A Review on the Relationship between SGLT2 Inhibitors and Cancer

Risk of increasing breast and bladder cancer remains a safety issue of SGLT2 (sodium glucose cotransporter type 2) inhibitors, a novel class of antidiabetic agent. We reviewed related papers published before January 29, 2014, through Pubmed search. Dapagliflozin and canagliflozin are the first two approved SGLT2 inhibitors for diabetes therapy. Although preclinical animal toxicology did not suggest a cancer risk of dapagliflozin and overall tumor did not increase, excess numbers of female breast cancer and male bladder cancer were noted in preclinical trials (without statistical significance). This concern of cancer risk hindered its approval by the US FDA in January, 2012. New clinical data suggested that the imbalance of bladder and breast cancer might be due to early diagnosis rather than a real increase of cancer incidence. No increased risk of overall bladder or breast cancer was noted for canagliflozin. Therefore, the imbalance observed with dapagliflozin treatment should not be considered as a class effect of SGLT2 inhibitors and the relationship with cancer for each specific SGLT2 inhibitor should be examined individually. Relationship between SGLT2 inhibition and cancer formation is still inconclusive and studies with larger sample size, longer exposure duration, and different ethnicities are warranted

Nuclear localization of orphan receptor protein kinase (Ror1) is mediated through the juxtamembrane domain

<p>Abstract</p> <p>Background</p> <p>Several receptor tyrosine kinases (RTKs) such as EGFR, FGFR, TRK, and VEGFR are capable of localizing in the cell nucleus in addition to their usual plasma membrane localization. Recent reports also demonstrate that nuclear-localized RTKs have important cellular functions such as transcriptional activation. On the basis of preliminary bioinformatic analysis, additional RTKs, including receptor tyrosine kinase-like orphan receptor 1 (Ror1) were predicted to have the potential for nuclear subcellular localization. Ror1 is a receptor protein tyrosine kinase that modulates neurite growth in the central nervous system. Because the nuclear localization capability of the Ror1 cytoplasmic domain has not been reported, we examined the cellular expression distribution of this region.</p> <p>Results</p> <p>The Ror1 cytoplasmic region was amplified and cloned into reporter constructs with fluorescent tags. Following transfection, the nuclear distribution patterns of transiently expressed fusion proteins were observed. Serial deletion constructs were then used to map the juxtamembrane domain of Ror1 (aa_471-513) for this nuclear translocation activity. Further site-directed mutagenesis suggested that a KxxK-16 aa-KxxK sequence at residues 486-509 is responsible for the nuclear translocation interaction. Subsequent immunofluorescence analysis by cotransfection of Ran and Ror1 implied that the nuclear translocation event of Ror1 might be mediated through the Ran pathway.</p> <p>Conclusions</p> <p>We have predicted several RTKs that contain the nuclear localization signals. This is the first report to suggest that the juxtamembrane domain of the Ror1 cytoplasmic region mediates the translocation event. Ran GTPase is also implicated in this event. Our study might be beneficial in future research to understand the Ror1 biological signaling pathway.</p

Genomic sequence of temperate phage Smp131 of Stenotrophomonas maltophilia that has similar prophages in xanthomonads

Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacterium previously named as Xanthomonas maltophilia. This organism is an important nosocomial pathogen associated with infections in immunocompromised patients. Clinical isolates of S. maltophilia are mostly resistant to multiple antibiotics and treatment of its infections is becoming problematic. Several virulent bacteriophages, but not temperate phage, of S. maltophilia have been characterized

Whole-body vibration training effect on physical performance and obesity in mice

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity

Study of the River Bed Variation after the Baling Check-Dam Failure

The study provides longitudinal and cross-sectional analysis of 8 pieces topography data collected from 1980 to 2011 and bed material particle size based on three investigations conducted between 2008 and 2012. The mainstream topography data in December 2007 shows that the head-cutting distance was about 3 kilometers after the dam broke. The topography data since 2008 displays that river the channel is stable as well. The topography data shows that the longitudinal section in the tributary had a head-cutting distance of about 3 kilometers after the dam broke, and the river channel still is showing adjustment behavior. The scour-and-fill analysis result of the mainstream cross-section shows that the transverse adjust changed significantly upstream from the dam location from 2006-2008. The particle size of the bed material has shown a trend from coarsening to fining according to different sampling points. Therefore, the river bed is still adjusting continuously. Finally, this study is based on a debris flow and sediment laden flow numerical model. The simulation result is fit for river-bed changes after dam-break.2007年石門水庫上游的巴陵防砂壩潰壩事件，導致上游河床沖刷約20公尺，下游最大淤積約10公尺。本文蒐集巴陵防砂壩1980至2011年潰壩前後8次地形測量資料與2008-2012年共進行三次河床質粒徑調查以分析潰壩對於河床變動及河床質粒徑變化的影響。結果顯示，巴陵壩潰壩3個月後河床已逐漸趨於動態平衡，河床質粒徑整體有粗化再細化的趨勢。最後，本文以適用於土石流及高含砂水流的數值模式進行潰壩事件模擬，並利用河床測量成果進行比較

Frequency Dependent Alterations in Regional Homogeneity of Baseline Brain Activity in Schizophrenia

Low frequency oscillations are essential in cognitive function impairment in schizophrenia. While functional connectivity can reveal the synchronization between distant brain regions, the regional abnormalities in task-independent baseline brain activity are less clear, especially in specific frequency bands. Here, we used a regional homogeneity (ReHo) method combined with resting-state functional magnetic resonance imaging to investigate low frequency spontaneous neural activity in the three different frequency bands (slow-5:0.01–0.027 Hz; slow-4:0.027–0.08 Hz; and typical band: 0.01–0.08 Hz) in 69 patients with schizophrenia and 62 healthy controls. Compared with controls, schizophrenia patients exhibited decreased ReHo in the precentral gyrus, middle occipital gyrus, and posterior insula, whereas increased ReHo in the medial prefrontal cortex and anterior insula. Significant differences in ReHo between the two bands were found in fusiform gyrus and superior frontal gyrus (slow-4> slow-5), and in basal ganglia, parahippocampus, and dorsal middle prefrontal gyrus (slow-5> slow-4). Importantly, we identified significant interaction between frequency bands and groups in the inferior occipital gyrus and caudate body. This study demonstrates that ReHo changes in schizophrenia are widespread and frequency dependent

Identification of novel DNA methylation inhibitors via a two-component reporter gene system

<p>Abstract</p> <p>Background</p> <p>Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation. While procainamide is much safer than 5-aza-2'-deoxycytidine, it requires high concentrations to be effective in DNA demethylation in suppressing cancer cell growth. Thus, our laboratories have embarked on the pharmacological exploitation of procainamide to develop potent DNA methylation inhibitors through lead optimization.</p> <p>Methods</p> <p>We report the use of a DNA methylation two-component enhanced green fluorescent protein reporter system as a screening platform to identify novel DNA methylation inhibitors from a compound library containing procainamide derivatives.</p> <p>Results</p> <p>A lead agent IM25, which exhibits substantially higher potency in <it>GSTp1 </it>DNA demethylation with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2'-deoxycytidine, was identified by the screening platform.</p> <p>Conclusions</p> <p>Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to develop novel DNA methylation inhibitors, of which the translational potential in cancer therapy/prevention is currently under investigation.</p

) The Influence of Low-powered Family LED Lighting on Eyes in Mice Experimental Model

Abstract: Ocular tissue damage because of exposure to visible light has been demonstrated by the results of human and animal studies. The short-wavelength visible light between 430 nm to 500 nm (blue light) is especially associated with retina damage. Recently, new powerful sources and relatively inexpensive blue energy of LED (light emitting diodes) family lamps in home illumination are available. The aim of this study is to investigate the effects of illumination source from the low-powered and the conscious spectrum source of LED family lamps on retina tissues. The illumination source of LED family lamps was analyzed from 300 nm to 800 nm using an UVvisible spectrophotometer. In animal experiments, young adult mice were assigned to expose to family LED light for 2h every day ranging 2 to 4 weeks or light environment using LED family lamps for 39 weeks. After LED light treatment, sections of eyes were stained with hematoxylin and examined using histopathology. The data clearly demonstrated irradiation of the white LED is above 400 nm and is not within the ultraviolet light region. However, the analysis of spectrum distribution demonstrated that the family LED lighting exhibited power-peak at 450 nm is within the blue light region. Histological results showed that the photoreceptor layer is significantly reduced in thickness after 4 weeks of LED exposure 2h every day or LED illuminated environment. This study provides important data regarding the efficacy and safety of LED light in family illumination. It is impossible to consider these degenerative changes are related unavoidably part of their mechanism of action or an avoidable toxic effect

Look, the World is Watching How We Treat Migrants! The Making of the Anti-Trafficking Legislation during the Ma Administration

Employing the spiral model, this research analyses how anti-human trafficking legislation was promulgated during the Ma Ying-jeou (Ma Yingjiu) presidency. This research found that the gov- ernment of Taiwan was just as accountable for the violation of mi- grants’ human rights as the exploitive placement agencies and abusive employers. This research argues that, given its reliance on the United States for political and security support, Taiwan has made great ef- forts to improve its human rights records and meet US standards for protecting human rights. The reform was a result of multilevel inputs, including US pressure and collaboration between transnational and domestic advocacy groups. A major contribution of this research is to challenge the belief that human rights protection is intrinsic to dem- ocracy. In the same light, this research also cautions against Taiwan’s subscription to US norms since the reform was achieved at the cost of stereotyping trafficking victimhood, legitimising state surveillance, and further marginalising sex workers