Certain small GTP-binding proteins control the enzymatic activity of a family of closely related serine-threonine kinases known as mitogen-activated protein kinases (MAPKs). In turn, these MAPKs, ...such as p44(mapk) and p42(mapk), referred to herein as MAPKs, and stress-activated protein kinases, also termed c-Jun N-terminal kinases (JNKs), phosphorylate and regulate the activity of key molecules that ultimately control the expression of genes essential for many cellular processes. Whereas Ras controls the activation of MAPK, we and others have recently observed that two members of the Rho family of small GTP-binding proteins, Rac1 and Cdc42, regulate the activity of JNKs. The identity of molecules communicating Rac1 and Cdc42 to JNK is still poorly understood. It has been suggested that Pak1 is the most upstream kinase connecting these GTPases to JNK; however, we have observed that coexpression of Pak1 with activated forms of Cdc42 or Rac1 diminishes rather than enhances JNK activation. This prompted us to explore the possibility that kinases other than Pak might participate in signaling from GTP-binding proteins to JNK. In this regard, a computer-assisted search for proteins containing areas of homology to that in Pak1 that is involved in binding to Rac1 and Cdc42 led to the identification of mixed lineage kinase 3 (MLK3), also known as protein-tyrosine kinase 1, as a potential candidate for this function. In this study, we found that MLK3 overexpression is sufficient to activate JNK potently without affecting the phosphorylating activity of MAPK or p38. Furthermore, we present evidence that MLK3 binds the GTP-binding proteins Cdc42 and Rac1 in vivo and that MLK3 mediates activation of MEKK-SEK-JNK kinase cascade by Rac1 and Cdc42. Taken together, these findings strongly suggest that members of the novel MLK family of highly related kinases link small GTP-binding proteins to the JNK signaling pathway.
We report the first observation of the decay Λ c+ → pK+π- using a 980 fb-1 data sample collected by the Belle detector at the KEKB asymmetric-energy e+e- collider. This is the first observation of a ...doubly Cabibbo-suppressed decay of a charmed baryon. We measure the branching ratio of this decay with respect to its Cabibbo-favored counterpart to be B ( Λ c+ → pK+π- ) / B ( Λ c+ → pK-π+ ) = ( 2.35±0.27±0.21 ) ×10-3 , where the uncertainties are statistical and systematic, respectively.
We report a measurement of the ratio R(D*)=B(B¯0→D*+τ−ν¯τ)/B(B¯0→D*+ℓ−ν¯ℓ), where ℓ denotes an electron or a muon. The results are based on a data sample containing 772×106 BB¯ pairs recorded at the ...ϒ(4S) resonance with the Belle detector at the KEKB e+e− collider. We select a sample of B0B¯0 pairs by reconstructing both B mesons in semileptonic decays to D*∓ℓ±. We measure R(D*)=0.302±0.030(stat)±0.011(syst), which is within 1.6σ of the Standard Model theoretical expectation, where the standard deviation σ includes systematic uncertainties. We use this measurement to constrain several scenarios of new physics in a model-independent approach.
Recent Japanese clinical practice guidelines for gastrointestinal stromal tumor (GIST) indicates that surgical resection is optionally considered for small (<2cm), asymptomatic and biopsy-negative ...gastric submucosal tumors (SMTs), when they show size enlargement during “watchful waiting” period. The true impact of surgery for those lesions, however, has not been fully understood. The aim of this study was to determine its clinical significance.
From January 2005 to April 2012, 99 patients with gastric SMTs underwent surgery. Twenty-one of them, which had tumor growth during observation period, were enrolled in the retrospective analysis. Data included patient background data, clinicopathological features, surgical outcomes and prognosis. Data were presented as median (range).
All patients (12 males, 9 females), with age of 64 (48-74), had their lesions detected by routine health check-up. No clinical symptom was presented. Tumor was located in upper (n = 9), middle (8), and lower (4) body of the stomach, respectively. The tumor was 2.0 (0.8-4.0) cm in size at their initial detection, and enlarged up to 3.2 (2.0-7.0) cm at the end of “watchful waiting” period of 63 (8-181) months. As surgical procedure, laparoscopic partial gastrectomy was performed in 18, open partial gastrectomy in 2, and open proximal gastrectomy for 1 patient, respectively. The operating time was 115 (49-247) min, with blood loss of 20 (0-230) ml. No major complications were noted in the series. Postoperative histologic examination revealed GIST (19) and schwanomma (2). Although 14 out of 19 GISTs were categorized into “none” (1), “very low” (12), and “low” (1) risk according to Miettinen's classification, 5 cases of “moderate” risk were identified in the series. No recurrences/metastases were noted in 21.7 (0.9-75.1) months of postoperative follow-up.
Our study revealed the existence of moderate risk GISTs in asymptomatic, small gastric SMTs with size enlargement during preoperative observation. Laparoscopic surgery was safely applied to majority of those cases (85.7%). Prompt surgical intervention should therefore be considered, when gastric SMTs under watchful waiting show size enlargement.
All authors have declared no conflicts of interest.
The histologic effects of chemoradiation therapy (CRT) for esophageal cancer, which determine the benefit obtained from a salvage operation, are difficult to evaluate preoperatively. We therefore ...investigated whether or not the morphologic features of esophageal cancer tissue after CRT can be correlated with the histologic features of the tissue. Seventy-six patients with advanced esophageal squamous cell carcinoma underwent CRT followed by esophagectomy. The effects of CRT were evaluated by histologic examination of the residual tumors in the surgical specimen and correlated with clinicopathologic factors, including postoperative prognosis. The histologic effects of CRT were used to classify tumors as grade 1 (CRT poorly effective; 23 cases, 30.3%); grade 2 (CRT moderately effective; 31 cases, 40.8%); or grade 3 (CRT completely effective with no residual tumors; 22 cases, 28.9%). Among the gross findings of the removed esophagus, significant correlation with the CRT effects was observed in the case of wall thickness and ulceration but not in the case of longitudinal tumor length. Tumors with no wall thickening or ulceration were never classified as grade 1, whereas tumors with both wall thickening and ulceration were frequently rated as grade 1 (18/30, 60%). Microscopic examination of grade 2 tumors (23/31, 74.1%) revealed residual tumor cells growing below the mucosal layer, whereas tumor cells were exposed to the esophageal surface in 22 out of 23 patients with grade 1 tumors. The morphologic features after CRT can be used to evaluate its histologic effect, especially in the case of grade 1 tumors. However, the detection and prediction of grade 2 tumors remains difficult because of the presence of small amounts of residual tumor underneath the mucosa.
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