Inhibition of misfolded N-CoR induced survival pathway in APL by Artemisinin

Master'sMASTER OF SCIENC

Psychometric properties and measurement equivalence of the Multidimensional Fatigue Syndrome Inventory- Short Form (MFSI-SF) amongst breast cancer and lymphoma patients in Singapore.

BackgroundCurrently, several fatigue measurement instruments are available to evaluate and measure cancer-related fatigue. Amongst them, Multidimensional Fatigue Syndrome Inventory-Short Form (MFSI-SF) is a self-reported instrument and a multidimensional scale that aims to capture the global, somatic, affective, cognitive and behavioural symptoms of fatigue. This study examines the psychometric properties and measurement equivalence of the English and Chinese versions of MFSI-SF in breast cancer and lymphoma patients in Singapore.MethodsPatients were recruited from National Cancer Centre Singapore. Validity, reliability and responsiveness of MFSI-SF were evaluated in this study. Convergent validity was evaluated by correlating total and subscales of MFSI-SF to known related constructs in EORTC QLQ-C30. Known group validity was assessed based on patients' cancer stage, pain, insomnia and depression symptoms. Reliability was evaluated by Cronbach's α. Responsiveness analyses were performed with patients who have undergone at least one cycle of chemotherapy. Multiple regression was used to compare the total and subscale scores of MSFI-SF between the two language versions.ResultsData from 246 (160 English and 86 Chinese version) breast cancer and lymphoma patients were included in the study. Moderate to high correlations were observed between correlated MFSI-SF subscales and EORTC QLQ-C30 domains (|r| = 0.524 to 0.774) except for a poor correlation (r = 0.394) observed between MFSI-SF vigour subscale and EORTC QLQ-C30 role functioning subscale. Total MFSI-SF scores could differentiate between patients with higher depression, pain and insomnia status. Internal consistency of MFSI-SF was also high (α = 0.749 to 0.944). Moderate correlation was observed between change in total MFSI-SF score and change in fatigue symptom scale score and global QoL score on EORTC QLQ-C30 (|r| = 0.478 and 0.404 respectively). Poor correlations were observed between change in scores of hypothesised subscales (|r| = 0.202 to 0.361) except for a moderate correlation between change in MFSI-SF emotional fatigue score and change in EORTC QLQ-C30 emotional functioning domain score. Measurement equivalence was established for all subscales and total MFSI-SF score except for the emotional and vigour subscales.ConclusionsThis study supports the use of MFSI-SF as a reasonably valid scale with good internal consistency for measuring fatigue levels in the Singapore cancer population

Fucosyltransferase 1 and 2 play pivotal roles in breast cancer cells.

FUT1 and FUT2 encode alpha 1, 2-fucosyltransferases which catalyze the addition of alpha 1, 2-linked fucose to glycans. Glycan products of FUT1 and FUT2, such as Globo H and Lewis Y, are highly expressed on malignant tissues, including breast cancer. Herein, we investigated the roles of FUT1 and FUT2 in breast cancer. Silencing of FUT1 or FUT2 by shRNAs inhibited cell proliferation in vitro and tumorigenicity in mice. This was associated with diminished properties of cancer stem cell (CSC), including mammosphere formation and CSC marker both in vitro and in xenografts. Silencing of FUT2, but not FUT1, significantly changed the cuboidal morphology to dense clusters of small and round cells with reduced adhesion to polystyrene and extracellular matrix, including laminin, fibronectin and collagen. Silencing of FUT1 or FUT2 suppressed cell migration in wound healing assay, whereas FUT1 and FUT2 overexpression increased cell migration and invasion in vitro and metastasis of breast cancer in vivo. A decrease in mesenchymal like markers such as fibronectin, vimentin, and twist, along with increased epithelial like marker, E-cadherin, was observed upon FUT1/2 knockdown, while the opposite was noted by overexpression of FUT1 or FUT2. As expected, FUT1 or FUT2 knockdown reduced Globo H, whereas FUT1 or FUT2 overexpression showed contrary effects. Exogenous addition of Globo H-ceramide reversed the suppression of cell migration by FUT1 knockdown but not the inhibition of cell adhesion by FUT2 silencing, suggesting that at least part of the effects of FUT1/2 knockdown were mediated by Globo H. Our results imply that FUT1 and FUT2 play important roles in regulating growth, adhesion, migration and CSC properties of breast cancer, and may serve as therapeutic targets for breast cancer

Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.

ST3Gal1 is a key sialyltransferase which adds α2,3-linked sialic acid to substrates and generates core 1 O-glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1-silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF-β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC-MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O-glycans are sialyl-3T and disialyl-T. ST3GAL1-silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF-β1 by 2- to 3-fold and thereby dampening TGF-β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse-free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (p = 0.025, HR = 2.967, 95% CI = 1.14-7.67). Since TGF-β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF-β1 upregulates ST3Gal1 to circumvent the negative impact of VASN

Screening for Sarawak Paddy Landraces with Resistance to Yellow Rice Stem Borer, Scirpophaga incertulas (Walker) (Lepidoptera: Crambidae)

The yellow rice stem borer, Scirpophaga incertulas (Walker) is a prevalent pestin paddy fields worldwide. In Sarawak, a survey on pest of paddy carried out from 2009 to 2011 covering 166 paddy fields revealed that rice stem borers caused 11.4% of total paddy damage. In order to reduce the damage, identifying resistance paddy variety is crucial. The objective of this study was to screen Sarawak paddy landraces with resistance toS. incertulas. Twelve Sarawak paddy landraces were selected randomly for this study. Antixenosis resistance screening was performed in aquariums (60 x 28 x 33 cm). Three replications of one-month-old seedlings were randomly arranged in aquarium and exposed to adult S. incertulas. The number and position of egg mass on each plant were recorded. Egg mass abnormalities were also observed. For antibiosis, rice culms of two-month old seedlings from each landrace were infested with larvae. The length of surviving larvae from five rice culms was measured. The experiment revealed variations in landrace of preference for ovipositing. Among the twelve Sarawak paddy landraces, Kanowit was more preferred by S. incertulas for ovipositing in comparison to other paddy landraces suggesting susceptibility towards the pest. Abaxial leaf surface was the preferred oviposition site. There was no clear antibiosis response of the paddy landraces towards S. incertulas larvae in this study

Maritime threat response

This report was prepared by Systems Engineering and Analysis Cohort Nine (SEA-9) Maritime Threat Response, (MTR) team members.Background: The 2006 Naval Postgraduate School (NPS) Cross-Campus Integrated Study, titled “Maritime Threat Response” involved the combined effort of 7 NPS Systems Engineering students, 7 Singaporean Temasek Defense Systems Institute (TDSI) students, 12 students from the Total Ship Systems Engineering (TSSE) curriculum, and numerous NPS faculty members from different NPS departments. After receiving tasking provided by the Wayne E. Meyer Institute of Systems Engineering at NPS in support of the Office of the Assistant Secretary of Defense for Homeland Defense, the study examined ways to validate intelligence and respond to maritime terrorist attacks against United States coastal harbors and ports. Through assessment of likely harbors and waterways to base the study upon, the San Francisco Bay was selected as a representative test-bed for the integrated study. The NPS Systems Engineering and Analysis Cohort 9 (SEA-9) Maritime Threat Response (MTR) team, in conjunction with the TDSI students, used the Systems Engineering Lifecycle Process (SELP) [shown in Figure ES-1, p. xxiii ] as a systems engineering framework to conduct the multi-disciplinary study. While not actually fabricating any hardware, such a process was well-suited for tailoring to the team’s research efforts and project focus. The SELP was an iterative process used to bound and scope the MTR problem, determine needs, requirements, functions, and to design architecture alternatives to satisfy stakeholder needs and desires. The SoS approach taken [shown in Figure ES-2, p. xxiv ]enabled the team to apply a systematic approach to problem definition, needs analysis, requirements, analysis, functional analysis, and then architecture development and assessment.In the twenty-first century, the threat of asymmetric warfare in the form of terrorism is one of the most likely direct threats to the United States homeland. It has been recognized that perhaps the key element in protecting the continental United States from terrorist threats is obtaining intelligence of impending attacks in advance. Enormous amounts of resources are currently allocated to obtaining and parsing such intelligence. However, it remains a difficult problem to deal with such attacks once intelligence is obtained. In this context, the Maritime Threat Response Project has applied Systems Engineering processes to propose different cost-effective System of Systems (SoS) architecture solutions to surface-based terrorist threats emanating from the maritime domain. The project applied a five-year time horizon to provide near-term solutions to the prospective decision makers and take maximum advantage of commercial off-the-shelf (COTS) solutions and emphasize new Concepts of Operations (CONOPS) for existing systems. Results provided insight into requirements for interagency interactions in support of Maritime Security and demonstrated the criticality of timely and accurate intelligence in support of counterterror operations.This report was prepared for the Office of the Assistant Secretary of Defense for Homeland DefenseApproved for public release; distribution is unlimited

Comparison of Mortality Outcomes in Acute Myocardial Infarction Patients With or Without Standard Modifiable Cardiovascular Risk Factors

Background: Acute myocardial infarction (AMI) cases have decreased in part due to the advent of targeted therapies for standard modifiable cardiovascular disease risk factors (SMuRF). Recent studies have reported that ST-elevation myocardial infarction (STEMI) patients without SMuRF (termed "SMuRF-less") may be increasing in prevalence and have worse outcomes than "SMuRF-positive" patients. As these studies have been limited to STEMI and comprised mainly Caucasian cohorts, we investigated the changes in the prevalence and mortality of both SMuRF-less STEMI and non-STEMI (NSTEMI) patients in a multiethnic Asian population. Methods: We evaluated 23,922 STEMI and 62,631 NSTEMI patients from a national multiethnic registry. Short-term cardiovascular and all-cause mortalities in SMuRF-less patients were compared to SMuRF-positive patients. Results: The proportions of SMuRF-less STEMI but not of NSTEMI have increased over the years. In hospitals, all-cause and cardiovascular mortality and 1-year cardiovascular mortality were significantly higher in SMuRF-less STEMI after adjustment for age, creatinine, and hemoglobin. However, this difference did not remain after adjusting for anterior infarction, cardiopulmonary resuscitation (CPR), and Killip class. There were no differences in mortality in SMuRF-less NSTEMI. In contrast to Chinese and Malay patients, SMuRF-less patients of South Asian descent had a two-fold higher risk of in-hospital all-cause mortality even after adjusting for features of increased disease severity. Conclusion: SMuRF-less patients had an increased risk of mortality with STEMI, suggesting that there may be unidentified nonstandard risk factors predisposing SMuRF-less patients to a worse prognosis. This group of patients may benefit from more intensive secondary prevention strategies to improve clinical outcomes

Association between smoking status and outcomes in myocardial infarction patients undergoing percutaneous coronary intervention

Smoking is one of the leading risk factors for cardiovascular diseases, including ischemic heart disease and hypertension. However, in acute myocardial infarction (AMI) patients, smoking has been associated with better clinical outcomes, a phenomenon termed the “smoker’s paradox.” Given the known detrimental effects of smoking on the cardiovascular system, it has been proposed that the beneficial effect of smoking on outcomes is due to age differences between smokers and non-smokers and is therefore a smoker’s pseudoparadox. The aim of this study was to evaluate the association between smoking status and clinical outcomes in ST-segment elevation (STEMI) and non-STEMI (NSTEMI) patients treated by percutaneous coronary intervention (PCI), using a national multi-ethnic Asian registry. In unadjusted analyses, current smokers had better clinical outcomes following STEMI and NSTEMI. However, after adjusting for age, the protective effect of smoking was lost, confirming a smoker’s pseudoparadox. Interestingly, although current smokers had increased risk for recurrent MI within 1 year after PCI in both STEMI and NSTEMI patients, there was no increase in mortality. In summary, we confirm the existence of a smoker’s pseudoparadox in a multi-ethnic Asian cohort of STEMI and NSTEMI patients and report increased risk of recurrent MI, but not mortality, in smokers