In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.     

Aplastic anaemia with 13q-: a benign subset of bone marrow failure responsive to immunosuppressive therapy

In an attempt to determine the pathological significance of a long arm deletion of chromosome 13 (13q-) in bone marrow failure syndrome, we reviewed the clinical records of nine patients who were initially diagnosed with aplastic anaemia due to bone marrow hypoplasia without dysplasia. Six patients responded to immunosuppressive therapy and the other three improved with steroids. None of the patients developed acute leukaemia (follow up: 54-129 months) and the estimated 5-year survival was 78%. These findings indicate that pancytopenia with 13q- represents bone marrow failure of a benign nature, similar to aplastic anaemia without karyotypic abnormalities, rather than preleukaemia.     

Chronic obstructive pulmonary disease (COPD) burden in Japan--confronting COPD Japan survey

To grasp the burden and management status of COPD in Japan, a large telephone survey was conducted. In initial screening 400 individuals > or =45 years were identified as either having been given a diagnosis of COPD or fulfilling criteria for their respiratory-related symptoms and smoking history (baseline population) and they were recruited for a detailed investigation (interview sample). They were asked about demographic information, exacerbation, impact of COPD on daily life, and management and treatment. Of the 400 interview samples, 209 subjects (52%) had a diagnosis of COPD, and the remaining 191 ones (48%) were not, retrospectively. It was confirmed that proportions of a current smoker in the COPD (35.4%) and non-COPD (35.6%) groups were almost at the same level. The use of inhaled bronchodilators, recommended by guidelines in 157 treated subjects, was 16% or less, whereas respiratory conditions affected daily activities in 70% of all the subjects. In conclusion, COPD in Japanese subjects significantly affects daily life yet is undiagnosed; there is a need to improve COPD diagnosis and management by general practitioners through disseminating guidelines for diagnosis, management, and prevention of COPD in Japan.     

Nectin-4 expression contributes to tumor proliferation,angiogenesis and patient prognosis in human pancreatic cancer

Background

Nectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans. Recent studies have also suggested some roles for Nectin-4 in several human cancers. However, the precise roles and clinical relevance of Nectin-4 in tumors are largely unknown.

Methods

Nectin-4 expression was investigated in 123 patients with pancreatic cancer by immunohistochemistry. Furthermore, we investigated the association of Nectin-4 in pancreatic cancer with tumor proliferation, angiogenesis and immunity by using immunohistochemistry and siRNA interference method.

Results

Patients with high Nectin-4 expression had poorer postoperative prognosis than those with low expression. Importantly, multivariate analysis indicated that Nectin-4 expression had a significant independent prognostic value in pancreatic cancer (HR = 1.721, 1.085-2.730; P = 0.021). Tumor Nectin-4 expression was significantly correlated with Ki67 expression. In addition, siRNA-mediated gene silencing of Nectin-4 significantly inhibited the cell proliferation in human pancreatic cancer cells, Capan-2 and BxPC-3. Furthermore, Nectin-4 expression was also positively correlated with VEGF expression and intratumoral microvessel density. However, there were no significant correlations of tumor Nectin-4 expression with tumor-infiltrating T cells.

Conclusion

Nectin-4 is a significant prognostic predictor, and may play a critical role in pancreatic cancer. Nectin-4 may be novel therapeutic target for pancreatic cancer.     

Fabrication of tissue‐engineered cell sheets by automated cell culture equipment

Most cells for regenerative medicine are currently cultured manually. In order to promote the widespread use of regenerative medicine, it will be necessary to develop automated culture techniques so that cells can be produced in greater quantities at lower cost and with more stable quality. In the field of regenerative medicine technology, cell sheet therapy is an effective tissue engineering technique whereby cells can be grafted by attaching them to a target site. We have developed automated cell culture equipment to promote the use of this cell sheet regenerative treatment. This equipment features a fully closed culture vessel and circuit system that avoids contamination with bacteria and the like from the external environment, and it was designed to allow 10 cell sheets to be simultaneously cultured in parallel. We used this equipment to fabricate 50 sheets of human oral mucosal epithelial cells in five automated culture tests in this trial. By analyzing these sheets, we confirmed that 49 of the 50 sheets satisfied the quality standards of clinical research. To compare the characteristics of automatically fabricated cell sheets with those of manually fabricated cell sheets, we performed histological analyses using immunostaining and transmission electron microscopy. The results confirmed that cell sheets fabricated with the automated cell culture are differentiated in the same way as cultures fabricated manually.     

Osteoplastic bone metastasis in esophageal squamous cell cancer: report of a case

This report presents a case of esophageal squamous cell cancer with osteoplastic bone metastasis. A 58-year-old male patient underwent multimodality treatment for esophageal cancer. Sclerotic changes resembling bone metastasis from prostate cancer were detected in the 4th thoracic and the 5th lumber vertebral body soon after the adjuvant chemoradiotherapy. Systemic examinations revealed no primary cancer as a cause of osteoplastic bone metastasis and no esophageal cancer recurrence. A needle biopsy revealed metastases of esophageal squamous cell cancer with osteoplastic changes. Multiple sclerotic changes were detected in the systemic bones at that time, and new carcinomatous bilateral pleural effusion developed. The drastic systemic progression of the cancer caused the rapid deterioration of the patient's general condition.     

Surgical management of small bowel metastases from primary carcinoma of the lung

Purpose  

To investigate the treatment and outcomes in a series of seven cases of small bowel metastases from lung cancer.     

Characteristic Immunophenotype of Solid Subtype Component in Lung Adenocarcinoma

Background

Lung adenocarcinomas represent a morphologically heterogeneous tumor composed of an admixture of different histologic subtypes (lepidic, papillary, acinar, and solid subtype). The presence of a solid subtype component is reported to be associated with a poorer prognosis. The aim of this study was to evaluate the characteristic immunophenotype of the solid subtype component compared with the immunophenotypes of other components.

Methods

We analyzed the clinicopathological characteristics of stage I adenocarcinoma patients with predominant solid subtype disease. Furthermore, we immunostained adenocarcinomas with predominant lepidic, papillary, acinar, and solid subtype components (n?=?23 each) for 10 molecular markers of tumor invasiveness and scored the results.

Results

Patients showing predominance of the solid subtype component (solid subtype adenocarcinoma) had a poorer prognosis than those showing predominance of the lepidic, papillary, or acinar component. Lymphovascular invasion was more often detected in solid subtype tumors than in others. The solid subtype component showed a significantly stronger staining intensity of laminin-5 expression than the lepidic, papillary, and acinar components (P?<?0.001, P?<?0.001, and P?=?0.016, respectively). The fibronectin and vimentin expression levels were also significantly higher in the solid subtype component than in other components. This immunostaining character was validated by using mixed-subtype adenocarcinomas containing all four components in the same tumor.

Conclusions

This study concluded that the solid subtype component in lung adenocarcinomas exhibit the invasive immunophenotype, including increased laminin-5 expression, compared with the other components, which may be associated with a poorer prognosis.     

Preservation of the Pyloric Ring Has Little Value in Surgery for Pancreatic Head Cancer: A Comparative Study Comparing Three Surgical Procedures

Background

Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial.

Methods

In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved.

Results

The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P?=?0.0012). The serum albumin concentration and total lymphocyte count at 1?year postoperatively were significantly higher in the SSPPD group than in the PPPD group (P?=?0.0303 and P?=?0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7?months, respectively), although the differences did not reach statistical significance.

Conclusions

Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer.