PURPOSE: To examine the association between WC and BMI on disability among older adults from LAC. METHODS: Cross-sectional, multicenter city study of 5786 subjects aged 65 years and older from the Health, Well-Being and Aging in Latin America and the Caribbean (SABE) study (1999-2000). Sociodemographic variables, smoking status, medical conditions, BMI, WC, and activities of daily living (ADL) were obtained. RESULTS: Prevalence of high WC (HWC)(>88cm) in women ranged from 48.5%(Havana) to 72.7%(Mexico City), while among men (>102cm) it ranged from 12.5%(Bridgetown) to 32.5%(Santiago). The associations between WC and ADL disability were "J" shaped, with higher risks of ADL disability observed above 110cm for women in Bridgetown, Santiago, Havana, and Montevideo. The association in Sao Paulo is plateau with higher risk above 100cm, and the association in Mexico City is closer to linear. Among men the associations were "U"(Bridgetown, Sao Paulo, and Havana),"J" shaped (Montevideo), plateau (Santiago), and closer to linear in Mexico City. When WC and BMI were analyzed together, we found that participants from Sao Paulo, Santiago, Havana, and Montevideo in the overweight or obese category with HWC were significantly more likely to report ADL disability after adjusting for all covariates. CONCLUSION: The findings of this study suggest that both general and abdominal adiposity are associated with disability and support the use of WC in addition to BMI to assess risk of disability in older adults.

Previously, we demonstrated potent antineoplastic activity of a distinctive histone deacetylase inhibitor (HDACI), AR42, against chemoresistant CP70 ovarian cancer cells in vitro and in vivo. Here, in follow-up to that work, we explored AR42 global mechanisms-of-action by examining drug-associated, genome-wide microRNA and mRNA expression profiles, which differed from those of the well-studied HDACI vorinostat. Expression of microRNA genes in negative correlation, and transcription factor genes in positive correlation, with their "target" coding gene (mRNA) transcripts, were identified and subjected to gene ontology analyses. Those evaluations showed AR42 gene expression patterns to negatively correlate with Wnt signaling (> 18-fold induction of SFRP1), the epithelial-to-mesenchymal transition (40% decreased ATF1), and cell cycle progression (33-fold increased 14-3-3σ). By contrast, AR42 transcriptome alterations correlated positively with extrinsic ("death receptor") apoptosis (> 2.3-fold upregulated DAPK) and favorable ovarian cancer histopathology and prognosis. Inhibition of Wnt signaling was experimentally validated by:(1)> 2.6-fold reduced Wnt reporter activity; and (2) 36% reduction in nuclear, activated β-catenin. Likely AR42 induction of multiple (type I or type II autophagic) cell death cascades was further supported by 57% decreased reliance upon reactive oxygen, increased mitochondrial membrane disruption, and caspase independence, as compared with vorinostat. Taken together, we demonstrate distinct antineoplastic pathway alterations, in aggressive ovarian cancer cells, following treatment with a promising HDACI, AR42. These combined computational and experimental approaches may also represent a straightforward means for mechanistic studies of other promising antineoplastics, and/or the identification of agents that may complement epigenetic therapies.

Colorectal cancer (CRC) has one of the highest incidences among all cancers. The majority of CRCs are sporadic cancers that occur in individuals without family histories of CRC or inherited mutations. Unfortunately, whole-genome expression studies of sporadic CRCs are limited. A recent study used microarray techniques to identify a predictor gene set indicative of susceptibility to early-onset CRC. However, the molecular mechanisms of the predictor gene set were not fully investigated in the previous study. To understand the functional roles of the predictor gene set, in the present study we applied a subpathway-based statistical model to the microarray data from the previous study and identified mechanisms that are reasonably associated with the predictor gene set. Interestingly, significant subpathways belonging to 2 KEGG pathways (focal adhesion; natural killer cell-mediated cytotoxicity) were found to be involved in the early-onset CRC patients. We also showed that the 2 pathways were functionally involved in the predictor gene set using a text-mining technique. Entry of a single member of the predictor gene set triggered a focal adhesion pathway, which confers anti-apoptosis in the early-onset CRC patients. Furthermore, intensive inspection of the predictor gene set in terms of the 2 pathways suggested that some entries of the predictor gene set were implicated in immunosuppression along with epithelial-mesenchymal transition (EMT) in the early-onset CRC patients. In addition, we compared our subpathway-based statistical model with a gene set-based statistical model, MIT Gene Set Enrichment Analysis (GSEA). Our method showed better performance than GSEA in the sense that our method was more consistent with a well-known cancer-related pathway set. Thus, the biological suggestion generated by our subpathway-based approach seems quite reasonable and warrants a further experimental study on early-onset CRC in terms of dedifferentiation or differentiation, which is underscored in EMT and immunosuppression.

Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.

A disadvantage of three-dimensional (3D) isotropic acquisition in whole-heart coronary MRI is the prolonged data acquisition time. Isotropic 3D radial trajectories allow undersampling of k-space data in all three spatial dimensions, enabling accelerated acquisition of the volumetric data. Compressed sensing (CS) reconstruction can provide further acceleration in the acquisition by removing the incoherent artifacts due to undersampling and improving the image quality. However, the heavy computational overhead of the CS reconstruction has been a limiting factor for its application. In this article, a parallelized implementation of an iterative CS reconstruction method for 3D radial acquisitions using a commercial graphics processing unit is presented. The execution time of the graphics processing unit-implemented CS reconstruction was compared with that of the C++ implementation, and the efficacy of the undersampled 3D radial acquisition with CS reconstruction was investigated in both phantom and whole-heart coronary data sets. Subsequently, the efficacy of CS in suppressing streaking artifacts in 3D whole-heart coronary MRI with 3D radial imaging and its convergence properties were studied. The CS reconstruction provides improved image quality (in terms of vessel sharpness and suppression of noise-like artifacts) compared with the conventional 3D gridding algorithm, and the graphics processing unit implementation greatly reduces the execution time of CS reconstruction yielding 34-54 times speed-up compared with C++ implementation. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). While previous studies indicate that indirubin is a promising therapeutic agent for CML, the molecular mechanism of action of indirubin is not fully understood. We report here that indirubin derivatives (IRDs) potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells. Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl (KCL-22M), and CD34-positive primary CML cells from patients. Autophosphorylation of Src family kinases (SFKs) was strongly inhibited in K562 and KCL-22M cells at 5 μM E804, and in primary CML cells at 10 μM E804, although higher concentrations partially inhibited autophosphorylation of Bcr-Abl. Previous studies indicate that SFKs cooperate with Bcr-Abl to activate downstream Stat5 signaling. Activation of Stat5 was strongly blocked by E804 in CML cells. E804 down-regulated expression of Stat5 target proteins Bcl-x(L) and Mcl-1, associated with induction of apoptosis. In sum, our findings identify IRDs as potent inhibitors of the SFK/Stat5 signaling pathway downstream of Bcr-Abl, leading to apoptosis of K562, KCL-22M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients.

This paper presents a high-speed and high-efficiency capsule endoscopy system. Both a transmitter and a receiver were optimized for its application through an analysis of the human body channel. On-Off Keying (OOK) modulation is utilized to achieve low power consumption of the in-body transmitter. A Low Drop Output (LDO) regulator is adopted to prevent performance degradation in the event of a voltage-drop in the battery. The receiver adopts super-heterodyne structure to obtain high sensitivity, considering the link budget from the previous analysis. The receiver and transmitter were fabricated using the CMOS 0.13 Ým process. The output power of the transmitter is -1.6 dBm and its efficiency is 27.7%. The minimum sensitivity of the receiver is -80dBm at a Bit Error Ratio (BER) of 3.10-6. An outer wall loop antenna is adopted for the capsule system to ensure a small size. The integrated system is evaluated using a liquid human phantom and a living pig, resulting in clean captured images.

This paper describes a method for the selective precipitation and purification of a monovalent protein (carbonic anhydrase is used as a demonstration) from cellular lysate using ammonium sulfate and oligovalent ligands. Oligovalent ligands induce the formation of protein-ligand aggregates. At an appropriate concentration of dissolved ammonium sulfate, these complexes precipitate. The purification involves three steps: i) the removal of high-molecular weight impurities through the addition of ammonium sulfate to the crude cell lysate; ii) the introduction of an oligovalent ligand and the selective precipitation of the target protein-ligand aggregates from solution; and iii) the removal of the oligovalent ligand from the precipitate by dialysis to release the target proteins. The increase of mass and volume of the proteins upon aggregate formation reduces their solubility, and results in the selective precipitation of these aggregates. The use of a trivalent ligand gave human carbonic anhydrase in 82 % yield and 95 % purity from crude cellular lysate. This method provides a chromatography-free strategy of purifying monovalent proteins, for which appropriate oligovalent ligands can be synthesized, and combines the selectivity of affinity-based purification with the convenience of salt-induced precipitation.