Ephexin4 is a RhoG-specific guanine nucleotide exchange factor that interacts with the EphA2 receptor in breast cancer cells.

Isolates of human T-lymphotropic virus type I (HTLV-I) were phylogenetically analyzed from native inhabitants in India and South America (Colombia and Chile) and from Ainu (regarded as pure Japanese descendants from the preagricultural "Jomon" period). Their genomes were partially sequenced together with isolates from Gabon in central Africa and from Ghana in West Africa. The phylogenetic tree was constructed from the sequence data obtained and those of previously reported HTLV-I isolates and simian T-lymphotropic virus type I (STLV-I) isolates. The heterogeneity of HTLV-I was recently recognized, and one major type, generally called the "cosmopolitan" type, contained Japanese, Caribbean, and West African isolates. The phylogenetic tree constructed in the present study has shown that this cosmopolitan type can be further grouped into three lineages (subtypes A, B, and C). Subtype A consists of some Caribbean, two South American, and some Japanese isolates, including that from the Ainu, in addition to an Indian isolate, and subtype B consists of other Japanese isolates in addition to another Indian isolate, suggesting that there might be at least two ancestral lineages of the Japanese HTLV-I. Subtype A implies a close connection of the Caribbean and South American natives with the Japanese and thereby a possible migration of the lineage to the American continent via Beringia in the Paleolithic era. Subtype C consists of the West African and other Caribbean isolates, indicating that not all but part of the Caribbean strains directly originated from West Africa probably during the period of slave trade. The tree also has shown that the HTLV-I isolate from Gabon in central Africa forms a cluster with STLV-I from a chimpanzee, suggesting a possible interspecies transmission between man and the chimpanzee in the past. No specific clustering was observed in the tree in relation to manifestations of the disease such as adult T-cell leukemia and HTLV-I-related neurological disorders. Thus, the topology of the phylogenetic tree reflects the movement of people carrying the virus in the past.

Purpose: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxiainducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas.Experimental Design: In this study, we examined HIF [HIF-1␣ (HIF1) and HIF-2␣ (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis.Results: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T 1 and T 2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant.Conclusions: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.

Elderly patients with a history of heavy smoking and poor pulmonary function should be regarded as a high-risk group of patients for developing pneumonia and very careful selection is required before subjecting such patients to extended esophagectomy.

BACKGROUND PTEN is a candidate tumor‐suppressor gene in a variety of malignant tumors. The prognostic importance of PTEN product protein (PTEN) and its correlation with clinicopathologic characteristics have yet to be delineated in patients with esophageal carcinoma. METHODS Specimens from 97 patients with esophageal squamous cell carcinoma were used for the immunohistochemical evaluation of PTEN expression. RESULTS PTEN expression was detected in the nucleus in 48 specimens (49.5%). There were statistically significant correlations between nuclear PTEN expression and macroscopic tumor classification, T stage, and American Joint Committee on Cancer (AJCC) stage (P < 0.01), indicating that PTEN expression was down‐regulated by advancement of the disease process. There were no statistically significant correlations between nuclear PTEN expression and the intensity and extent of cytoplasmic PTEN expression. The 10‐year overall survival rate was significantly better in patients with positive nuclear PTEN expression (n = 48 patients) compared with the rate in patients with negative nuclear PTEN expression (n = 49 patients; P < 0.01). The results of a multivariate analysis of factors that were prognostic for survival showed that AJCC stage (P < 0.05; relative risk, 2.038) and negative nuclear PTEN expression (P < 0.05; relative risk, 1.825) were significant factors indicative of poor survival. CONCLUSIONS Nuclear PTEN expression may be a favorable biologic marker and a useful prognostic indicator in patients with esophageal squamous cell carcinoma. Cancer 2002;94:1955–60. © 2002 American Cancer Society. DOI 10.1002/cncr.10410

SUMMARY:Several previous reports indicated that partial hepatectomy (PH) when combined with splenectomy enhances the regenerative capacity of the liver, most probably due to the removal of unknown inhibitory factors released from the spleen. Transforming growth factor (TGF)-␤1 is a major antiproliferative factor for the hepatocytes, and the role of splenic TGF-␤1 in liver regeneration is yet to be clarified. The splenic expression of TGF-␤1 and its secretion into the portal circulation from the spleen were evaluated in a standardized two-thirds hepatectomy model in rats. Rats in the control group underwent only the hepatectomy, while splenectomy was added in the splenectomy group. The hepatocyte proliferation rate was assessed by proliferating cell nuclear antigen (PCNA) immunostaining, and the results were compared with the TGF-␤1 kinetics in the portal blood. Significant increase in PCNA index and decrease in portal TGF-␤1 level were noticed in the splenectomy group at 48 hours after PH compared with the control group. Both TGF-␤1 protein and mRNA expression level in the spleen were strongest at 48 hours after PH and coincided with the peak of the plasma TGF-␤1 level. TGF-␤ type II receptor (T␤R-II) expression in the liver after PH was assessed immunohistochemically. The expression of T␤R-II decreased at 12 hours and returned to preoperative level at 24 hours after PH in both groups. The changes of T␤R-II expression were similar in both groups, and the significant difference was not observed at 48 hours after PH. Namely, splenectomy did not alter the expression of T␤R-II in remnant liver at the peak of hepatocytes proliferation. In conclusion we found that TGF-␤1 was produced and secreted by the spleen during the early phase of liver regeneration and removal of the spleen enhanced proliferation of hepatocytes. Splenectomy thus may exert a salutary effect in selected patients with jeopardized regenerative capacity of the liver. (Lab Invest 2003, 83:1595-1603.

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), can effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles are non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level is sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables minimally invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.

Dendrite development is required for establishing proper neuronal connectivity. Rho-family small GTPases have been reported to play important roles in the regulation of dendritic growth and morphology. However, the molecular mechanisms that control the activities of Rho GTPases in developing dendrites are not well understood. In the present study we found Dock4, an activator of the small GTPase Rac, to have a role in regulating dendritic growth and branching in rat hippocampal neurons. Dock4 is highly expressed in the developing rat brain, predominantly in hippocampal neurons. In dissociated cultured hippocampal neurons, the expression of Dock4 protein is up-regulated after between 3 and 8 days in culture, when dendrites begin to grow. Knockdown of endogenous Dock4 results in reduced dendritic growth and branching. Conversely, overexpression of Dock4 with its binding partner ELMO2 enhances the numbers of dendrites and dendritic branches. These morphological effects elicited by Dock4 and ELMO2 require Rac activation and the C-terminal Crk-binding region of Dock4. Indeed, Dock4 forms a complex with ELMO2 and CrkII in hippocampal neurons. These findings demonstrate a new function of the Rac activator Dock4 in dendritic morphogenesis in hippocampal neurons.