We evaluated the role of placental protein 13 (PP13; galectin 13) in the process of trophoblast invasion and decidual necrosis. Immunohistochemical analysis for PP13, immune cells, human placental lactogen, cytokeratin, and apoptosis markers was performed on 20 elective pregnancy termination specimens between 6 and 15 weeks of gestation. Placental protein 13 was localized to syncytiotrophoblasts in the chorionic villi and to occasional multinucleated luminal trophoblasts within converted decidual spiral arterioles. Cytotrophoblasts, anchoring trophoblasts, and invasive trophoblasts did not stain for PP13. Extracellular PP13 aggregates were found around decidual veins associated with T-cell-, neutrophil- and macrophage-containing decidual zones of necrosis (ZONEs). We hypothesize that PP13 is secreted into the intervillus space, drains through the decidua basalis veins, and forms perivenous PP13 aggregates which attract and activate maternal immune cells. Thus, syncytiotrophoblast-derived PP13 may create a ZONE that facilitates trophoblast invasion and conversion of the maternal spiral arterioles.

The aim of this study is to investigate regeneration in a segmental bone defect using a novel fibrinogen-based hydrogel material. The use of hydrogels made from poly(ethylene glycol) (PEG) conjugated to fibrinogen for this purpose may be better to conventional fibrin-based materials as it offers an additional degree of control over the structural characteristics and biodegradation of the material. At the same time, it maintains some of the inherent biofunctionality of the fibrinogen molecule. PEGylated fibrinogen hydrogels with various degrees of proteolytic resistance based on PEG and fibrinogen composition were designed for slow, intermediate, and fast biodegradation. The hydrogels were implanted into 7-mm segmental rat tibial defects without additional osteoinductive factors with the rationale that the ingrowth matrix will displace the normal fibrin clot while sustaining a similar healing effect for a longer duration. Histological and X-ray results confirmed that the extent and distribution of newly formed bone in the defect after 5 weeks strongly parallels the biodegradation pattern of the implanted material. When compared to nonunions in animals treated with the fast-degrading implants and untreated control animals, the rats implanted with the intermediate-degrading material exhibited osteoneogenesis. This data supports the hypothesis that the perseverance of the PEGylated fibrinogen material can be synchronized with the optimal healing characteristics of a segmental osseous defect and that the consequent sustained release of fibrinogen fragments facilitates the osteogenic response at the injury site. The PEGylated fibrinogen material may, therefore, be a highly efficacious material for promoting the healing of bone defects and especially nonunion fractures.

Carcinomas are tumors of epithelial origin accounting for over 80% of all human malignancies. A substantial body of evidence implicates oncogenic signaling by receptor tyrosine kinases (RTKs) in carcinoma development. Here we investigated the expression of Sef, a novel inhibitor of RTK signaling, in normal human epithelial tissues and derived malignancies. Human Sef (hSef) was highly expressed in normal epithelial cells of breast, prostate, thyroid gland and the ovarian surface. By comparison, substantial downregulation of hSef expression was observed in the majority of tumors originating from these epithelia. Among 186 primary carcinomas surveyed by RNA in situ hybridization, hSef expression was undetectable in 116 cases including 72/99 (73%) breast, 11/16 (69%) thyroid, 16/31 (52%) prostate and 17/40 (43%) ovarian carcinomas. Moderate reduction of expression was observed in 17/186, and marked reduction in 40/186 tumors. Only 13/186 cases including 12 low-grade and one intermediate grade tumor retained high hSef expression. The association of hSef downregulation and tumor progression was statistically significant (Po0.001). Functionally, ectopic expression of hSef suppressed proliferation of breast carcinoma cells, whereas inhibition of endogenous hSef expression accelerated fibroblast growth factor and epidermal growth factor-dependent proliferation of cervical carcinoma cells. The inhibitory effect of hSef on cell proliferation combined with consistent downregulation in human carcinoma indicates a tumor suppressor-like role for hSef, and implicates loss of hSef expression as a common mechanism in epithelial neoplasia.

The mildly atypical, but not frankly malignant, histological features as well as the protracted clinical course support definition of the tumour as 'littoral cell haemangioendothelioma'. Low rate of Ki67 staining and diploid DNA histogram with low S-phase fraction of the tumours are in accordance with a low-grade malignancy. Literature review revealed two other cases of littoral cell tumours with disseminated disease that may be other examples of littoral cell haemangioendothelioma. Littoral cell haemangioendothelioma should be distinguished from the overtly malignant splenic angiosarcomas, of which a few may show splenic lining cell differentiation with some immunohistochemical features of littoral cells. Due to difficulties in predicting biological behaviour based on histological features of splenic littoral cell tumours, a long-term follow-up for these patients, especially for those with atypical histology, is recommended.

Myeloproliferative neoplasms (MPNs) are malignant disorders originating from clonal expansion of a single neoplastic stem cell and characteristically show an increase in bone marrow reticulin fibers. Lysyl oxidases (LOXs) are copper‐dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin. Expression of LOX gene family members is increased in disorders associated with increased fibrosis. To evaluate involvement of LOX gene family in various MPNs. In‐situ hybridization was used to detect Lysyl‐Oxidase family members in bone marrow biopsies from patients with different MPNs. We compared normal bone marrows and those from patients with polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis (PMF). Serum levels of lysyl‐oxidase from patients with PMF and healthy controls were also examined. LOX gene family was not detected in normal bone marrows. All members of the LOX gene family were over expressed in PMF. In other MPNs a differential pattern of expression was observed. Differences in gene expression were statistically significant (P < 0.010). The medianserum LOX levels in normal controls was 28.4 ± 2.5 ng\ml and 44.6 ± 9.44 ng\ml in PMF (P = 0.02). The varying pattern of expression of LOX genes may reflect differences in the pathophysiology of bone marrow fibrosis in these MPNs. These observations could be used as the basis for future targeted therapy directed against bone marrow fibrosis. Am. J. Hematol. 88:355–358, 2013. © 2013 Wiley Periodicals, Inc.

BackgroundChronic spontaneous urticaria (CSU) is considered an autoimmune disorder in 50% of cases at least, in which T‐ and mast cell mediators are considered to be the primary cause of symptoms. However, H1‐antihistamines, cyclosporine A, and omalizumab fail to achieve complete symptom amelioration in up to 70% of patients. This suggests that other inflammatory pathways are involved and that additional and more effective treatments need to be developed.ObjectiveThis preliminary report examines the possibility that interleukin‐17 (IL‐17), a cytokine involved in the pathogenesis of many autoimmune diseases, may contribute to CSU and its inhibition may offer a relevant therapeutic target.MethodsThe expression of IL‐17A in skin biopsies of 20 CSU patients and 10 healthy controls was determined by quantitative histomorphometry. We also assessed the response to secukinumab (anti‐IL‐17A) treatment patients of eight severe CSU (7‐day urticaria activity score UAS7 32‐40) who were H1‐antihistamine and omalizumab‐resistant.ResultsIncreased numbers of CD4+ T cells and mast cells were present in both lesional and non‐lesional skin of CSU patients compared with healthy controls. Both types of cells were strongly positive for IL‐17A and found to be in close proximity to each other. All eight patients treated with the anti‐IL‐17A antibody, secukinumab, showed significant improvement in CSU disease activity. The action of secukinumab was shown to be relatively slow in onset. The significant reduction in disease activity from baseline UAS7 was demonstrated to be 55% and 82% at 30 and 90 days, respectively.ConclusionsThese findings suggest that IL‐17 is involved in the pathogenesis of CSU and that IL‐17 should be investigated as a therapeutic target in future studies with larger numbers of patients.

In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

Experimental studies have suggested that insulin (INS) plays an important role in small intestinal growth and development. In the present study we investigated the effect of oral INS on structural intestinal adaptation and enterocyte proliferation and loss via apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection, SBS rats underwent 75% small bowel resection, and SBS-INS rats underwent bowel resection and were treated with oral INS given in the drinking water from the 3rd to the 15th postoperative day. Parameters of intestinal adaptation (bowel and mucosal weight, mucosal DNA and protein, villous height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. SBS-INS rats demonstrated a significant increase (vs SBS rats) in jejunal and ileal overall bowel and mucosal weight, ileal mucosal DNA and protein, ileal villous height, and crypt depth. SBS-INS rats also showed an increased cell proliferation index in jejunum and ileum and decreased apoptotic index in jejunum compared to SBS animals. In conclusion, in a rat model of SBS, oral INS strongly enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis.