The burden of amyloidosis on the gastrointestinal tract of an ankylosing spondylitis patient

We present a 26-year-old man with edema, ascites and bloody diarrhea that later proved to be due to gastrointestinal and renal amyloidosis. Interestingly, he was also diagnosed as having ankylosing spondylitis,-possibly after a delay of 12 years. The obscure diagnosis and challenging treatment of secondary amyloidosis are further discussed.Electronic Supplementary Material Supplementary material (with figures in color) is available in the online version of this article at .Abbreviations AS ankylosing spondylitis     

SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis

Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis–free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications.The metastatic progression of breast cancer accounts for the majority of disease-related mortality. A major rate-limiting step in metastasis is the loss of function of the metastasis suppressor genes, which block a cascade of crucial steps including the loss of adhesion of primary tumor cells, intravasation into the blood and lymphatics with subsequent extravasation at distant sites, and the formation of new colonies. Despite the identification of the first metastasis suppressor gene, nonmetastatic 23 (NM23), nearly two decades ago (1), only a handful of new metastasis suppressors have been identified in recent years using candidate gene approaches (2, 3). It is likely that the current catalog of metastasis suppressor genes remains incomplete despite the vast sequencing efforts due to the possibility that a subset of genes regulated by epigenetic mechanisms may have eluded traditional discovery procedures (4–6). To identify these elusive metastasis suppressor genes, which are functionally compromised in late-stage disease (7–9), we took advantage of a well-established breast cancer progression cell line model system sharing the same genetic linage (Fig. 1A) (10). This model system consists of five cell lines that represent the various stages of breast cancer progression based on the MCF10A cell line: MCF10AneoT (NeoT), MCF10AT1Kcl2 (MII), MCF10CA1h (MIII), and MCF10CA1a (MIV). NeoT cells were generated by overexpression of HRAS in MCF10A cells and rarely exhibit growth following injection into nude mice. MII cells were generated by single xenograft passaging of NeoT cells. When injected subcutaneously (s.c.) into nude mice, MII cells generally form benign tumors that progress to carcinoma one out of four times; hence they mimic the early stage, carcinoma in situ. MIII and MIV cells were isolated from tumors formed by MII cells. MIII cells represent carcinoma, as in general they metastasize at a very low frequency, which requires a prolonged incubation period. On the other hand, MIV cells have the potential to readily seed lung metastases and represent the final stages of a breast cancer, metastatic carcinoma. We compared the gene expression profiles of these latter three model cell lines and leveraged large amounts of publically available breast tumor gene expression profiling data (11–13) by applying multiple bioinformatics filters to identify candidate metastasis suppressor genes.Open in a separate windowFig. 1.Identification of SDPR as a candidate metastasis suppressor gene. (A) Schematic depiction of the generation of breast cancer progression cell line model system. The model consists of five cell lines representing different stages of breast cancer progression. MI, normal breast epithelial cells; NeoT and MII, carcinoma in situ; MIII, carcinoma; and MIV, metastatic carcinoma. (B) Hierarchical clustering of gene expression profiles from MII, MIII, and MIV cells for the genes whose expression differ at least twofold between each cell line. Two clusters, cluster 6 and 7, are magnified because expressions of the genes in these two clusters are significantly suppressed in metastatic MIV cells compared with nonmetastatic MII and MIII. (C) The schematic summary of our strategy for the selection of SDPR as the top candidate metastasis suppressor.Here, we report the discovery of the phosphatidylserine-interacting protein, serum deprivation response (SDPR) (also known as cavin-2), as a bona fide metastasis suppressor. Thus far, studies on SDPR function have been limited to its role as a regulator of caveolae formation (14), and its potential direct involvement in cancer has not been previously described. However, it has been reported that SDPR expression is down-regulated significantly in not only breast cancer but also in cancers of kidney and prostate (15). Moreover, SDPR protein down-regulation was observed in serum from patients with malignant kidney tumors, and hence it was suggested as a possible diagnostic marker to discriminate malignant tumors from benign formations (16). Interestingly, SDPR is localized to 2q32-33, a region with a significant level of loss of heterozygosity that is associated with a high degree of recurrence in breast cancer (17, 18). Our results indicate that SDPR is capable of specifically inhibiting the metastatic growth of breast cancer cells.     

Intracranial hemorrhage in infants as a serious,and preventable consequence of late form of vitamin K deficiency: a selfie picture of Turkey,strategies for tomorrow

Purpose

Vitamin K deficiency bleeding is one of the most common causes of acquired hemostatic disorder in early infancy. Although vitamin K is practiced routinely after every birth in Turkey, children with type of vitamin K deficiency bleedings (L-VKDB) can be encountered. We aimed to evaluate the clinical features of the children with L-VKDB reported from Turkey.

Methods

Between 1995 and 2013, 48 studies reporting 534 children with L-VKDB were evaluated in this study.

Results

Of the 534 reported children (178 girls, 356 boys), 486 (91 %) were extremely breastfed. The most common bleeding sites were intracranial hemorrhage, gastrointestinal, and umbilical in 414 (77.4 %), 33 (6.2 %), and 33 (6.2 %) children, respectively, and 35 (6.6 %) children had been diagnosed incidentally without any bleeding. The etiology of 399 (74.7 %) children were classified as idiopathic, whereas 135 (25.3 %) were secondary. Intramuscular vitamin K was administered in 248 (46.4 %), not administered in 228 (42.7 %), and the administration of vitamin K were not determined in 58 (10.9 %) children. The outcomes of Turkish cohort showed that 111 (20.8) children died, 257 (48.1 %) cases developed neurologic deficit (mainly epilepsy and psychomotor retardation), and only 166 (31.1 %) patients recovered without squeal.

Conclusions

The compliance of prophylactic measures in Turkey does not seem to be satisfactory. As a further measure of tomorrow, we vigorously emphasize that a national surveillance program may be initiated. An additional intramuscular dose or oral supplementation of vitamin K especially for exclusively breast-fed infants may reduce this catastrophic problem in our country.     

The Efficacy of Biofeedback Treatment in Patients with Fecal Incontinence

Background: The initial treatment for fecal incontinence (FI) includes supportive treatment and medical treatment. If the initial treatment fails, biofeedback therapy (BFT) is recommended. However, there are limited and conflicting results in the literature supporting the beneficial effect of BFT for FI. The aim of the study is to analyze the efficacy of BFT in 126 patients who have FI due to several causes.Methods: The data of 126 patients (88 females (69.8%) and 38 males (30.2%)) were collected retrospectively. Colonoscopy, anorectal manometry (ARM), and 3D-Endoanal ultrasonography (EAUS) were performed for all patients before applying BFT. In addition, all patients received toilet training instruction and training in Kegel and other pelvic floor strengthening exercises from an experienced nurse, before BFT.Results: The median age of participants was 54 years (range 18-75 years). While 80 patients (63.5%) had clinical and manometric benefit from BFT, 46 patients (36.5%) did not respond to BFT. According to the EAUS and ARM findings, BFT was beneficial in patients who had partial external sphincter failure, and was unsuccessful in patients who had both internal and external sphincter failure, both internal and external sphincter tears, and external sphincter tear rates of more than 25%. After BFT, significant increases in squeeze pressures were observed, with this increase being higher in the positive-response group.Conclusion: The results suggest that BFT is effective in the treatment of FI for specific patient populations.     

Chromosome changes in metastatic human melanoma

Cytogenetic studies were performed on human malignant melanoma cells from eight metastatic lesions. Five tumors displayed near-triploid and three near-diploid chromosome numbers. Chromosomes #1,#6,#7, followed by #2 and #9, were found to be most frequently involved in structural aberrations. Aberrations involving chromosome #1, with deletions or translocations of 1p, involving region 1p12-1p22 in seven of eight breakpoints of the p arm were observed. Seven of nine breakpoints of 6q were located at region 6q15-6q21. Most of the breakpoints on chromosome #7 occurred near the centromeric region. All tumors had additional chromosome material involving 1q, chromosome #7 (7q in two tumors), and in five tumors an increased dose of chromosome #6 (6p in one tumor). The nonrandom breakpoints of these and other chromosomes involved diverse bands, including loci of oncogenes and fragile sites. The observation of nonrandom chromosomal changes in advanced malignant melanoma suggests that genes important in the progression of melanoma are located on chromosomes #1,#6, and #7.