Evid Based Complement Alternat Med. 2013; 2013: 969824.

The main purpose of this pilot study was to evaluate a combination of EA and drug therapy, namely, treatment with the insulin sensitizer, rosiglitazone, and to explore whether this improves insulin activity among type 2 diabetic patients. Therefore, we performed a clinical randomized controlled trial (RCT) on type 2 diabetic patients treated with rosiglitazone alone and compared these with patients treated with rosiglitazone combined with EA. The endpoints assessed were a reduction in blood glucose levels and/or improvements in insulin activity.

We have shown previously that mutual antagonism between apoptosis and autophagy inducers could make the system bistable but does not make the apoptosis activation irreversible (see Figure 5 in [35]). We also showed that its irreversibility depends on extra positive feedback loops such as those between Bcl2 (crosstalk element) and caspases (apoptosis inducer). In the present study, we performed ER inhibitor washout experiments with TM and DTT to study the irreversible activation of apoptosis (Figure 6). Our study showed that earlier washout of high level of stressor prevented further drop in cell viability while late washout diminished the viability further similar to continuous treatment with excessive level of ER stressor. The immunoblot data show that autophagy remains active at short treatment, while late washout cannot block apoptosis induction (Figure 7).

We also showed that autophagy-dependent survival has an important antiapoptotic effect in the presence of various ER stressors and achieves this by directly influencing the threshold for apoptosis activation (Figure 5). We observed that inhibition of autophagy with 3-methyladenine leads to activation of apoptosis even at low stress levels, while hyperactivation of autophagy with metyrapone pretreatment delays the activation of apoptosis at severe ER stress. These results undoubtedly suggest that the activation threshold of self-killing mechanism is sensitive to autophagy. Antiapoptotic role of autophagy under ER stress suggests that apoptosis activation also depends on autophagy inactivation. Since autophagy gets rapidly downregulated when apoptosis switches on (Figures 2, 3, S5, and S6) we claim that a mutual antagonism between autophagy and apoptosis inducers has a crucial role in controlling the decision-making process with respect to various ER stressors. We observed that the threshold for the activation of apoptosis is influenced by the stochasticity of cell population (Figures 4 and 5). Therefore, individual cells have different activation threshold, which in turn influences the time of activation of apoptosis. We think this is due to the critical slowing down phenomenon near the activation threshold of apoptosis. Therefore, apoptosis gets activated with a time lag in the cells with activation threshold closer to the actual stress level while time lag is decreased in cells with activation threshold further away from the actual stress level. However the sigmoid characteristic of autophagy induction is the same in both single cell and cell population simulations. These results suggest that experiments studying cell population (i.e., immunoblotting) are sufficient to give a good description about the dynamical characteristic of autophagy induction with respect to ER stress. However, single cell experiments would be essential to carry out for the analysis of apoptosis induction in the future.

These changes were accompanied by increased Sgk-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR.

M2 markers spontaneously produced by BAL cells significantly increase in parallel with an increase in fibrotic lung remodeling as reflected by the chest X-ray type of the disease, meanwhile median TNF release decreases. The importance of CCL17 is underlined by a recent study demonstrating that ... For further evaluation we determined whether....

We have shown that... Therefore, we hypothesized that...and that .....To test this hypothesis, we accomplished a comprehensive analysis of... In addition, we explored whether

Mol Carcinog. 2010 January; 49(1): 94–103.

In summary, we have demonstrated that similar to human colorectal cancer, AOM induced mouse colonic tumors display global DNA hypomethylation and aberrantly hypermethylated genes. Further studies of the epigenetic alterations using genome wide assays should provide a comprehensive assessment of the methylation state of the DNA in these tumors and will demonstrate the potential of this model to be used to further study the molecular pathology of aberrant DNA methylation in colorectal cancer.

J Clin Oncol. 2011 August 1; 29(22): 3056–3064.

Limitations of this study should be considered. The majority of SNs are initially ascertained by self report, which may result in underestimation of true incidence rates. Additionally, although CCSS has collected detailed chemotherapy exposures and radiation dosimetry and volume measures relating to the primary cancer, only limited information was available regarding treatment of SNs, restricting risk factor analyses to primary cancer exposures only. Clearly, exposures resulting from treatment of subsequent neoplasms could impact subsequent cancer risk. The limitation of not having the SN treatment information to include in the risk factor analysis does not detract from the findings and clinical implications of the high cumulative incidence of multiple subsequent neoplasms. Finally, systematic and precise determination of SN occurrence as in field versus out of the radiation field was not possible in many of the occurrences, because exact information regarding location of the SN was not always available either from the respondent or as noted on the pathology report.

Mol Med Rep. 2012 April; 5(4): 1116–1120.

Identification of CSC markers is the first step in CSC research. Many molecules have been used to identify a subpopulation of cancer cell lines or tumor samples which possess CSC properties. For example, in breast cancer both CD44 high/CD24 low and ALDH are CSC markers. CD133 is also a promising CSC marker for brain tumors and colon cancers (4). The ALDH superfamily of NAD(P)+-dependent multifunctional enzymes catalyze the oxidation of various aldehydes to their corresponding carboxylic acids. ALDH isozymes are widely distributed in tissues and organs. ALDH was first demonstrated to be highly enriched in hematopoietic stem cells. Stem cells isolated using Aldefluor assays have been utilized in regenerative medicine, such as bone marrow transplantation (14). Recently, ALDH activity has been reported to be a CSC marker in certain solid tumors, including breast, lung, liver, pancreas, prostate and colon cancers. In this study, Aldefluor assays were applied to enrich a subset of cells with CSC characteristics from the Tca8113 tongue squamous cell carcinoma cell line. To determine the functional differences between sorted ALDH+ and ALDH− fractions, we compared their proliferation and found that ALDH+ Tca8113 cells proliferated faster than ALDH− cells in vitro.Self-renewal and differentiation are essential properties of CSCs. Our in vitro differentiation assays showed that ALDH+ cells were able to differentiate into ALDH− cells, and to maintain undifferentiated ALDH+ parts. By contrast, ALDH− cells did not generate ALDH+ cells under the same conditions. Non-adherent sphere formation assays have been accepted to evaluate putative CSC activity. This assay predicts that a CSC can be serially passaged for many cycles and generates a tumorsphere resembling the primary sphere. Our sphere formation and differentiation results demonstrated that ALDH+ cells could self-renew and differentiate to ALDH− cells. We also observed that a small portion of sorted ALDH− cells survived in serum-free medium and formed spheres, which may be caused by the contamination during FACS sorting procedure. Together, these data confirmed that ALDH activity is valuable in identifying tongue squamous cell carcinoma stem cells. Kang et al (7) recently reported that CD133 may be a potential tumor-initiating marker for the Tca183 cell line. They carried out similar experiments and showed that CD133+ cells possessed a higher ability of proliferation, differentiation and sphere formation than CD133− cells. It will be interesting to test whether these two markers identify the same subpopulation of Tca183 cells.

Am J Hypertens. 2005 January; 18(1): 88–98.

Hypertension is a major cause of the disproportionately high rates of coronary heart disease (CHD), stroke, and renal disease in African Americans compared to whites.1,2 African Americans suffer from a higher incidence, prevalence, and severity of hypertension than whites,3 with increased end-organ damage4 and lower treatment rates.5 Cardiovascular disease (CVD) is a primary contributor to the disparities in health and health care between African Americans and white Americans.6,7

Diabetes Care. 2009 April; 32(4): 580–584.

The generalizability of results to other populations may be limited due to different intervention effects and complication rates (for example, due to variable expertise of surgical teams) or health care costs (which may vary across countries). As discussed in an editorial of the Journal of the American Medical Association regarding the original RCT (20), the trial was not powered to detect low-probability events including postoperative mortality (21). However, there is evidence to show that the trial results (zero operative mortality) have been replicated under nontrial conditions (22). Data are not available regarding the average resource use of LAGB patients in other parts of the world. The trend toward shorter stays under outpatient LAGB in the U.S. suggests that the Australian costs may be relatively high. In conclusion, from an economic perspective, surgically induced weight loss appears to be a cost-effective intervention for managing recently diagnosed type 2 diabetes in obese patients.

Am J Cancer Res. 2015 Jan 15;5(2):498-513.

Autophagy also may have synergistic effect on apoptosis, hence affecting the development of colorectal carcinoma. Other authors have also reported that the expressions of autophagy-related gene LC3 and Beclin-1 increase in colorectal carcinoma and these expressions are in accordance with those of anti-apoptotic genes p53 and Bcl-2 [24]. Under conditions in which apoptosis was induced with 5-fluorouracil (5-FU) or cisplatin, the apoptosis increased when autophagy was inhibited by 3-MA [25,26]. Reagents which inhibit autophagy are even thought as a combination therapy with antitumor drugs to enhance the therapeutic effect [27]. In order to study the effect of starvation-induced autophagy mediated by ART1 in the progression of CT26 cells, we observed the apoptosis and growth ability of GFP-ART1 group in the absence or presence of 3-MA. Data from the present study show that inhibition of starvation-induced autophagy in ART1-GFP CT26 cells promotes apoptosis and inhibits proliferation. This suggests that autophagy, which is regulated by ART1, may contribute to the survival of cancer cells under starvation conditions.

Evid Based Complement Alternat Med. 2013; 2013: 969824.

Although the insulin sensitizer rosiglitazone improves insulin sensitivity, there are some adverse effects in terms of liver function and the induction of fluid retention. Since EA has been shown to improve insulin activity in our previous studies [12, 13], a combination of EA's effects in terms of enhancing insulin activity with the use of an insulin sensitizer may potentially be a new modality for the treatment of diabetes mellitus in humans [14]. In addition, this combined therapy may also improve insulin sensitivity and regulate the secretion of insulin, which ought to help to block any worsening of pancreas functioning.

Evid Based Complement Alternat Med. 2013; 2013: 969824.

Acupuncture is a part of traditional Chinese medicine. According to traditional Chinese medicine theory, acupuncture regulates “Qi and Blood” and is likely to affect the bioavailability of substances taken internally and in the process may influence the absorption, distribution, metabolism, and/or excretion of substances [9]. In addition, researchers have begun using electroacupuncture (EA) rather than classical acupuncture. This approach combines traditional needle acupuncture with an electrical current passing through the needles into the acupoints. This seems to produce hypoglycemic responses, and, using EA at different frequencies, also causes the release of endogenous opioid peptides that activate specific receptors [10]. In this context, the potential of EA as a treatment for hyperinsulinemia is an important issue because type 2 DM may eventually develop into pancreatic failure [11].

Evid Based Complement Alternat Med. 2013; 2013: 969824.

Diabetes mellitus is a syndrome associated with a disordered metabolism and inappropriate hyperglycemia that can be due to either an absolute deficiency in insulin secretion or reduction in the biological effectiveness of insulin. Type 2 diabetes is the predominant form of diabetes worldwide and accounts for 90% of cases globally [1, 2]. Alarming increases in the prevalence of diabetes have occurred in Asia [3]. A number of factors have been shown to play an important role in the development of the disease and these include excessive caloric intake, a sedentary lifestyle, and abdominal visceral obesity [4]. In addition, many circulating inhibitors, including free fatty acids (FFAs), have also been found to be involved in reducing insulin sensitivity [5]. From a pathology point of view, patients with type 2 diabetes have a number of metabolic abnormalities including (1) resistance to the action of insulin in muscle, fat tissue, and liver; (2) defective insulin secretion, especially under glucose stimulus; and (3) increased glucose production by the liver [6].Management of type 2 diabetes is a great challenge to physicians both because of the disease's complex pathology and because of the multiple chronic complications associated with the disease. The usual treatment for type 2 diabetes mellitus includes life style modification, exercise, diet therapy, oral antihyperglycemic drugs, and insulin. The thiazolidinediones represent a unique class of drug that may directly decrease insulin resistance by enhancing insulin action in skeletal muscle, liver, and adipose tissue [7]. Two of these compounds, rosiglitazone and pioglitazone, have been approved for clinical use in type 2 diabetic patients. In the UK Prospective Diabetes Study (UKPDS), reduction in the risk of microvascular complications (retinopathy, nephropathy, and neuropathy) was found in the intensive treatment group of patients with new onset type 2 diabetes [8]. However, it should be realized that there are possible unfavorable events associated with achieving lower glycemic targets such as hypoglycemia, bulky combinations of medications, and expense. Although present-day management of type 2 diabetes is more effective than before, as time goes by the effectiveness of drug treatment deteriorates in these patients. Novel therapies and different kinds of treatment for type 2 diabetes need to be developed in the future.