Role of insulin-like growth factor binding protein-3 in 1, 25-dihydroxyvitamin-d 3 -induced breast cancer cell apoptosis.

Insulin-like growth factor I (IGF-I) is implicated in breast cancer development and 1, 25-dihydroxyvitamin D3 (1, 25-D3) has been shown to attenuate prosurvival effects of IGF-I on breast cancer cells. In this study the role of IGF binding protein-3 (IGFBP-3) in 1, 25-D3-induced apoptosis was investigated using parental MCF-7 breast cancer cells and MCF-7/VD(R) cells, which are resistant to the growth inhibitory effects of 1, 25-D3. Treatment with 1, 25-D3 increased IGFBP-3 mRNA expression in both cell lines but increases in intracellular IGFBP-3 protein and its secretion were observed only in MCF-7. 1, 25-D3-induced apoptosis was not associated with activation of any caspase but PARP-1 cleavage was detected in parental cells. IGFBP-3 treatment alone produced cleavage of caspases 7, 8, and 9 and PARP-1 in MCF-7 cells. IGFBP-3 failed to activate caspases in MCF-7/VD(R) cells; however PARP-1 cleavage was detected. 1, 25-D3 treatment inhibited IGF-I/Akt survival signalling in MCF-7 but not in MCF-7/VD(R) cells. In contrast, IGFBP-3 treatment was effective in inhibiting IGF-I/Akt pathways in both breast cancer lines. These results suggest a role for IGFBP-3 in 1, 25-D3 apoptotic signalling and that impaired secretion of IGFBP-3 may be involved in acquired resistance to vitamin D in breast cancer

Sui Generis database right: ripe for review?

In a digital era unoriginal collections of data, particularly those in electronic form, have new significance and value. Digital technology also renders such collections of information uniquely vulnerable to copying. The Directive on the legal protection of databases created a new sui generis right for databases in which there has been (qualitatively or quantitatively) substantial investment in obtaining, verifying or presenting the contents against unauthorised extraction or re-use of the whole or a substantial part. However, over-protection of such databases may remove essential information from the public domain, particularly where it constitutes an exclusive source. Under protection may be equally damaging, if the incentive to collate information is undermined by free-riding competition. It is as necessary, therefore, to strike as careful a balance of protection for unoriginal databases as for other intellectual property rights. The case of British Horseracing Board Limited v William Hill Organisation (2001) confirms infinitely extendable protection for dynamic databases, and their contents. The information at issue lay within the public domain, however the database maker constituted its only effective source. Fears of inhibiting information flow have contributed to debate over database protection in the United States, where copyright and unfair competition provide a lesser degree of support to database makers. Consequently, whether the new right encourages investment in creating databases as well as allowing access to database-stored information, is questionable. The question is timely for the Directive is due for review. At the same time both WIPO and the US are debating new provisions, and the Court of Appeal has referred questions of interpretation of the Directive to the European Court of Justice. It is time to reconsider, in particular, the draft Directive's proposed compulsory licences for the sui generis right. Alternatively, the exceptions to infringement could be better adapted to allow for private uses of information, or a better solution might lie in a form of unfair competition law restricted to parasitic conduct and unjust enrichment, without protection for the underlying information content

A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3

Persistent low-level variants in a subset of viral genes are highly predictive of poor outcome in immunocompromised patients with cytomegalovirus infection

ABSTRACT Background Human cytomegalovirus is the most common and serious opportunistic infection after solid organ and haematopoietic stem cell transplantation. In this study, we used whole-genome cytomegalovirus data to investigate viral factors associated with the clinical outcome. Methods We sequenced cytomegalovirus samples from 16 immunocompromised paediatric patients with persistent viraemia. 8/16 patients died of complications due to cytomegalovirus infection. We also sequenced samples from 35 infected solid organ adult recipients of whom one died with cytomegalovirus infection. Results We showed that samples from both groups have fixed variants at resistance sites and mixed infections. NGS sequencing also revealed non-fixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with non-fixed variants in these patients. These genes formed a viral signature which discriminated patients with cytomegalovirus infection who died from those that survived with high accuracy (AUC=0.96). Lymphocyte numbers for a subset of patients showed no recovery post-transplant in the patients who died. Conclusions We hypothesise that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T cell function, potentially identifying early, those patients requiring non-pharmacological interventions

Sensitivity of selected organ dissection to diagnose Taenia solium cysticercosis in pigs from endemic areas

Taenia solium, also known as the pork tapeworm, is a neglected zoonotic parasite which is endemic in many developing countries, including Zambia. The tapeworm causes two disease conditions in humans: (1) taeniosis, which is the intestinal tapeworm infection, obtained after consumtion of raw/undercooked infected pork; and (2) cysticercosis, which is the metacestode larval stage infection, obtained after ingestion of tapeworm eggs. A human tapeworm carrier can excrete high numbers of eggs with the stool (100 000 eggs per day) and is thus an important source of environmental contamination. The transmission of cysticercosis is thus enhanced with poor sanitation and the lack of clean drinking water. After ingestion of the eggs, oncospheres hatch in the intestine and disseminate to several body tissues, including the central nervous system. Infection of the central nervous system with cysticerci is called neurocysticercosis, which is a major cause of acquired epilepsy worldwide

ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass

Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer