Role of Dok-1 and Dok-2 in Leukemia Suppression

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok(Dok-1) and p56dok-2(Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis

c-Abl phosphorylates Dok1 to promote filopodia during cell spreading

Filopodia are dynamic F-actin structures that cells use to explore their environment. c-Abl tyrosine kinase promotes filopodia during cell spreading through an unknown mechanism that does not require Cdc42 activity. Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts. When activated by cell adhesion, c-Abl phosphorylates Y361 of Dok1, promoting its association with the Src homology 2 domain (SH2)/SH3 adaptor protein Nck. Each signaling component was critical for filopodia formation during cell spreading, as evidenced by the finding that mouse fibroblasts lacking c-Abl, Dok1, or Nck had fewer filopodia than cells reexpressing the product of the disrupted gene. Dok1 and c-Abl stimulated filopodia in a mutually interdependent manner, indicating that they function in the same signaling pathway. Dok1 and c-Abl were both detected in filopodia of spreading cells, and therefore may act locally to modulate actin. Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck

Clinical preferences for DME in Japan

Aims/Introduction: To determine the current clinical preferences of anti‐vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan. Materials and Methods: This was a descriptive cross‐sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists. Results: The results showed that 81.2% preferred intravitreal injections of anti‐VEGF antibodies as the first‐line therapy. The most important indicators for beginning anti‐VEGF therapy were: the best‐corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti‐VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub‐Tenon steroid injection were preferred. The contraindications for anti‐VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti‐VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately. Conclusions: Our results present the current clinical preferences of anti‐VEGF treatment for DME in Japan. The best‐corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti‐VEGF treatment as first‐line therapy and prefer the 1 + pro re nata regimen

Day Surgery ヒガエリ シュジュツ ノ ゲンジョウ

From May 1999, the Day Surgery for the operations of inguinal hernia, cholecystolithiasis and benign thyroid tumor were introduced in our department. Twenty nine patients (5 inguinal hernia repairs in children, 11 tension free inguinal hernia repairs in adults, 8 laparoscopic cholecystectomies, 3 extirpations of benign thyroid tumors, 1 extirpation of giant breast tumor, 1 extirpation of skin tumor in child) were attempted to put the Day Surgery into practice. 2 cases (one : inguinal hernia of child, another inguinal hernia of adult) were not successful because of postoperative complications like wound pain. The day surgery for 27 cases were successfully carried out. As the Day Surgery has benefits of cutting down on expenses, saving time and reducing mental fatigue, the feelings of satisfaction of all of these patients were remarkably high. The system of the Day Surgery was almost established in our department , so we actively would like to extend the kinds of operations suitable for the Day Surgery

Clinical preferences and trends of anti-vascular endothelial growth factor treatments for diabetic macular edema in Japan

Aims/IntroductionTo determine the current clinical preferences of anti‐vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan.Materials and MethodsThis was a descriptive cross‐sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists.ResultsThe results showed that 81.2% preferred intravitreal injections of anti‐VEGF antibodies as the first‐line therapy. The most important indicators for beginning anti‐VEGF therapy were: the best‐corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti‐VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub‐Tenon steroid injection were preferred. The contraindications for anti‐VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti‐VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately.ConclusionsOur results present the current clinical preferences of anti‐VEGF treatment for DME in Japan. The best‐corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti‐VEGF treatment as first‐line therapy and prefer the 1 + pro re nata regimen