Prospective Association of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis.

BACKGROUND: Taking fewer than the widely promoted "10 000 steps per day" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines. METHODS: Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional hazards regression analyses were completed using study-specific quartiles and hazard ratios (HR) and 95% CI were meta-analyzed with inverse-variance-weighted random effects models. RESULTS: The mean age of participants was 63.2±12.4 years and 52% were women. The mean follow-up was 6.2 years (123 209 person-years), with a total of 1523 CVD events (12.4 per 1000 participant-years) reported. There was a significant difference in the association of steps per day and CVD between older (ie, ≥60 years of age) and younger adults (ie, <60 years of age). For older adults, the HR for quartile 2 was 0.80 (95% CI, 0.69 to 0.93), 0.62 for quartile 3 (95% CI, 0.52 to 0.74), and 0.51 for quartile 4 (95% CI, 0.41 to 0.63) compared with the lowest quartile. For younger adults, the HR for quartile 2 was 0.79 (95% CI, 0.46 to 1.35), 0.90 for quartile 3 (95% CI, 0.64 to 1.25), and 0.95 for quartile 4 (95% CI, 0.61 to 1.48) compared with the lowest quartile. Restricted cubic splines demonstrated a nonlinear association whereby more steps were associated with decreased risk of CVD among older adults. CONCLUSIONS: For older adults, taking more daily steps was associated with a progressively decreased risk of CVD. Monitoring and promoting steps per day is a simple metric for clinician-patient communication and population health to reduce the risk of CVD.

Effect of home-based resistance training on chemotherapy relative dose intensity and tolerability in colon cancer: The FORCE randomized control trial.

BACKGROUND: Many patients with colon cancer cannot fully adhere to postoperative chemotherapy due to dose-limiting toxicities, resulting in lower relative dose intensity (RDI) and potentially compromising overall survival. This study examined whether home-based resistance training (RT) during adjuvant chemotherapy improves RDI and patient-reported toxicities versus usual care (UC) in colon cancer patients. METHODS: Multicenter, randomized control trial (RCT) conducted at community and academic practices. Enrollment of patients receiving postoperative chemotherapy for colon cancer occurred between February 23, 2018, and September 29, 2021; final follow-up was March 21, 2022. Participants were randomized to RT (n = 90) or UC (n = 91) for the duration of chemotherapy. Participants in the RT group engaged in twice weekly home-based progressive RT. At the end of the study, UC was given an online exercise program. RESULTS: Among 181 randomized patients (mean age, 55.2 [SD, 12.8] years, 95 [52.5%] were men), there were no differences in the mean RDI among those in RT (79% [SD, 19%]) and those in UC (82% [SD, 19%]); (mean difference -0.04 [95% confidence interval (CI), -0.09 to 0.02]). Assignment to RT did not significantly reduce the number of moderate/severe symptoms per week across follow-up (relative rate: 0.94 [95% CI, 0.72-1.22]). Additionally, time since randomization did not significantly modify the effect of RT on the overall number of symptoms (p = .06). CONCLUSIONS: Among patients with colon cancer, these results do not support home-based RT as an adjunct to chemotherapy specifically to improve planned treatment intensity.

Analysis of the Types of Retracted COVID-19 Articles Published in PubMed-Listed Journals.

OBJECTIVES: Periodically, medical publications are retracted. The reasons vary from minor situations, such as author attributions, which do not undermine the validity of the data or the analysis in the article, to serious reasons, such as fraud. Understanding the reasons for retraction can provide important information for clinicians, educators, researchers, journals, and editorial boards. METHODS: The PubMed database was searched using the term "COVID-19" (coronavirus disease 2019) and the term limitation "retracted publication." The characteristics of the journals with retracted articles, the types of article, and the reasons for retraction were analyzed. RESULTS: This search recovered 196 articles that had been retracted. These retractions were published in 179 different journals; 14 journals had >1 retracted article. The mean impact factor of these journals was 8.4, with a range of 0.32-168.9. The most frequent reasons for retractions were duplicate publication, concerns about data validity and analysis, concerns about peer review, author request, and the lack of permission or ethical violation. There were significant differences between the types of article and the reasons for retraction but no consistent pattern. A more detailed analysis of two particular retractions demonstrates the complexity and the effort required to make decisions about article retractions. CONCLUSIONS: The retraction of published articles presents a significant challenge to journals, editorial boards, peer reviewers, and authors. This process has the potential to provide important benefits; it also has the potential to undermine confidence in both research and the editorial process.

Deletion of Slc6a14 reduces cancer growth and metastatic spread and improves survival in KPC mouse model of spontaneous pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal. There is a dire need for better therapeutic targets. Cancer cells have increased demand for sugars, amino acids, and lipids and therefore up-regulate various nutrient transporters to meet this demand. In PDAC, SLC6A14 (an amino acid transporter (AAT)) is up-regulated, affecting overall patient survival. Previously we have shown using in vitro cell culture models and in vivo xenograft mouse models that pharmacological inhibition of SLC6A14 with α-methyl-l-tryptophan (α-MLT) attenuates PDAC growth. Mechanistically, blockade of SLC6A14-mediated amino acid transport with α-MLT leads to amino acid deprivation, eventually inhibiting mTORC1 signaling pathway, in tumor cells. Here, we report on the effect of Slc6a14 deletion on various parameters of PDAC in KPC mice, a model for spontaneous PDAC. Pancreatic tumors in KPC mice show evidence of Slc6a14 up-regulation. Deletion of Slc6a14 in this mouse attenuates PDAC growth, decreases the metastatic spread of the tumor, reduces ascites fluid accumulation, and improves overall survival. At the molecular level, we show lower proliferation index and reduced desmoplastic reaction following Slc6a14 deletion. Furthermore, we find that deletion of Slc6a14 does not lead to compensatory up-regulation in any of the other amino transporters. In fact, some of the AATs are actually down-regulated in response to Slc6a14 deletion, most likely related to altered mTORC1 signaling. Taken together, these results underscore the positive role SLC6A14 plays in PDAC growth and metastasis. Therefore, SLC6A14 is a viable drug target for the treatment of PDAC and also for any other cancer that overexpresses this transporter.

Marijuana Use in Middle and High School Students: Insights from the 2020 National Youth Tobacco Survey.

OBJECTIVE: The use of marijuana by middle and high school students could have important consequences, including physical harm, poor decision making, increased use of tobacco products, and involvement in the legal system. Determining the level of use by students provides the initial information needed to understand the extent of the problem and possible approaches to reducing student use. METHODS: The National Youth Tobacco Surveys provide important information about the frequency of use of nicotine and tobacco products by a representative sample of students in schools in the United States. The 2020 survey included a question about the use of marijuana by survey respondents. The results from the survey were analyzed using descriptive statistics and logistic regression to model the association between the use of marijuana and the use of electronic or conventional cigarettes. RESULTS: The final survey from 2020 included 13,357 students, with 6537 male respondents and 6820 female respondents. Ages ranged from younger than 12 to 18 and older years; 961 students used both cigarettes and marijuana, and 1880 students used both electronic cigarettes (e-cigarettes) and marijuana. The adjusted odds ratio for the use of marijuana increased in female students, in non-Hispanic Black students, Hispanic students, and all ages from 13 through 18 and older. The perception of harm associated with either e-cigarettes or cigarettes did not change the odds ratio for using marijuana. Students who did not smoke cigarettes or did not smoke e-cigarettes had significantly lower odds ratios for using marijuana. CONCLUSIONS: The 2020 National Youth Tobacco Survey indicates that approximately 18.4% of middle school and high school students have used marijuana. Parents, educators, public health officials, and policymakers need to understand that there is a relatively high use of marijuana among students and that education programs should focus on its use with or without other tobacco products.

Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics.

Breast cancer (BC) is a heterogeneous condition and comprises molecularly distinct subtypes. An imbalance in the levels of epigenetic histone deacetylases (HDACs), modulating estrogen accumulation, especially 17ß-estradiol (E2), promotes breast tumorigenesis. In the present study, analyses of The Cancer Genome Atlas (TCGA) pan-cancer normalized RNA-Seq datasets revealed the dysregulation of 16 epigenetic enzymes (among a total of 18 members) in luminal BC subtypes, in comparison to their non-cancerous counterparts. Explicitly, genomic profiling of these epigenetic enzymes displayed increases in HDAC1, 2, 8, 10, 11, and Sirtuins (SIRTs) 6 and 7, and decreases in HDAC4-7, -9, and SIRT1-4 levels, respectively, in TCGA breast tumors. Kaplan-Meier plot analyses showed that these HDACs, with the exception of HDAC2 and SIRT2, were not correlated with the overall survival of BC patients. Additionally, disruption of the epigenetic signaling in TCGA BC subtypes, as assessed using both heatmaps and boxplots, was associated with the genomic expression of factors that are instrumental for cholesterol trafficking/utilization for accelerating estrogen/E2 levels, in which steroidogenic acute regulatory protein (STAR) mediates the rate-limiting step in steroid biosynthesis. TCGA breast samples showed diverse expression patterns of a variety of key steroidogenic markers and hormone receptors, including LIPE, CYP27A1, STAR, STARD3, CYP11A1, CYP19A1, ER, PGR, and ERBB2. Moreover, regulation of STAR-governed steroidogenic machinery was found to be influenced by various transcription factors, i.e., CREB1, CREM, SF1, NR4A1, CEBPB, SREBF1, SREBF2, SP1, FOS, JUN, NR0B1, and YY1. Along these lines, ingenuity pathway analysis (IPA) recognized a number of new targets and downstream effectors influencing BCs. Of note, genomic, epigenomic, transcriptional, and hormonal anomalies observed in human primary breast tumors were qualitatively similar in pertinent BC cell lines. These findings identify the functional correlation between dysregulated epigenetic enzymes and estrogen/E2 accumulation in human breast tumors, providing the molecular insights into more targeted therapeutic approaches involving the inhibition of HDACs for combating this life-threatening disease.

Likelihood of Adolescents Trying Conventional or Electronic Cigarettes Varies with Their Use and Perception of Harm and Addictiveness of Other Tobacco Products, Including Cigars.

OBJECTIVES: Developing a comprehensive understanding of tobacco product use among adolescents requires information about the use of conventional cigarettes; electronic cigarettes (e-cigarettes); other tobacco products such as cigars, little cigars, and cigarillos (CCLCs); and smokeless tobacco. In particular, the use of products other than cigarettes may have important implications for additional smoking-related behaviors and the health of students and adolescents. METHODS: The National Youth Tobacco Surveys for 2017, 2018, and 2019 were aggregated to analyze the characteristics of middle school and high school students who had used tobacco products, such as CCLCs. Information collected included age, sex, race, and perceptions about harm and addiction related to tobacco products. Multiple logistic regression models were used to evaluate the associations between having used conventional/e-cigarettes and having used CCLCs, while adjusting for the perceived harm of conventional/e-cigarettes, sex, age, and other risk factors. RESULTS: These combined surveys included 50,172 responses; 6836 respondents (13.6%) had tried CCLCs. Male students used these products more frequently than female students. Students in older age groups (15, 16, 17, and 18 and older,) had used these products more frequently than younger students. The odds for students in this CCLCs subgroup trying conventional cigarettes decreased in those who thought that conventional cigarettes could cause "some harm" or "a lot of harm." The odds for having tried e-cigarettes in the CCLCs subgroup decreased in those who thought that e-cigarettes could cause harm and increased in those who thought that conventional cigarettes could cause "little harm" or "a lot of harm." CONCLUSIONS: More than 10% of middle school and high school students have used CCLCs. The majority of students in this subgroup also have used either conventional cigarettes or e-cigarettes. Understanding possible harm with cigarette use is significantly associated with the reduced use of conventional and e-cigarettes, and using CCLCs independently contributes to the increased risk of using conventional and e-cigarettes. The frequent use of several tobacco products makes surveys in this age group more complicated and indicates that educational efforts and public policies regarding tobacco need to include all tobacco products.

Nucleated red blood cells as a biomarker for mortality in neonates following cardiac surgery.

INTRODUCTION: Nucleated red blood cells (NRBCs) are immature red cells that under normal conditions are not present in the peripheral circulation. Several studies have suggested an association between elevated NRBC and poor outcome in critically ill adults and neonates. We sought to determine if elevations in NRBC value following cardiac surgery and following clinical events during the hospital stay can be used as a biomarker to monitor for mortality risk in neonates post-cardiac surgery. MATERIALS AND METHODS: We constructed a retrospective study of 264 neonates who underwent cardiac surgery at Children's Hospital, New Orleans between 2011 and 2020. Variables included mortality and NRBC value were recorded following cardiac surgery and following peri-operative clinical events. The study was approved by LSU Health IRB. Sensitivity, specificity, receiver operating characteristic (ROC) curves with area under the curve (AUC) and logistic regression analysis were performed. RESULTS: Thirty-six patients (13.6%) died, of which 32 had an NRBC value ≥10/100 white blood cell (WBC) during hospitalisation. Multi-variable analysis found extracorporeal membrane oxygenation use (OR 10, 95% CI 2.9-33, p=<0.001), NRBC ≥10/100 WBC (OR 16.1, CI 4.1-62.5, p ≤ 0.001) and peak NRBC in the 14-day period post-cardiac surgery (continuous variable, OR 1.05, 95% CI 1.0-1.09, p = 0.03), to be independently associated with mortality. Using a cut-off NRBC value of 10/100 WBC, there was an 88.9% sensitivity and a 90.8% specificity, with ROC curve showing an AUC of 0.9 and 0.914 for peak NRBC value in 14 days post-surgery and entire hospitalisation, respectively. CONCLUSIONS: NRBC ≥10/100 WBC post-cardiac surgery is strongly associated with mortality. Additionally, NRBC trend appears to show promise as an accurate biomarker for mortality.

Study on spoilage potential and its molecular basis of Shewanella putrefaciens in response to cold conditions by Label-free quantitative proteomic analysis.

To elucidate how Shewanella putrefaciens survives and produces spoilage products in response to cold conditions, the metabolic and protease activity of S. putrefaciens DSM6067 cultured at three different temperatures (30 °C, 10 °C, and 4 °C) was studied by determining the bacterial growth, total volatile basic nitrogen (TVB-N), biogenic amines, extracellular protease activity, as well as the differential expressed proteins via Label-free quantitative proteomics analysis. The lag phase of the strain cultured at 10 °C and 4 °C was about 20 h and 120 h longer than at 30 °C, respectively. The TVB-N increased to 89.23 mg N/100 g within 28 h at 30 °C, and it needed at least 72 h and 224 h at 10 °C and 4 °C, respectively. Cold temperatures (10 °C and 4 °C) also inhibited the yield factors and the extracellular protease activity per cell at the lag phase. However, the protease activity per cell and the yield factors of the sample cultivated at 10 °C and 4 °C well recovered, especially at the mid and latter stages of the log phase. The further quantitative proteomic analysis displayed a complex biological network to tackle cold stress: cold stress responses, nutrient uptake, and energy conservation strategy. It was observed that the protease and peptidase were upregulated, so as to the degradation pathways of serine, arginine, and aspartate, which might lead to the accumulation of spoilage products. This study highlighted the spoilage potential of S. putrefaciens still should be concerned even at low temperatures.

Development of cell-based high throughput luminescence assay for drug discovery in inhibiting OCT4/DNA-PKcs and OCT4-MK2 interactions.

Amplification-independent c-MYC overexpression is suggested in multiple cancers. Targeting c-MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c-MYC activity in cancer, we identified two kinases, MAPKAPK2 (MK2) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which phosphorylate the Ser111 and the Ser93 residues of OCT4, respectively, to transcriptionally activate c-MYC. Using these observations, we present here a novel cell-based luminescence assay to identify compounds that inhibit the interaction between these kinases and OCT4. After screening approximately 80,000 compounds, we identified 56 compounds ("hits") that inhibited the luminescence reaction between DNA-PKcs and OCT4, and 65 hits inhibiting the MK2-OCT4 interaction. Using custom antibodies specific for pOCT4S93 and pOCT4S111 , the "hits" were validated for their effect on OCT4 phosphorylation and activation. Using a two-step method for validation, we identified two candidate compounds from the DNA-PKcs assay and three from the MK2 assay. All five compounds demonstrate a significant ability to kill cancer cells in the nanomolar range. In conclusion, we developed a cell-based luminescence assay to identify novel inhibitors targeting c-MYC transcriptional activation, and have found five compounds that may function as lead compounds for further development.

Association of the All-Patient Refined Diagnosis-Related Groups Severity of Illness and Risk of Mortality Classification with Outcomes.

OBJECTIVES: Diagnosis-related groups (DRGs) is a patient classification system used to characterize the types of patients that the hospital manages and to compare the resources needed during hospitalization. The DRG classification is based on International Classification of Diseases diagnoses, procedures, demographics, discharge status, and complications or comorbidities and compares hospital resources and outcomes used to determine how much Medicare pays the hospital for each "product/medical condition." The All-Patient Refined DRG (APR-DRG) incorporated severity of illness (SOI) and risk of mortality (ROM) into the DRG system to adjust for patient complexity to compare resource utilization, complication rates, and lengths of stay. METHODS: This study included 18,478 adult patients admitted to a tertiary care center in Lubbock, Texas during a 1-year period. We recorded the APR-DRG SOI and ROM and some clinical information on these patients, including age, sex, admission shock index, admission glucose and lactate levels, diagnoses based on International Classification of Diseases, Tenth Revision discharge coding, length of stay, and mortality. We compared the levels of SOI and ROM across this clinical information. RESULTS: As the levels of SOI and ROM increase (which indicates increased disease severity and risk of mortality), age, glucose levels, lactate levels, shock index, length of stay, and mortality increased significantly (P < 0.001). Multiple logistic regression analysis demonstrated that each unit increase in ROM and SOI level was significantly associated with an 11.45 and a 10.37 times increase in the odds of in-hospital mortality, respectively. The C-statistics for the corresponding models are 0.947 and 0.929, respectively. When both ROM and SOI were included in the model, the magnitudes of increase in odds of in-hospital mortality were 5.61 and 1.17 times for ROM and SOI, respectively. The C-statistic is 0.949. CONCLUSIONS: This study indicates that the APR-DRG SOI and ROM scores provide a classification system that is associated with mortality and correlates with other clinical variables, such as the shock index and lactate levels, which are available on admission.

Effectiveness of sodium-glucose co-transporter-2 inhibitors on ischaemic heart disease.

AIM: To compare the cardiovascular risks between users and non-users of sodium-glucose co-transporter-2 (SGLT2) inhibitors based on electronic medical record data from a large integrated healthcare system in South Louisiana. MATERIALS AND METHODS: Demographic, anthropometric, laboratory and medication prescription information for patients with type 2 diabetes who were new users of SGLT2 inhibitors, either as initial treatments or as add-on treatments, were obtained from electronic health records. Mediation analysis was performed to evaluate the association of use of SGLT2 inhibitors and changes of metabolic risk factors with the risk of incident ischaemic heart disease. RESULTS: A total of 5338 new users of SGLT2 inhibitors were matched with 13 821 non-users. During a mean follow-up of 3.26 years, 2302 incident cases of ischaemic heart disease were defined. After adjusting for multiple confounding factors, patients using SGLT2 inhibitors had a lower risk of incident ischaemic heart disease compared to patients not using SGLT2 inhibitors (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.73). Patients using SGLT2 inhibitors also had a lower risk of incident ischaemic heart disease within 6 months (HR 0.36, 95% CI 0.25-0.44), 12 months (HR 0.40, 95% CI 0.32-0.49), 24 months (HR 0.53, 95% CI 0.43-0.60) and 36 months (HR 0.65, 95% CI 0.54-0.73), respectively. Reductions in systolic blood pressure partly mediated lowering risk of ischaemic heart disease among patients using SGLT2 inhibitors. CONCLUSIONS: The real-world data in the present study show the contribution of SGLT2 inhibitors to reducing risk of ischaemic heart disease, and their benefits beyond glucose-lowering.

Octahydro-Protoberberine and Protoemetine-Type Alkaloids from the Stems of Alangium salviifolium and Their Cytotoxicity.

Two octahydro-protoberberine alkaloids, alangiifoliumines A (1) and B (2), and two new protoemetine derivatives, alangiifoliumines C (3) and D (4), together with 11 known compounds, have been isolated from the stems of Alangium salviifolium. While the structures of these compounds were elucidated by spectroscopic methods, the absolute configurations of the new alkaloids were determined by conformational analysis and time-dependent density functional theory-electronic circular dichroism spectra calculations on selected stereoisomers. Compounds 1 and 2 represent the first 5,8,8a,9,12,12a,13,13a-octahydro-protoberberine derivatives, in which the aromatic ring D was reduced to cyclohexene. All the compounds isolated were evaluated for their cytotoxic activity against three human cancer cell lines: A-549, HeLa, and SKOV-3. Alkaloids 1, 3, and 6-14 exhibited inhibitory effects against all three human cancer cell lines, with half-maximal inhibitory concentration (IC50) values in the range of 3 nM to 9.4 µM.

Developmental programming: Sex-specific programming of growth upon prenatal bisphenol A exposure.

In both human and animals, in utero exposure to bisphenol A (BPA), an endocrine-disrupting chemical used in the production of plastics and epoxy resins, has been shown to affect offspring reproductive and metabolic health during adult life. We hypothesized that the effect of prenatal exposure to environmentally relevant doses of BPA will be evident during fetal organogenesis and fetal/postnatal growth trajectory. Pregnant ewes were administered BPA subcutaneously from 30 to 90 days of gestation (term 147 days). Fetal organ weight, anthropometric measures, maternal/fetal hormones and postnatal growth trajectory were measured in both sexes. Gestational BPA administration resulted in higher accumulation in male than female fetuses only at fetal day 65, with minimal impact on fetal/maternal steroid milieu in both sexes at both time points. BPA-treated male fetuses were heavier than BPA-treated female fetuses at fetal day 90 whereas this sex difference was not evident in the control group. At the organ level, liver weight was reduced in prenatal BPA-treated female fetuses, while heart and thyroid gland weights were increased in BPA-treated male fetuses relative to their sex-matched control groups. Prenatal BPA treatment also altered the postnatal growth trajectory in a sex-specific manner. Males grew slower during the early postnatal period and caught up later. Females, in contrast, demonstrated the opposite growth trend. Prenatal BPA-induced changes in fetal organ differentiation and early life growth strongly implicate translational relevance of in utero contributions to reproductive and metabolic defects previously reported in adult female offspring.

Flabellipparicine, a Flabelliformide-Apparicine-Type Bisindole Alkaloid from Tabernaemontana divaricata.

Four new monoterpenoid bisindole alkaloids, flabellipparicine (1), 19,20-dihydrovobparicine (2), 10'-demethoxy-19,20-dihydrovobatensine D (3), and 3'-(2-oxopropyl)ervahanine A (4), and 10 known monoterpenoid indole alkaloids were isolated from the stems of Tabernaemontana divaricata. All structures were elucidated based on spectroscopic methods, and the absolute configuration of 1 was established using conformational analysis and TDDFT-ECD calculation of selected stereoisomers. Compound 1 represents the first flabelliformide-apparicine-type bisindole alkaloid, in which the flabelliformide-like unit connects to the apparicine-like unit with a C-3-C-22' bond and an N-1-C-16' bond to form an uncommon five-membered ring between the two monomers. All alkaloids were evaluated for their cytotoxicity against two human cancer cell lines, MCF-7 and A-549. Compounds 2, 4, and 14 exhibited cytotoxicity against MCF-7 and A-549 with IC50 values in the range of 2 nM to 8 µM.

Three New Cytotoxic Monoterpenoid Bisindole Alkaloids from Tabernaemontana bufalina.

Three new bisindole alkaloids, 3'-(2-oxopropyl)-19,20-dihydrotabernamine (1: ), 3'-(2-oxopropyl)-ervahanine B (2: ), 19,20-dihydrovobparicine (3: ), and 20 known compounds were isolated from the aerial parts of Tabernaemontana bufalina. The structures of these alkaloids were elucidated using spectroscopic methods. The absolute configurations of 1: -3: were determined by the circular dichroic exciton chirality method. Compounds 1: -23: were screened for their cytotoxicity against two human cancer cell lines, A-549 and MCF-7. Ten compounds (1: -3, 10, 14, 16, 17, 19, 22: , and 23: ) exhibited inhibitory effects against the two human cancer cells with IC50 values of 1.19 ~ 6.13 µM.

A simulation-based sample size calculation method for pre-clinical tumor xenograft experiments.

Pre-clinical tumor xenograft experiments usually require a small sample size that is rarely greater than 20, and data generated from such experiments very often do not have censored observations. Many statistical tests can be used for analyzing such data, but most of them were developed based on large sample approximation. We demonstrate that the type-I error rates of these tests can substantially deviate from the designated rate, especially when the data to be analyzed has a skewed distribution. Consequently, the sample size calculated based on these tests can be erroneous. We propose a modified signed log-likelihood ratio test (MSLRT) to meet the type-I error rate requirement for analyzing pre-clinical tumor xenograft data. The MSLRT has a consistent and symmetric type-I error rate that is very close to the designated rate for a wide range of sample sizes. By simulation, we generated a series of sample size tables based on scenarios commonly expected in tumor xenograft experiments, and we expect that these tables can be used as guidelines for making decisions on the numbers of mice used in tumor xenograft experiments.

Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy.

Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells in vitro and in vivo and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.

A 12-week evaluation of annatto tocotrienol supplementation for postmenopausal women: safety, quality of life, body composition, physical activity, and nutrient intake.

BACKGROUND: Evidence suggests that tocotrienols may benefit bone health in osteopenic women. However, their safety in this population has never been investigated. This study was to evaluate the safety of a 12-week supplementation of annato tocotrienol in postmenopausal osteopenic women, along with effects of the supplementation on quality of life, body composition, physical activity, and nutrient intake in this population. METHODS: Eighty nine postmenopausal osteopenic women were randomly assigned to 3 treatment arms: (1) Placebo (430 mg olive oil/day), (2) Low tocotrientol (Low TT) (430 mg tocotrienol/day from DeltaGold 70 containing 300 mg tocotrienol) and (3) High tocotrienol (High TT) (860 mg tocotrienol/day from DeltaGold 70 containing 600 mg tocotrienol) for 12 weeks. DeltaGold 70 is an extract from annatto seed with 70% tocotrienol consisting of 90% delta-tocotrienol and 10% gamma-tocotrienol. Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, bilirubin, kidney function (blood urea nitrogen and creatinine), electrolytes, glucose, protein, albumin, and globulin at 0, 6, and 12 weeks. Serum tocotrienol and tocopherol concentrations were assessed and pills counted at 0, 6, and 12 weeks. Quality of life, body composition, physical activity, and dietary macro- and micro-nutrient intake were evaluated at 0 and 12 weeks. A mixed model of repeated measures ANOVA was applied for analysis. RESULTS: Eighty seven subjects completed the study. Tocotrienol supplementation did not affect liver or kidney function parameters throughout the study. No adverse event due to treatments was reported by the participants. Tocotrienol supplementation for 6 weeks significantly increased serum delta-tocotrienol level and this high concentration was sustained to the end of study. There was no difference in serum delta-tocotrienol levels between the Low TT and the High TT groups. No effects of tocotrienol supplementation were observed on quality of life, body composition, physical activity, and nutrient intake. CONCLUSIONS: Annatto-derived tocotrienol up to 600 mg per day for 12 weeks appeared to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. Tocotrienol supplementation for 12 weeks did not affect body composition, physical activity, quality of life, or intake of macro- and micro-nutrients in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02058420 . TITLE: Tocotrienols and bone health of postmenopausal women.

Study on the spoilage potential of Pseudomonas fluorescens on salmon stored at different temperatures.

The bacterial kinetics and quality indexes [sensory quality, total volatile basic nitrogen (TVB-N), thiobarbituric acid value, biogenic amine, and amino acids] were analyzed on salmon inoculated with Pseudomonas fluorescens during storage under different temperatures (30, 10, and 4 °C). The bacterial kinetics revealed that P. fluorescens showed a steady growth at low temperatures (10 and 4 °C). The TVB-N yield factors of the sample stored at 4 °C indicated that each bacterial cell of P. fluorescens displayed greater spoilage activity at low temperatures. A remarkable correlation was found between the production of biogenic amines and bacterial counts. The results also highlighted that P. fluorescens cultured at 4 °C had higher demand for amino acids.