Novel compound heterozygous mutations in DYNC2H1 in a patient with severe short‐rib polydactyly syndrome type III phenotype

Short‐rib polydactyly syndrome type III is an autosomal recessive lethal skeletal ciliopathy, which is phenotypically similar to nonlethal asphyxiating thoracic dystrophy. Mutations in DYNC2H1 have been identified in both of these disorders, indicating that they are variants of a single disorder. However, short‐rib polydactyly syndrome type III is the more severe variant. Here, we report novel compound heterozygous mutations in DYNC2H1 (p.E1894fsX10 and p.R3004C) in a patient with typical short‐rib polydactyly syndrome type III phenotype. R3004 is located within the microtubule‐binding domain of DYNC2H1, and its substitution is predicted to disrupt the interaction with microtubules. Considering the severe phenotype of our patient, our findings suggest that R3004 may be a key residue for the microtubule‐binding affinity of dynein.     

Tumor inoculation site affects the development of cancer cachexia and muscle wasting

The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor‐bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF‐β family, and found that levels of IL‐6, TNF‐α and activin A increased in both groups of tumor‐bearing mice. Eotaxin and G‐CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor‐bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment.     

Activation of capsaicin-sensitive sensory neurons by carvedilol, a nonselective beta-blocker, in spontaneous hypertensive rats

We performed a study in spontaneous hypertensive rats (SHR) to determine whether carvedilol, a nonselective beta-adrenoceptor antagonist, activates capsaicin-sensitive sensory neurons (CSSNs), thereby promoting the release of calcitonin gene-related peptide (CGRP), a neuropeptide with an important role in maintenance of cardiovascular homeostasis. Carvedilol given intravenously at a dose of 0.3 mg/kg transiently decreased the mean arterial blood pressure (MABP) and increased renal tissue blood flow with increases in CGRP levels in plasma and kidney. These effects induced by carvedilol were not seen in animals pretreated with capsazepine, an antagonist of capsaicin. Although 1.0 mg/kg cavedilol markedly decreased MABP, it neither increased renal tissue blood flow nor CGRP levels in plasma and kidney. Prazosin, a selective alpha(1)-adrenoceptor antagonist, and bisoprolol, a selective beta(1)-adrenoceptor antagonist, decreased MABP with capsazepine, showing no antagonistic action in either cases, and these agents increased neither renal tissue blood flow nor levels of CGRP in plasma and kidney. Both ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol], a selective beta(2)-adrenoceptor antagonist, at a dose of 0.25 mg/kg and capsaicin mimicked effects induced by 0.3 mg/kg carvedilol. Administration of 1.0 mg/kg ICI 118,551 produced effects similar to those induced by 1.0 mg/kg carvedilol. These observations strongly suggested that the low dose of carvedilol might activate CSSNs in SHR to increase the release of CGRP, thereby decreasing blood pressure with an increase in renal tissue blood flow. The effects induced by carvedilol seemed to be mediated by its beta(2)-adrenoceptor blockade activity.     

Prostate cancer gene therapy

With the advance in genetic engineering, tumor biology and immunology, gene therapy has been recognized as a promising new treatment option for cancer including prostate cancer. Several clinical trials of prostate cancer gene therapy are currently underway, using therapeutic genes which include suicide genes, immunomodulatory genes, tumor suppressor genes and anti-oncogenes. Although the gene therapy for prostate cancer as a clinical alternative is still early stage which requires several technological breakthrough, some information obtained from clinical trial indicates full potential of prostate cancer gene therapy. Concordant progress both in the basic research and gene therapy technology will make prostate cancer gene therapy ready for wide-scale of practice in the future. In this report, general concept and current progress in prostate cancer gene therapy are summarized.     

ONO-5334, a cathepsin K inhibitor,improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats

This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis.     

Overexpression of Hypoxia Inducible Factor-1 Alpha is an Independent Risk Factor for Recurrence After Curative Resection of Colorectal Liver Metastases

Background

Hypoxia inducible factor-1α (HIF-1α) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF-1α expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1α expression in colorectal liver metastasis (CRLM).

Methods

We retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1α expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF-1α expression between the primary tumor and the corresponding liver metastases.

Results

We found a significant positive correlation between HIF-1α expression in liver metastases and PIK3CA mutation status (p = 0.019). A significant correlation was also observed between the expressions of HIF-1α and VEGF in liver metastases and primary tumors (p = 0.015, 0.024, respectively). High HIF-1α expression in liver metastases was an independent risk factor for recurrence (p = 0.031).

Conclusions

Our results suggest a possible induction of HIF-1α expression by mutant PIK3CA. The expressions of HIF-1α and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1α was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1α represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1α expression.