Highlights d ALS-causing mutations found within the gene encoding the glycosyltransferase GLT8D1 d Five ALS-associated GLT8D1 mutations proximate to the substrate binding site d GLT8D1 mutations exhibit in vitro cytotoxicity and impair enzyme activity d GLT8D1 mutations induce motor deficits in zebrafish consistent with ALS

Endocrine therapy in breast cancer survivors can cause severe 'climacteric' symptoms, which may compromise therapy adherence. To determine whether such symptoms can be treated with herbal medication containing black cohosh in the form of isopropanolic Cimicifuga racemosa extract (iCR) alone or in fixed combination with St John's wort (Hypericum perforatum [HP]) (iCR þ HP), a systematic literature search was conducted. Results were viewed in relation to experimental data and metabolism of endocrine therapies. Most breast cancer survivors receiving endocrine therapy experienced reductions in climacteric symptoms under iCR/iCR þ HP. Tamoxifen's interference potential may be countered by using higher iCR doses or iCR þ HP. No estrogen-like effects at the breast or on hormones were seen. After breast cancer, even if receiving tamoxifen, patients using iCR/iCR þ HP had significantly increased recurrence-free survival rates compared to non-users. These results are substantiated by experimental data demonstrating antiproliferative and anti-invasive effects of iCR in breast cancer cells and enhancement of the antineoplastic effects of tamoxifen. There are no known clinical interactions for iCR and HP with endocrine therapies. The HP extract used in iCR þ HP did not exhibit any clinically relevant interaction potential. In conclusion, with its positive benefit-risk profile, iCR/iCR þ HP may offer a safe non-hormonal therapeutic option for breast cancer survivors receiving endocrine therapy.

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C4.4A is a member of the Ly6 family, with low homology to uPAR. It has been detected mainly on metastasizing carcinoma cells and proposed to be involved in wound healing. So far, C4.4A has been observed as an orphan receptor, and its functional activity has not been explored. Using recombinant rat C4.4A (rrC4.4A) made in a eukaryotic expression system, we demonstrate by immunohistology that C4.4A ligands are strongly expressed in tissues adjacent to squamous epithelia of, e.g., tongue and esophagus, the expression pattern partly overlapping with laminin (LN) and complementing the C4.4A expression that is found predominantly on the basal layers of squamous epithelium. ELISA screening of several components of the extracellular matrix revealed selective binding of rrC4.4A to LN1 and LN5 and that transfection of the BSp73AS tumor line with C4.4A cDNA (BSp73AS-1B1) promoted LN1 and LN5 binding. Binding of BSp73AS-1B1 to LN5 and, less markedly, LN1 induced spreading, lamellipodia formation and migration. C4.4A also associates with galectin-3 in nontransformed tissues and tumor lines. There is evidence that the association of C4.4A with galectin-3 influences LN adhesion. C4.4A was described originally as a metastasis-associated molecule. Our findings that LN1 and LN5 are C4.4A ligands, that galectin-3 associates with C4.4A and that C4.4A ligand binding confers a migratory phenotype are well in line with the supposed metastasis association. ' 2005 Wiley-Liss, Inc.Key words: C4.4A; laminin; galectin; cell migration LNs are adhesive glycoproteins found in the basement membrane. Fifteen LN isoforms have been identified. 1 LN isoforms are tissue-specific and expressed in a developmentally regulated pattern. 2,3 Cell adhesion to LN plays an important role in maintaining normal tissue organization. LNs promote cell adhesion and migration, 4 are involved in the control of cell proliferation and gene expression 5 and stimulate neurite outgrowth, 6 the multitude of functions being brought about by a large array of receptors. 7 The most prominent LN receptors are integrins, but distinct receptors have also been described, e.g., a-dystroglycan, syndecans, the 67 kDa LN receptor and galectins. 7,8 a-Dystroglycan provides a link between the basement membrane and the dystrophin-actin cytoskeleton. 9 Its binding to LN is Ca 2þ -dependent 10 and requires carbohydrate moieties. 11 Binding of syndecans 2 and 4 to LN5 induces expression of MMP-1. 12 Moreover, syndecan 1 interacts with unprocessed LN5 in migrating keratinocytes, and this interaction depends on the presence of the glycosaminoglycan chain. 13 Galectins belong to the family of galactose-specific lectins and bind the lactosamine-type sugars on LN1. 8 However, at high concentrations, galectins 3 and 1 can downregulate adhesion to LN, probably by blocking the cellular attachment sites. 14,15 The 67 kDa LN receptor can act in concert with a6b4 to promote cell adhesion to LN1. 16 It is also involved in the degradation of LN1 and the release of motility fragments. 17 The GPI-ancho...

C4.4A is a member of the Ly-6 family with restricted expression in non-transformed tissues. C4.4A expression in human cancer has rarely been evaluated. Thus, it became important to explore C4.4A protein expression in human tumour tissue to obtain an estimate on the frequency of expression and the correlation with tumour progression, the study focusing on colorectal cancer. The analysis of C4.4A in human tumour lines by western blot and immunoprecipitation using polyclonal rabbit antibodies that recognize different C4.4A epitopes revealed C4.4A oligomer and heavily glycosylated C4.4A isoform expression that, in some instances, inhibited antibody binding and interaction with the C4.4A ligand galectin-3. In addition, tumour cell lines released C4.4A by vesicle shedding and proteolytic cleavage. C4.4A was expressed in over 80% of primary colorectal cancer and liver metastasis with negligible expression in adjacent colonic mucosa, inflamed colonic tissue and liver. This compares well with EpCAM and CO-029 expression in over 90% of colorectal cancer. C4.4A expression was only observed in about 50% of pancreatic cancer and renal cell carcinoma. By de novo expression in colonic cancer tissue, we consider C4.4A as a candidate diagnostic marker in colorectal cancer, which possibly can be detected in body fluids.

Past reviews on Cimicifuga racemosa (CR) without differentiation between extracts, quality, and indication altogether led to inconsistent data. Therefore, for the first time, we meet the requirements of the system's logic of evidence-based phytotherapy by taking into consideration extracts, pharmaceutical quality (reflected in a regulatory status as medicinal product), and indication. A literature search for clinical studies examining CR's efficacy and safety for menopausal complaints was conducted. The results were sorted by type of extract, regulatory status, and indication. Accordingly, Oxford Levels of Evidence (LOE) and Grades of Recommendation (GR) were determined. CR extracts demonstrated a good to very good safety in general, on estrogen-sensitive organs and the liver. However, only registered CR medicinal products were able to prove their efficacy. Best evidence was provided by the isopropanolic CR extract (iCR): the multitude of studies including more than 11,000 patients demonstrated consistent confirmatory evidence of LOE 1b (LOE 1a for safety) leading to GR A. The studies on the ethanolic extract BNO 1055 including more than 500 patients showed exploratory evidence of LOE 2b resulting in GR B. A positive benefit-risk profile is stated and limited to Cimicifuga racemosa products holding a marketing authorisation for treating climacteric complaints.

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