors (HER2-negative), triple-negative tumors, and HER2-positive tumors. The type of surgery feasible prior to neoadjuvant chemotherapy was compared with the actual surgery performed. RESULTS: The overall increase in breast-conserving surgery was 37% (73 of 198). In patients with ductal and lobular carcinomas this increase was 41% (63 of 152, 95% confidence interval [95% CI] 0.34-0.49) and 20% (7 of 35, 95% CI 0.10-0.36), respectively (P = 0.02). Half of the patients with lobular carcinoma had to undergo a secondary mastectomy because of incomplete resection margins. In ER-positive, triple-negative and HER2-positive tumors, the increase in breast-conserving surgery was 39% (42 of 109, 95% CI 0.30-0.48), 24% (11 of 45, 95% CI 0.14-0.38), and 45% (20 of 44, 95% CI 0.32-0.60) (P = 0.11). The pCR rate in ductal and lobular carcinomas was 12% (23 of 195) and 2% (1 of 42), respectively (P = 0.09). In ER-positive, triple-negative and HER2-positive tumors the pCR rates were 2% (3 of 138), 28% (16 of 57), and 18% (10 of 56), respectively. Multivariate analysis showed that the receptor-based subtype was the only significant predictor of pCR (P = 0.004). CONCLUSION: In lobular tumors the benefit with regard to breast-conserving surgery of neoadjuvant chemotherapy is questionable. Although in ER-positive tumors the pCR rate is low, the increase in breast-conserving surgery was remarkable in ductal ER-positive tumor

Cardiac oxygen supply is compromised during the night in hypertensive patients

The enhanced heart rate and blood pressure soon after awaking increases cardiac oxygen demand, and has been associated with the high incidence of acute myocardial infarction in the morning. The behavior of cardiac oxygen supply is unknown. We hypothesized that oxygen supply decreases in the morning and to that purpose investigated cardiac oxygen demand and oxygen supply at night and after awaking. We compared hypertensive to normotensive subjects and furthermore assessed whether pressures measured non-invasively and intra-arterially give similar results. Aortic pressure was reconstructed from 24-h intra-brachial and simultaneously obtained non-invasive finger pressure in 14 hypertensives and 8 normotensives. Supply was assessed by Diastolic Time Fraction (DTF, ratio of diastolic and heart period), demand by Rate-Pressure Product (RPP, systolic pressure times heart rate, HR) and supply/demand ratio by Adia/Asys, with Adia and Asys diastolic and systolic areas under the aortic pressure curve. Hypertensives had lower supply by DTF and higher demand by RPP than normotensives during the night. DTF decreased and RPP increased in both groups after awaking. The DTF of hypertensives decreased less becoming similar to the DTF of normotensives in the morning; the RPP remained higher. Adia/Asys followed the pattern of DTF. Findings from invasively and non-invasively determined pressure were similar. The cardiac oxygen supply/demand ratio in hypertensive patients is lower than in normotensives at night. With a smaller night-day differences, the hypertensives’ risk for cardiovascular events may be more evenly spread over the 24 h. This information can be obtained noninvasively

Diffuse glioma growth: a guerilla war

In contrast to almost all other brain tumors, diffuse gliomas infiltrate extensively in the neuropil. This growth pattern is a major factor in therapeutic failure. Diffuse infiltrative glioma cells show some similarities with guerilla warriors. Histopathologically, the tumor cells tend to invade individually or in small groups in between the dense network of neuronal and glial cell processes. Meanwhile, in large areas of diffuse gliomas the tumor cells abuse pre-existent “supply lines” for oxygen and nutrients rather than constructing their own. Radiological visualization of the invasive front of diffuse gliomas is difficult. Although the knowledge about migration of (tumor)cells is rapidly increasing, the exact molecular mechanisms underlying infiltration of glioma cells in the neuropil have not yet been elucidated. As the efficacy of conventional methods to fight diffuse infiltrative glioma cells is limited, a more targeted (“search & destroy”) tactic may be needed for these tumors. Hopefully, the study of original human glioma tissue and of genotypically and phenotypically relevant glioma models will soon provide information about the Achilles heel of diffuse infiltrative glioma cells that can be used for more effective therapeutic strategies

The role of WNK in modulation of KCl cotransport activity in red cells from normal individuals and patients with sickle cell anaemia

Abstract: Abnormal activity of red cell KCl cotransport (KCC) is involved in pathogenesis of sickle cell anaemia (SCA). KCC-mediated solute loss causes shrinkage, concentrates HbS, and promotes HbS polymerisation. Red cell KCC also responds to various stimuli including pH, volume, urea, and oxygen tension, and regulation involves protein phosphorylation. The main aim of this study was to investigate the role of the WNK/SPAK/OSR1 pathway in sickle cells. The pan WNK inhibitor WNK463 stimulated KCC with an EC50 of 10.9 ± 1.1 nM and 7.9 ± 1.2 nM in sickle and normal red cells, respectively. SPAK/OSR1 inhibitors had little effect. The action of WNK463 was not additive with other kinase inhibitors (staurosporine and N-ethylmaleimide). Its effects were largely abrogated by pre-treatment with the phosphatase inhibitor calyculin A. WNK463 also reduced the effects of physiological KCC stimuli (pH, volume, urea) and abolished any response of KCC to changes in oxygen tension. Finally, although protein kinases have been implicated in regulation of phosphatidylserine exposure, WNK463 had no effect. Findings indicate a predominant role for WNKs in control of KCC in sickle cells but an apparent absence of downstream involvement of SPAK/OSR1. A more complete understanding of the mechanisms will inform pathogenesis whilst manipulation of WNK activity represents a potential therapeutic approach

Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape

The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies