To identify novel biomarkers of metastasis of colorectal cancer (CRC), we developed an orthotopic implantation model of murine CRC and selected in vivo M5, a subclone of the SW480 CRC cell line with enhanced potential for metastasis to the liver. We compared the differences in the gene expression profiles between M5 and SW480 cells using gene expression profiling. We found that expression of special AT-rich sequence-binding protein 2 (SATB2) was down-regulated in M5 cells. Immunohistochemical analysis of 146 colorectal tumour samples showed that underexpression of SATB2 was strongly correlated with poor prognosis, tumour invasion, lymph node metastasis, distant metastasis, and Dukes' classification for CRC. Univariate and multivariate survival analyses further showed that SATB2 expression was a potential favourable prognostic factor for CRC. These results demonstrated not only that SATB2 is a potential novel prognostic factor for CRC, but also that selection of a highly metastatic clone of SW480 in vivo coupled with gene expression profiling is a powerful approach to identifying prognostic markers for CRC.

IntroductionDonor T cells are responsible for both GVHD and GVL reactions after allogeneic HSCT. The activation status of T cells is modulated by dendritic cells (DCs), the most potent and professional antigenpresenting cells (APCs). 1,2 Both host and donor DCs have been shown to play critical roles in regulating GVHD and GVL effects after MHC-mismatched HSCT. 3-7 GVHD can be initiated by residual APCs that directly present host antigen (Ag) to donor T cells, 5 whereas GVHD intensity can be modulated by donor APCs that present host Ag to donor T cells via indirect antigen presentation. 1,3,8 However, despite extensive investigations of the role of host DCs on GVHD pathophysiology, much less is known about the mechanisms by which donor APCs activate and regulate donor T cells. A previous study by MacDonald et al 9 demonstrated that depleting CD11c ϩ donor conventional DCs (CDCs) reduced the severity of GVHD in mice. The same group then demonstrated that conventional donor cDCs isolated from the spleen are the most effective population in presenting alloantigen and stimulating naive donor T-cell responses early post-bone marrow transplantation (BMT). 3 Recently, using 2 allogeneic murine BMT models (C57BL/ 63B10.BR and C3H3C57BL/6), we showed that addition of donor bone marrow cells enriched for pre-pDCs to a graft composed of purified HSC and T cells significantly improved long-term leukemia-free survival without increasing GVHD compared with recipients of donor HSC and T cells. 10 Of note, higher numbers of IFN-␥-producing donor T cells were seen among recipients of pDCs. 10 The aim of the present work was to further define the mechanism by which donor pre-pDCs modulate the alloreactivity of donor T cells. Based on the marked up-regulation of IFN-␥ in donor T cells cotransplanted with bone marrow enriched for pre-pDCs, 10,11 we hypothesized that IFN-␥-responsive genes in donor pre-pDCs might be involved in their immunomodulatory activity.Using highly purified populations of donor pre-pDCs, we observed that IFN-␥ signaling by donor T cells to donor pre-pDCs led to increased indoleamine-2,3-dioxygenase (IDO) expression in donor pDCs and that IDO production by donor pDCs suppressed the GVHD activity of donor T cells and changed the balance between regulatory and inflammatory donor T cells. These data support a new paradigm for immune regulation in allogeneic HSCT in which donor DCs first activate donor T cells and then subsequently limit GVHD through IDO-dependent modulation of inflammation. Methods Mice B10.BR (H-2K k ), C57BL/6 (B6, H-2K b ), and FVB (H-2K q ) mice, as well as congenic strains of B6 expressing CD45.1 or CD90.1, and IFN-␥, IFN-␥ receptor, and IDO1 knockout strains on the B6 background (IFN-␥ Ϫ/Ϫ , IFNGR1 Ϫ/Ϫ , and IDO1 Ϫ/Ϫ ), were purchased from The Jackson Laboratory. A congenic strain of B10.BR (H-2K k ) expressing CD90.1, named BA.B10, For personal use only. on May 10, 2018. by guest www.bloodjournal.org From was generated by crossing B6 CD90.1 and B10.BR mice and then backcrossing 10 generatio...

Background: Arrhythmias are reported during pregnancy, although hospitalization for these infrequent events is not fully characterized. The frequency and outcome of arrhythmias during pregnancy are unknown. Methods: Between 1992 and 2000, there were 136,422 pregnancy-related admissions to Parkland Memorial Hospital (Dallas, TX, USA). Using the discharge diagnosis data bank and the International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM) coding system, we identified 226 admissions (218 patients) where cardiac arrhythmias and intrauterine pregnancy were both reported. Results: The most common rhythm disturbances during pregnancy were sinus tachycardia (ST), sinus bradycardia (SB), or sinus arrhythmia (SA) (104 episodes/100,000 pregnancies). This was followed by paroxysmal supraventricular tachycardia (PSVT) and premature beats, with a frequency of 24/100,000 and 33/100,000, respectively. Paroxysmal supraventricular tachycardia occurred most frequently in the third trimester or peripartum. All episodes terminated spontaneously or were safely terminated with medical therapy. Advanced heart block or lethal arrhythmias were exceedingly rare during pregnancy. Conclusion: Most frequently reported cardiac arrhythmias in pregnancy are benign and do not require intervention. Supraventricular tachycardia (SVT), being one of the most common complicated cardiac arrhythmias during pregnancy, can be treated effectively and safely with standard medical therapy. Ventricular arrhythmias or high-degree atrioventricular block (AVB) during pregnancy are extremely rare. Cardiac arrest is also rare, and is often caused by a different etiology from the conventional ones for sudden cardiac death.

Background— Although the hemodynamic changes associated with atrial fibrillation (AF) have been extensively studied, the neural changes remain unclear. We hypothesized that AF is associated with an increase in sympathetic nerve activity (SNA) and that the irregular ventricular response contributes to this state of sympathoexcitation. Methods and Results— In 8 patients referred for an electrophysiological study, SNA, blood pressure (BP), central venous pressure (CVP), and heart rate were recorded during 3 minutes of normal sinus rhythm (NSR) and 3 minutes of induced AF. In 5 of 8 patients who converted to NSR, right atrial (RA) pacing was performed for 3 minutes in atrial pacing triggered by ventricular sensing mode triggered by playback of an FM tape previously recorded from the right ventricle during AF (RA-irregular) and atrial pacing inhibited by atrial sensing mode at a rate equal to the mean heart rate obtained during AF (RA-regular). SNA data were expressed as percentage of baseline during NSR. SNA increased in all 8 patients during induced AF compared with NSR (171±40% versus 100%, respectively; P <0.01). This was associated with a trend for a decrease in BP and an increase in CVP ( P =0.02). Similarly, SNA was significantly higher during RA-irregular pacing compared with RA-regular pacing (124±24% versus 91±20%, respectively; P =0.03). BP and CVP were not significantly different between the 2 pacing modes. Conclusions— Induced AF results in a significant increase in SNA, which is in part attributable to the irregular ventricular response. Our findings suggest that restoring NSR or regularity might be beneficial, particularly in patients with heart failure.

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The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.