Tenascin-X protein expression was studied in 183 effusions (137 carcinomas of different origin, 37 mesotheliomas, and 9 reactive effusions) and 178 solid lesions (122 ovarian/peritoneal carcinomas and 56 mesotheliomas) using immunohistochemistry. Quantitative polymerase chain reaction analysis showed significantly higher TNXB mRNA level in mesotheliomas compared with ovarian and breast carcinomas (P < 0.001). By immunohistochemistry, tenascin-X protein expression was significantly higher in malignant mesothelioma compared with metastatic carcinoma in effusions (34 of 37 vs. 31 of 137 positive cases; sensitivity = 92% and specificity = 77%; P < 0.001). Reactive mesothelial cells had focal or no tenascin-X expression. Tenascin-X protein was detected in 41 of 56 mesothelioma biopsy specimens and was uniformly absent from all 122 ovarian carcinomas (sensitivity = 73% and specificity = 100%; P < 0.001). Our data suggest that tenascin-X may be a new diagnostic marker of malignant mesothelioma in the differential diagnosis of cancers involving the serosal cavities, particularly in the differential diagnosis between this tumor and ovarian/peritoneal serous carcinoma. 

In this Opinion article, we discuss the impact of signaling motifs, kinase activity and ubiquitylation on clathrin-dependent endocytosis and lysosomal sorting of EGFR. In addition, we discuss potential explanations for contradicting reports, and propose models for the recruitment of ligand-activated EGFR to clathrin-coated pits as well as for lysosomal sorting of ligand-activated EGFR.

Interleukin (IL)-33 is a novel member of the IL-1 family of
cytokines that promotes Th2 responses in lymphocytes as well
as the activation of both mast cells and eosinophils via the
ST2 receptor. Additionally, IL-33 has been proposed to act as
a chromatin-associated transcriptional regulator in both
endothelial cells of high endothelial venules and chronically
 inflamed vessels. Here we show that nuclear IL-33 is expressed
in blood vessels of healthy tissues but down-regulated at the
earliest onset of angiogenesis during wound healing; in addition,
 it is almost undetectable in human tumor vessels. Accordingly,
 IL-33 is induced when cultured endothelial cells reach confluence
 and stop proliferating but is lost when these cells begin to migrate.
 However, IL-33 expression was not induced by inhibiting cell cycle
 progression in subconfluent cultures and was not prevented by
antibody-mediated inhibition of VE-cadherin. Conversely, IL-33
knockdown did not induce detectable changes in either expression
levels or the cellular distribution of either VE-cadherin or CD31.
 However, activation of endothelial cell cultures with either tumor
 necrosis factor-alpha or vascular endothelial growth factor and
subcutaneous injection of these cytokines led to a down-regulation
 of vascular IL-33, a response consistent with both its rapid
down-regulation in wound healing and loss in tumor endothelium.
In conclusion, we speculate that the proposed transcriptional
repressor function of IL-33 may be involved in the control of
endothelial cell activation.

Cell Prolif. 2008 Aug;41(4):645-59. Links
Reduced level of the spindle checkpoint protein BUB1B is associated
with aneuploidy in colorectal cancers.Burum-Auensen E, DeAngelis PM,
Schjølberg AR, Røislien J, Mjåland O, Clausen OP. LINK

Breast:
High vascular grades
determined by Chalkley counts were significantly associated with shorter
 distant disease-free survival and breast cancer-specific survival in all
 patients (P < 0.001, log-rank) and in node-negative patients not
receiving adjuvant systemic therapy (P < 0.05). In multivariate analysis,
 both CD34 and CD105 Chalkley counts showed prognostic significance for
 distant disease-free survival (P = 0.014 and P = 0.026), whereas CD34
 also showed prognostic significance for breast cancer-specific survival
 (P = 0.007). Vascular invasion and DTCs in the bone marrow showed
independent prognostic significance. DTC did not discriminate survival
 for CD34 low Chalkley counts, whereas a very poor prognosis was observed
 for DTC-positive patients with high CD34 counts. In node-negative patients
 not receiving systemic chemotherapy, high CD34 and high CD105 counts in
combination identified patients with unfavorable outcome, as opposed to
all other CD34/CD105 combinations. CONCLUSIONS: Improved identification
of risk groups could be obtained by adding CD34 and CD105 vascular analysis
 to DTC, vascular invasion, and other primary tumor factors. This may
 facilitate the selection of candidates for adjuvant systemic therapy.
Clin Cancer Res. 2008 Apr 15;14(8):2341-50. Links
Vascularization in primary breast carcinomas: its prognostic significance
 and relationship with tumor cell dissemination.Dhakal HP, Naume B,
Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G,
Bassarova A, Giercksky KE, Nesland JM. LINK

Published in Clin Exp Allergy. 2008 Jul 31.
Depletion of CD4(+)CD25(+)CD127(lo) regulatory T cells does not
 increase allergen-driven T cell activation.Skrindo I, Farkas L,
Kvale EO, Johansen FE, Jahnsen FL. Link
 

Davidson B,  Wang TL, Shih IeM, Berner A
Expression of the chromatin remodeling factor Rsf-1 is down-regulated in breast carcinoma effusions.
 Hum Pathol. 2008 Apr;39(4):616-22. Epub 2008 Mar 4

 Davidson B, Hadar R, Schlossberg A, Sternlicht T,
 Slipicevic A, Skrede M, Risberg B, Flørenes VA, Kopolovic J, Reich R.
Expression and clinical role of DJ-1, a negative regulator of PTEN,
in ovarian carcinoma.
Hum Pathol. 2008 Jan;39(1):87-95. Epub 2007 Oct 18. Links

Dong HP, Kleinberg L, Silins I, Flørenes VA, Tropé CG, Risberg B,
Nesland JM, Davidson B.Davidson B
 Death receptor expression is associated with poor response to
 chemotherapy and shorter survival in metastatic ovarian carcinoma.
Cancer. 2008 Jan 1;112(1):84-93.

Distinct functions of H-Ras and K-Ras in proliferation and survival of
 primary hepatocytes due to selective activation of ERK and PI3K.
Rosseland CM, Wierød L, Flinder LI, Oksvold MP, Skarpen E, Huitfeldt HS.
Laboratory for Toxicopathology, Institute of Pathology,
 Rikshospitalet-Radiumhospitalet Medical Centre,
University of Oslo, Norway. carola.rosseland@labmed.uio.no
Published in J Cell Physiol. 2008 Jun;215(3):818-26. Link 

Published in BMC Cell Biol. 2008 Apr 1;9:16.  Link

Published in J Cell Mol Med. 2008 Mar 4. [Epub ahead of print] Link

Nat Protoc. 2008;3(6):955-64.

Dong HP, Kleinberg L, Davidson B, Risberg B.

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet Medical Center, Ullernchaussen 70, Montebello, N-0310 Oslo, Norway.

We describe here a protocol for the detection of epithelial cells in effusions combined with quantification of apoptosis by flow cytometry (FCM). The procedure described consists of the following stages: culturing and induction of apoptosis by staurosporine in control ovarian carcinoma cell lines (SKOV-3 and OVCAR-8); preparation of effusion specimens and cell lines for staining; staining of cancer cells in effusions and cell lines for cell surface markers (Ber-EP4, EpCAM and CD45) and intracellular/nuclear markers of apoptosis (cleaved caspase-3 and caspase-8, and incorporated deoxyuridine triphosphates); and FCM analysis of stained cell lines and effusions. This protocol identifies a specific cell population in cytologically heterogeneous clinical specimens and applies two methods to measure different aspects of apoptosis in the cell population of interest. The cleaved caspase and deoxyuridine triphosphate incorporation FCM assays are run in parallel and require (including sample preparation, staining, instrument adjustment and data acquisition) 8 h. The culturing of cell lines requires 2-3 days and induction of apoptosis requires 16 h.

Regulatory T cells (T(regs)) may inhibit immunity against cancer.
 Induction and expansion of T(regs) in the immunosuppressive
microenvironment created by a growing tumour appear to be one
 of the mechanisms by which it can evade host defence. We studied
the impact of CD25+ T(regs) in a B cell lymphoma model in which
Rag2-/- mice received adoptive transfer of wild-type spleen cells
with or without CD25+ cells, and concurrently subcutaneous
inoculation of the B cell lymphoma cell line A20. We also examined
the effect of engaging the glucocorticoid-induced tumour necrosis
 factor receptor (GITR) - an approach reported previously to abrogate
 the suppressive effects of T(regs). Mice that received spleen cells
 depleted of CD25+ T(regs) showed significantly slower tumour growth
 and increased survival compared with mice that received unsorted
spleen cells. The T(reg)-depleted group also had significantly more
 CD8+ T cells infiltrating the tumours and higher levels of serum
immunoglobulin G subclasses. The anti-GITR treatment had no significant
 effect on tumour growth, survival or immunoglobulin production. In
the CD25-depleted group four of 10 mice developed clinical signs of
autoimmunity, in contrast to none in the non-depleted group. Forkhead
 box P3+ T cells were found in tumour-draining lymph nodes in mice
in the CD25-depleted group, suggesting an in vivo induction or
expansion of rare transferred donor T(regs). Thus, our study showed
 that removal of CD25+ T(regs) enhanced anti-tumour immunity against
local growth of a B cell lymphoma and that induction or expansion of
 T(regs) could be one mechanism by which the growing tumour evades
immune surveillance.

The respiratory tract has an approximate surface area of 70 m2 in
adult humans, which is in virtually direct contact with the outside
 environment. It contains a uniquely rich vascular bed containing
a large pool of marginated T cells, and harbours a layer of
single-cell-thick epithelial tissue through which re-oxygenation
of blood must occur uninterrupted for survival. It is therefore
not surprising that the respiratory tract is never more than a short
 step away from disaster. We have only a partial understanding of
 how immunological homeostasis is maintained in these tissues, but
it is becoming clear that the immune system has evolved a range of
specific mechanisms to deal with the unique problems encountered
 in this specialized microenvironment.

A well-developed HLA-DR+ network of antigen presenting cells
 was present in all samples, approximately 50% of the cells being
CD68+ macrophages and the remainder various subsets of dendritic cells.
 The density of HLA-DR+ cells increased significantly with age but was
 not related to atopy, clinical symptoms or lung function. Comparing
 the density of antigen-presenting cell subsets and clinical parameters,
 only the number of intraepithelial CD1a+ dendritic cells was
significantly increased in infants who had recently suffered a
respiratory infection. BALT structures were identified in 22 children,
 with no relation to lung function, atopic status or human rhinovirus
 positivity. Plasmacytoid dendritic cells and Foxp3+ Tregs were
 located primarily within these isolated lymphoid follicles.
CONCLUSION: A bronchial network of dendritic cells and macrophages
develops quite rapidly after birth, apparently independent of
clinical symptoms or atopy. The high frequency of BALT structures
containing putative tolerogenic dendritic cells and Tregs suggests
 that these lymphoid follicles play an important role in bronchial
immune homeostasis during infancy.

Davidson B,  Wang TL, Shih IeM, Berner A
Expression of the chromatin remodeling factor Rsf-1 is down-regulated in breast carcinoma effusions.
 Hum Pathol. 2008 Apr;39(4):616-22. Epub 2008 Mar 4

 Davidson B, Hadar R, Schlossberg A, Sternlicht T,
 Slipicevic A, Skrede M, Risberg B, Flørenes VA, Kopolovic J, Reich R.
Expression and clinical role of DJ-1, a negative regulator of PTEN,
in ovarian carcinoma.
Hum Pathol. 2008 Jan;39(1):87-95. Epub 2007 Oct 18. Links

Dong HP, Kleinberg L, Silins I, Flørenes VA, Tropé CG, Risberg B,
Nesland JM, Davidson B.Davidson B
 Death receptor expression is associated with poor response to
 chemotherapy and shorter survival in metastatic ovarian carcinoma.
Cancer. 2008 Jan 1;112(1):84-93.

Huitfeldts group propose that the requirement of adhesion for cells to proliferate in response to growth
factors, in part, may be explained by the MEK1 S298/T292 control of ERK2 nuclear translocation.
In addition, we suggest that ERK2 intracellular localization determines whether growth factors
mediate proliferation or survival and that the sorting occurs in an adhesion-dependent manner.