Chie Kawahara

Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44

For cancer metastasis, tumor cells present in the circulation must first adhere to the endothelium. Integrins play a central role in leukocyte adhesion to the endothelium and subsequent migration into tissues. The majority of tumor cells derived from solid cancers, including breast cancer, do not express integrins. We investigated the mechanisms of adhesion and transendothelial migration of cancer cells using breast carcinoma cell lines. Our results showed the following features of breast cancer cells: (1) HGF stimulated breast cancer cells by up-regulating CD44 expression in a concentration-dependent manner. (2) the maximum level of HGF-induced CD44 up-regulation on breast cancer cell lines occurred within 3 h. (3) HGF-induced up-regulation of CD44 was mediated by the tyrosine kinase signaling pathway. (4) HGF induced CD44-mediated adhesion of tumor cell lines to bone marrow-derived endothelial cells. (5) HGF did not change rolling of breast cancer cell lines on bone marrow-derived endothelial cells, but enhanced firm adhesion of cancer cells on endothelial cells under shear stress conditions. (6) HGF increased transendothelial migration of cancer cells. Our results indicate that HGF stimulates CD44-mediated adhesion of breast cancer cells to bone marrow-derived endothelial cells, which subsequently results in transendothelial migration of tumor cells. These results suggest that CD44 may confer the metastatic properties of breast cancer cells and, therefore, could be used as a target in future molecular cancer therapy.

Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic Plaques: A Randomized Controlled Trial

Background— Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results— A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions— Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

Reduced Progression to Type 2 Diabetes From Impaired Glucose Tolerance After a 2-Day In-Hospital Diabetes Educational Program : The Joetsu Diabetes Prevention Trial

OBJECTIVE—We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance (IGT) to type 2 diabetes, including analysis of changes in serum lipids, body weight, and blood pressure after the program. RESEARCH DESIGN AND METHODS—A total of 426 subjects (51 ± 9 years, BMI 24.6 ± 3.9 kg/m2) with newly diagnosed IGT were randomly assigned to three groups, 143 as the short-term hospitalization with diabetes education and support (STH) group, 141 as the nonhospitalization but diabetes education and support (DES) group, and 142 as the neither hospitalization nor education (control) group. RESULTS—The average follow-up was 3.1 years. The incidence of diabetes was 8.0, 10.7, and 13.2 cases per 100 person-years for STH, DES, and control groups, respectively. The incidence of diabetes was 42% lower (95% CI 33–51%) in the STH group and 27% lower (15–37%) in the DES group than in the control group. The incidence of diabetes was 21% lower (10–31%) in the STH group than in the DES group. CONCLUSIONS—The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months.

Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis

150cm; weight, 61.7 kg). Based on the presence of cardiomegaly on the chest radiogram, she was treated with diuretics (furosemide) by the dermatologists, in addition to water restriction. Psoriasis was known to be refractory to therapy, and treatment with calcipotriol (active form of vitamin D3 analogue, 50 μg/gm) ointment at a dose of 90g/week commenced on April 3, 2002. Anorexia started to appear at 19 days after initiation of calcipotriol treatment. After a couple of days, oliguria and clouding of consciousness developed. On April 22, serum calcium and sodium levels were elevated at 14.0mg/dl and 171mEq/ l, respectively. Unfortunately, serum parathyroid hormone was not measured at that time. Furthermore, she developed acute renal failure (blood urea nitrogen was elevated from 12 to 45mg/dl and serum creatinine increased from 0.7 to 2.3mg/dl). Consultation with our department was made on April 23, 2002. Physical examination at that time showed body weight of 46.2kg (body weight loss was 15.5kg from admission) and low blood pressure (98/50mmHg). Consciousness level was graded as cloudy (Glasgow Coma Scale 7). The greater part of her body was covered with psoriasis. Palpebral conjunctiva was slightly anemic, and oral mucosa was very dry. Laboratory studies (Table 1) showed proteinuria and urinary specific gravity of 1.019. Blood cell counts showed leukocytosis and slight anemia, but hematocrit tended to be high (45.4%), indicating severe dehydration. Serum Na, Cl, and Ca concentrations were elevated, as was urinary calcium concentration. Serum 1,25(OH)2D was also elevated (94.4 pg/ml), and renal impairment was recognized (Ccr 42.9ml/min). Based on these clinical features and laboratory findings, we discontinued treatment with calcipotriol and calcium lactate, and instead immediate measures were taken to ensure rehydration by intravenous saline and administration of bisphosphonates to reduce serum calcium concentration. Fortunately, she showed recovery Introduction

Incidence of type 2 diabetes in pre-diabetic Japanese individuals categorized by HbA1c levels: a historical cohort study.

Objective Reported incidence of type 2 diabetes estimated at the pre-diabetic stage differs widely (2.3–18.1% per year). Because clinicians need to know the risk of incident diabetes after a diagnosis of pre-diabetes, our objective was to estimate precise incidence of diabetes using baseline HbA1c levels. Methods A historical cohort study using electronic medical record data obtained between January 2008 and December 2013. A total of 52,781 individuals with HbA1c < 6.5% were assigned to one of six groups categorized by baseline HbA1c level: ≤ 5.5% (n=34,616), 5.6–5.7% (n=9,388), 5.8–5.9% (n=4,664), 6.0–6.1% (n= 2,338), 6.2–6.3% (n=1,257), and 6.4% (n=518). Participants were tracked until a subsequent diagnosis of diabetes or end of follow-up during a period of 5 years. Results During the follow-up period (mean 3.7 years), 4,369 participants developed diabetes. The incidence of diabetes in the first year was 0.7, 1.5, 2.9, 9.2, 30.4, and 44.0% in the six HbA1c groups, respectively. At five years the incidence was 3.6, 8.9, 13.8, 27.5, 51.6, and 67.8%, respectively (p < 0.0001 comparing the HbA1c ≤5.5% group to the other groups). After adjustment for confounding factors, the hazard ratios compared with the HbA1c ≤5.5% group were significantly elevated: 2.3 (95%CI 2.0–2.5), 3.4 (95%CI 2.9–3.7), 8.8 (95%CI 8.0–10.1), 26.3 (95%CI 23.3–30.1), and 48.7 (95%CI 40.8–58.1) in the five HbA1c groups (p < 0.0001). Conclusion By fractionating baseline HbA1c levels into narrower HbA1c range groups, accuracy of estimating the incidence of type 2 diabetes in subsequent years was increased. The risk of developing diabetes increased with increasing HbA1c levels, especially with the HbA1c level ≥ 6.2% in the first follow-up year.

Adult-onset idiopathic progressive acro-osteolysis with proximal symphalangism.

We experienced a 57‐year‐old female with adult‐onset non‐congenital idiopathic acro‐osteolysis combined with proximal symphalangism. At the age of 36, she developed severe pain and swelling of the toe base of both feet and underwent Clayton surgery. However, the size of her toes diminished progressively over the 5‐year period after surgery. At the age of 41, she suffered pain and swelling of the proximal interphalangeal (PIP) joints of fingers of both hands. These PIP joints became rigid and inflexible. Subsequently, she noticed shortening of the little finger of both hands, followed later by shortening of the index, middle, and ring fingers. At the age of 57, the thumbs began to shorten. Laboratory and endocrinological examinations were not abnormal. Finally, we diagnosed her with acro‐osteolysis combined with proximal symphalangism by radiological examination. In this case, previously unreported mutations of the Noggin gene were identified. This is the first case report of adult‐onset, non‐congenital idiopathic acro‐osteolysis combined with proximal symphalangism.

Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic PlaquesClinical Perspective: A Randomized, Controlled Trial

Background— Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results— A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions— Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic PlaquesClinical Perspective

Background— Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results— A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions— Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic Plaques

Background— Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results— A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions— Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.