The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel

Evaluating Students’ Perceived Stress, Sleep Quality, and Physical Activity in Exercise Is Medicine® On Campus Student-led Health Consultation Program

The American College of Sport Medicine created the Exercise is Medicine® (EIM) initiative to improve health through the promotion and prescription of physical activity. The EIM-On Campus (EIM-OC) initiative uses physical activity as a vital sign for promoting healthy behaviors among students and employees on a college campus. The EIM-OC initiative was launched at California State University, Monterey Bay (CSUMB) in Fall 2019. The purpose of this research project was to promote and evaluate college students’ health behaviors associated with the implementation of the EIM-OC initiative at CSUMB. We hypothesized significant improvements in perceived stress, sleep quality, and total physical activity time among participants. The research design was pre-post and tracked participants in the EIM-OC semester long consultation program. Fifteen CSUMB students participated in the consultation program. The Perceived Stress Scale (PSS), Pittsburgh Sleep Quality Index (PSQI), and the Godin-Leisure Time Exercise Questionnaire (GLTEQ) were administered online through an intake form before and after the consultation program. Dependent t-tests were performed to assess for pre- and post-differences in perceived stress (PS), sleep quality (SQ), and total physical activity (PA) time. Significance was set at = 0.05. Participant’s age was M=20.87, SD=3.34 years, with 60% being college junior status. There was a statistically significant improvement in students’ perceived stress levels (t=2.659, df=14, p=.019) pre (M=16.47, SD=5.630) and post (M=11.53, SD=6.424) intervention. There was also a statistically significant improvement in sleep quality (t=.3166, df=14, p=.007) pre (M=6.80, SD=2.981) and post (M=5.07, SD=2.963) intervention. There were improvements in total physical activity time, although it was not significant. The results of this research project indicate that peer advisor consultation programs can be effective in improving college-aged students’ perceived stress and sleep quality. These health behavior improvements are important contributors to college students’ lifelong health behavior habits, quality of life, and academic performance

Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival

Outcomes after hip or knee replacement surgery for osteoarthritis: A prospective cohort study comparing patients quality of life before and after surgery with age-related population norms

Objective: To compare the health-related quality of life of people with osteoarthritis before and after primary total hip and knee replacement surgery with that of the general Australian population. Design: A prospective cohort study. Setting: Three Sydney hospitals, public and private. Participants: Patients with osteoarthritis undergoing primary total hip (n = 59) and knee (n = 92) joint replacement surgery. Main outcome measure: Medical Outcomes Study Short Form (SF-36) scores before and 12 months after joint replacement surgery (compared with population norms). Results: Patients in each age group showed a significant improvement in health-related quality of life after joint replacement surgery in most scales of the SF-36, particularly physical function, role physical and bodily pain. SF-36 scores for the 42 hip-replacement patients aged 55-74 years improved to equal or exceed the population norm on all scales. SF-36 scores of the 52 knee replacement patients aged 55-74 years improved, but physical function and bodily pain scores remained significantly worse than the population norm. SF-36 scores for both hip (n = 17) and knee (n= 40) replacement patients aged 75 years and over improved significantly, becoming similar to population norms for this age group. Conclusions: Total hip or knee replacement for osteoarthritis significantly improves patient health and well-being at 12 months after surgery. Age alone should not be a barrier to surgery

Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells

Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors

Atmospheric sampling of Supertyphoon Mireille with NASA DC-8 aircraft on September 27,1991, during PEM-West A

The DC-8 mission of September 27, 1991, was designed to sample air flowing into Typhoon Mireille in the boundary layer, air in the upper tropospheric eye region, and air emerging from the typhoon and ahead of the system, also in the upper troposphere. The objective was to find how a typhoon redistributes trace constituents in the West Pacific region and whether any such redistribution is important on the global scale. The boundary layer air (300 m), in a region to the SE of the eye, contained low mixing ratios of the tracer species O3, CO, C2H6, C2H2, C3H8, C6H6and CS2 but high values of dimethylsulfide (DMS). The eye region relative to the boundary layer, showed somewhat elevated levels of CO, substantially increased levels of O3, CS2 and all nonmethane hydrocarbons (NMHCs), and somewhat reduced levels of DMS. Ahead of the eye, CO and the NMHCs remained unchanged, O3 and CS2 showed a modest decrease, and DMS showed a substantial decrease. There was no evidence from lidar cross sections of ozone for the downward entrainment of stratospheric air into the eye region; these sections show that low ozone values were measured in the troposphere. The DMS data suggest substantial entrainment of boundary layer air into the system, particularly into the eye wall region. Estimates of the DMS sulphur flux between the boundary layer and the free troposphere, based on computations of velocity potential and divergent winds, gave values of about 69 μg S m−2 d−1 averaged over a 17.5° grid square encompassing the typhoon. A few hours after sampling with the DC-8, Mireille passed over Oki Island, just to the north of Japan, producing surface values of ozone of 5.5 ppbv. These O3 levels are consistent with the low tropospheric values found by lidar and are more typical of equatorial regions. We suggest that the central eye region may act like a Taylor column which has moved poleward from low latitudes. The high-altitude photochemical environment within Typhoon Mireille was found to be quite active as evidenced by significant levels of measured gas phase H2O2 and CH3OOH and model-computed levels of OH

Chemical Characteristics of Continental Outflow Over the Tropical South Atlantic Ocean from Brazil and Africa

The chemical characteristics of air parcels over the tropical South Atlantic during September - October 1992 are summarized by analysis of aged marine and continental outflow classifications. Positive correlations between CO and CH3CL and minimal enhancements of C2CL40, and various ChloroFluoroCarbon (CFC) species in air parcels recently advected over the South Atlantic basin strongly suggest an impact on tropospheric chemistry from biomass burning on adjacent continental areas of Brazil and Africa. Comparison of the composition of aged Pacific air with aged marine air over the South Atlantic basin from 0.3 to 12.5 km altitude indicates potential accumulation of long-lived species during the local dry season. This may amount to enhancements of up to two-fold for C2H6, 30% for CO, and 10% for CH3Cl. Nitric oxide and NO(x) were significantly enhanced (up to approx. 1 part per billion by volume (ppbv)) above 10 km altitude and poorly correlated with CO and CH3Cl. In addition, median mixing ratios of NO and NO(x) were essentially identical in aged marine and continental outflow air masses. It appears that in addition to biomass burning, lightning or recycled reactive nitrogen may be an important source of NO(x) to the upper troposphere. Methane exhibited a monotonic increase with altitude from approx. 1690 to 1720 ppbv in both aged marine and continental outflow air masses. The largest mixing ratios in the upper troposphere were often anticorrelated with CO, CH3Cl, and CO2, suggesting CH, contributions from natural sources. We also argue, based on CH4/CO ratios and relationships with various hydrocarbon and CFC species, that inputs from biomass burning and the northern hemisphere are unlikely to be the dominant sources of CO, CH4 and C2H6 in aged marine air. Emissions from urban areas would seem to be necessary to account for the distribution of at least CH4 and C2H6. Over the African and South American continents an efficient mechanism of convective vertical transport coupled with large-scale circulations conveys biomass burning, urban, and natural emissions to the upper troposphere over the South Atlantic basin. Slow subsidence over the eastern South Atlantic basin may play an important role in establishing and maintaining the rather uniform vertical distribution of long-lived species over this region. The common occurrence of values greater than 1 for the ratio CH3OOH/H2O2 in the upper troposphere suggests that precipitation scavenging effectively removed highly water soluble gases (H2O2, HNO3, HCOOH, and CH3COOH) and aerosols during vertical convective transport over the continents. However, horizontal injection of biomass burning products over the South Atlantic, particularly water soluble species and aerosol particles, was frequent below 6 km altitude

Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

Intrinsic regulation of hemangioma involution by platelet-derived growth factor

Infantile hemangioma is a vascular tumor that exhibits a unique natural cycle of rapid growth followed by involution. Previously, we have shown that hemangiomas arise from CD133+ stem cells that differentiate into endothelial cells when implanted in immunodeficient mice. The same clonally expanded stem cells also produced adipocytes, thus recapitulating the involuting phase of hemangioma. In the present study, we have elucidated the intrinsic mechanisms of adipocyte differentiation using hemangioma-derived stem cells (hemSCs). We found that platelet-derived growth factor (PDGF) is elevated during the proliferating phase and may inhibit adipocyte differentiation. hemSCs expressed high levels of PDGF-B and showed sustained tyrosine phosphorylation of PDGF receptors under basal (unstimulated) conditions. Inhibition of PDGF receptor signaling caused enhanced adipogenesis in hemSCs. Furthermore, exposure of hemSCs to exogenous PDGF-BB reduced the fat content and the expression of adipocyte-specific transcription factors. We also show that these autogenous inhibitory effects are mediated by PDGF receptor-β signaling. In summary, this study identifies PDGF signaling as an intrinsic negative regulator of hemangioma involution and highlights the therapeutic potential of disrupting PDGF signaling for the treatment of hemangiomas