Faculty Bibliography

Background/Purpose: According to the California Department of Education, in Orange County (OC), California, almost 37% of 5th graders are overweight or obese, and low-income and minority youth are most impacted. Obesity causes long-term health issues and has intergenerational implications [Wang et al., 2019]. Team Kid PowerOC (KiPOWOC) is an academic-community partnership initiated in 2015 to support school health policies and coach 5th graders in Title I elementary schools through on-site mentorship for behavioral change during lunch and recess. In 2017, KiPOWOC began an annual 20-week program at Thorman Elementary (75% of students enrolled in the Free or Reduced Lunch program, and 95% Latinx).
Method(s): Quasi-experimental pretest posttest design, without a control site, implemented over two academic years. Annually, volunteer health coaches spend 700-minutes with 5th graders (Weekly: 25-min lessons, 20-min meal coaching, and 25- min active play sessions). Pre- and post-test assessments included BMI percentile (BMI%), blood pressure (BP), mile-run, and health behaviors (HABITS questionnaire). Unadjusted analyses: Two-sample paired t-test. Adjusted analyses: Bonferroni correction.
Result(s): n=142; All: Ages 9-11 years, 37.3% with overweight or obese BMI, 56% female, 73% no-sports participation; BMI%, mean(SD): pre 64.25(30.28), post 60.86(30.69), p=0.0009, sBP change -5 mm Hg, p<0.0001, change in mile run time -0.65 minutes, p<0.0001. Subgroup analyses: Obese BMI (BMI >95th percentile): BMI% change -1.88%, p=0.0011; Females: BMI% change -5.5%, p=0.0003, sBP change -5 mm Hg, p=0.0002; No sports participation: BMI% change -4.1%, p=0.0009, sBP change -5 mm Hg, p<0.0001. No significant findings were identified in health behaviors consistently across subgroups. All significant results held significance after Bonferroni correction for multiple comparisons, except sBP among children with obese BMI.
Conclusion(s): Overall, KiPOWOC demonstrated a significant impact on participants' BMI%, sBP, and mile run. In subgroup analyses, findings held significance among children with obese BMI, female sex, and no-sports participation for BMI% and mile run. A significant difference was also noted in sBP for children with female sex, and no-sports participation. Although identifying subgroup differences was not the initial goal of KiPOWOC, findings highlight that KiPOWOC may have greater impact among low-income children with these characteristics. This is of particular interest when considering that children from lowincome communities have higher risk of obesity and face barriers to sports participation [Towne et al., 2018]. Future studies of KiPOWOC will further explore the subgroup findings identified, analyze study impact with the use of a comparison site, and grow partnerships with Title I OC schools

Following the publication of this article, which was concerned with the expression of phosphorylated epidermal growth factor receptor (pEGFR) and cyclin D1 activation independently of the expression levels of cyclo-oxygenase-2, an interested reader drew to our attention apparent anomalies associated with the western blot data shown in Fig. 2C. Following an internal investigation at the New York University School of Medicine, we were requested to produce the original film, or the scan of the image of the film, for verification. Unfortunately, we were unable to provide the original film or scanned image to disprove the allegation, since the original pEGFR image could not be found. Therefore, the Investigation Committee recommended that this article be retracted, and we are withdrawing the article in line with the request. All the authors agree to the retraction of this paper. We sincerely regret any inconvenience this has caused. [the original article was published in the International Journal of Oncology 40: 13-20, 2012; DOI: 10.3892/ijo.2011.1211].

Melinjo (Gnetum gnemon L.) seed extract (MSE) and its active ingredient gnetin C (GC), a resveratrol dimer, have been shown to possess a broad spectrum of pharmacological activities. In this study, we investigated the antitumor activity of MSE and GC using human and murine tumor cell culture models in vitro. The antitumor activity of GC was compared with trans-resveratrol (tRV), a stilbenoid polyphenol. Our results show that MSE and GC at clinically achievable concentrations significantly inhibited the proliferation of pancreatic, prostate, breast, and colon cancer cell types (P < 0.05), without affecting normal cells. Interestingly, GC exerts enhanced antitumor activity than that of tRV (P < 0.05). MSE and GC significantly induced apoptosis in all the cancer cells, indicating MSE and GC inhibit tumor cell growth by inducing apoptosis (P < 0.001). Our findings provide evidence that MSE might induce apoptosis in cancer cells via caspase-3/7-dependent and -independent mechanisms. However, GC might trigger both early and late stage apoptosis in cancer cells, at least in part by activating caspase 3/7-dependent mechanisms. Furthermore, the antitumor efficacy of MSE observed in vitro was also validated in a widely used colon-26 tumor-bearing mouse model. Oral administration of MSE at 50 and 100 mg/kg per day significantly inhibited tumor growth, intratumoral angiogenesis, and liver metastases in BALB/c mice bearing colon-26 tumors (P < 0.05). In conclusion, our findings provide evidence that MSE and GC have potent antitumor activity. Most importantly, we provide the first evidence that MSE inhibits tumor growth, intratumoral angiogenesis, and liver metastasis in a colon-26 tumor-bearing mice.

Dysregulation of PI3K-AKT-mTOR pathway has been reported in various pathologies, such as cancer and insulin resistance. The proline-rich AKT substrate of 40-kDa (PRAS40), also known as AKT substrate 1 (AKT1S1), lies at the crossroads of these cascades and inhibits the activity of the mTOR complex 1 (mTORC1) kinase. This review discusses the role of PRAS40 and possible feedback mechanisms, and alterations in AKT/PRAS40/mTOR signaling that have been implicated in the pathogenesis of tumor progression. Additionally, we probed new datasets extracted from Oncomine, a cancer microarray database containing datasets derived from patient samples, to further understand the role of PRAS40 (AKT1S1). These data strongly supports the hypothesis that PRAS40 may serve as a potential therapeutic target for various cancers.

Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1'',2'':1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1'',2'':1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.

Background: Extracellular matrix (ECM) characteristics, including stiffness, geometry, chemistry, and spatial interaction with the neighboring cells and soluble factors are key components for cancer cell survival in a pathogenic tissue microenvironment (TME). However, poor performance of 2D in vitro systems and animal models for metastatic cancer types demands physiologically relevant well controlled 3D platforms to quantitatively assess (a) metastatic cancer stem cell survival (b) oncogenic mechanisms and (c) drug resistant phenotypes and (d) new drug efficacy. Advances in the "state of the art" 3D platforms with difference in matrix stiffness and viscoelastic properties are showing promising results in identifying changes in drug resistant phenotypes, cell behavior and gene expression profiles. Preliminary findings by us and others using 3D matrices for human multiple myeloma (MM) reveal promising results on cancer /stromal cell interactions. In this study we have shown that Hyaluronic acid (HA) based 3D hydrogel support human metastatic MM cancer cells survival and thus reveal new oncogenic mechanisms of drug resistant cancer stem cells. Experimental approaches: Bone marrow derived CD138 positive cells and BMSCs were isolated from MM patient samples (with IRB approval) using magnetically labeled CD138 MicroBeads (autoMACS Pro Starting Kit). Bone marrow stromal cells (BMSCs) were cultured as described by us earlier. Cell viability measurements and quantitative RT-PCR for c-myc and other related gene targets were performed using total RNA. Me-HA-3D hydrogels were created containing either fibronectin/collagen/laminin or ME-HA mixture of Matrigel/fibronectin/laminin in different ratios. Cells were grown as surface seeded or encapsulated in Me-HA gels, and analyzed between 4 and 21 days in the conditioned medium. Cell proliferation analysis was performed by both MTS and live dead cell assays using CFSE stain. Results: The overall cell viability by surface coating and in encapsulated gel was found to be higher than 80% for up to 21 days in all the conditions including changes in the UV cross linking time and gel stiffness. Colony forming units (CFU) of the mononuclear cells were higher (27%) at 21 days compared to the 4 days 3% (p>0.001). Spheroids were found on the surface of the hydrogels with PC-3 cells as well as inside the encapsulated hydrogels specifically for MM, and were higher in numbers (>30%) compared to that in surface coating (5%) p>0.001. qRT-PCR analysis determined c-myc, cyclin D1, E-cadherin, and ZEB-1 showed>4 fold increase (p>0.001) in encapsulated cells compared to that in cells transfected with siRNA for c-myc, suggesting c-myc mediated cell survival in 3D. Summary: Me-HA hydrogels are found to be suitable platform for the first time to identify new metastatic cancer phenotypes types and to investigate drug resistance mechanisms

Pulmonary Hypertension is characterized by pulmonary arterial remodeling and increased pressure in the pulmonary circulation. It is often associated with inflammation in the lungs and can lead to right heart failure. Our work shows that urban ambient pollution exacerbates the experimental pulmonary hypertension phenotype just like other types of inflammatory lung conditions. We aimed to identify microRNAs (miRNAs) that are differentially expressed in our mouse model. In addition, we examined plasma samples from individuals occupationally exposed to high levels of air pollution or cigarette smoke, and from controls. Our study is the first to show significantly de-regulated expression of three microRNA species (miR-135a, miR-21, miR-204) in the lungs of mice that were exposed to antigen and particulate matter and developed pulmonary hypertension. De-regulated levels of miR-21 and miR-204 have been reported in human pulmonary hypertension and in experimental pulmonary hypertension. MiR-135a is targeting STAT6 and upregulated expression has been reported in experimental asthma. Using human samples, our study showed that plasma levels of miR-21 and miR-135a, but not levels of miR-204, clustered individuals with high dose exposures and individuals with low dose environmental exposures. Current studies are aimed at identifying the cytokines that control these miRNAs' expression. The long range goal is to identify miRNAs that indicate an at-risk state of the pulmonary vasculature