Multipotent self-renewing hematopoietic stem cells (HSCs) regenerate the adult blood system following transplantation 1 , a curative therapy for numerous diseases such as immunodeficiencies and leukemias 2 . While significant effort has been applied to identify HSC maintenance factors through characterization of the in vivo bone marrow (BM) HSC Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant expression using newly generated-mediated conditional knockin mice. Mice carrying a heterozygous P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings.-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in-mutated mice. RNA sequencing of the -mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as, ,, ,, and Among the mutant-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

SummaryHematopoietic stem cells (HSCs) are considered one of the most promising therapeutic targets for the treatment of various blood disorders. However, due to difficulties in establishing stable maintenance and expansion of HSCs in vitro, their insufficient supply is a major constraint to transplantation studies. To solve these problems we have developed a fully defined, all-recombinant protein-based culture system. Through this system, we have identified hemopexin (HPX) and interleukin-1α as responsible for HSC maintenance in vitro. Subsequent molecular analysis revealed that HPX reduces intracellular reactive oxygen species levels within cultured HSCs. Furthermore, bone marrow immunostaining and 3D immunohistochemistry revealed that HPX is expressed in non-myelinating Schwann cells, known HSC niche constituents. These results highlight the utility of this fully defined all-recombinant protein-based culture system for reproducible in vitro HSC culture and its potential to contribute to the identification of factors responsible for in vitro maintenance, expansion, and differentiation of stem cell populations.

Background Plasminogen activators (PAs) and their inhibitors are thought to play an important role in tumor invasion and metastasis. However, there have been few reports in which histologic localization of PAs has been demonstrated in head and neck tumors. Methods We examined the patterns of expression of urokinase‐type plasminogen activator (u‐PA), tissue‐type plasminogen activator (t‐PA), plasminogen activator inhibitor 1 (PAI‐1), and vitronectin in head and neck squamous cell carcinomas using immunohistochemical techniques. We also studied the correlation between the immunohistologic expression of these fibrinolytic proteins and the clinical staging of the tumor. Results Of 28 tumor specimens, 15 (54%) showed immunoreactivity for u‐PA; 8 (36%), for t‐PA; and 23 ( 82%), for PAI‐1. There was a significant correlation between PAI‐1 expression and the extent of the primary tumor. Conclusions The present study demonstrates the existence and possible pathophysiologic significance of u‐PA and PAI‐1 in squamous cell carcinomas of the head and neck. © 1997 John Wiley & Sons, Inc. Head Neck 19: 611–616, 1997.

BACKGROUND Current goals for the treatment of carcinoma of the maxillary sinus include the preservation of vision, ability to eat, ability to communicate, and appearance as well as cure. METHODS Seventy‐five Japanese patients who presented with maxillary sinus carcinoma between 1979 and 1997 were analyzed retrospectively. There were 48 males and 27 females with a median age of 62 years. The mean follow‐up period was 73 months. All patients underwent multimodality therapy including surgery through a sublabial incision, radiotherapy, and regional chemotherapy. The regional lymph nodes were treated only in those patients with cervical lymph node involvement. RESULTS The 5‐year and 10‐year overall survival rates were 76% and 66%, respectively. In 65 patients with squamous cell carcinoma, the 5‐year and 10‐year overall survival rates were 77% and 66%, respectively. All 23 patients with orbital involvement retained the orbital contents and 17 patients demonstrated adequate ocular function. There was no disease recurrence reported among patients with involvement of the foramen rotundum or the foramen ovale, whereas two of the three patients with invasion of the foramen lacerum developed disease recurrence. There were 12 complications in 12 patients, including double vision (4 patients), cataracts (3 patients), trismus (4 patients), and fistula formation (1 patient). CONCLUSIONS Control of the primary tumor site is important in the curative treatment of patients with maxillary sinus carcinoma. Combined therapy with conservative surgery, radiotherapy, and regional chemotherapy appears to be an effective method for local control and the preservation of ocular function. Cancer 2000;89:1925–32. © 2000 American Cancer Society.