Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting Platelets for the Treatment of Cancer

The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer.
Mycophenolic acid augments interferon‐stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo

Mycophenolic acid (MPA) is a highly effective immunosuppressant that has broad antiviral activity against different viruses and can act in synergy with interferon‐α (IFN‐α) on hepatitis C virus (HCV) replication. MPA is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor but the antiviral mechanisms are less understood. The aim of this study was to investigate the inhibition of HCV infection by MPA and the molecular basis for its synergy with IFN‐α. The role of IMPDH and interferon‐stimulated genes (ISGs) was investigated in two HCV models using gain‐ or loss‐of‐function approaches. The in vivo effect of MPA treatment was studied in NOD/SCID mice engrafted with HCV replicon cells. Potent antiviral effects of MPA at clinically relevant concentrations were observed with both the subgenomic and JFH1‐derived infectious HCV models. MPA treatment in mice resulted in a specific and robust inhibition of HCV replication. Ectopic expression of an MPA‐resistant IMPDH2 mutant in HCV host cells completely reversed the antiproliferative effect of MPA but only partially affected the antiviral potency. However, similar to ribavirin, MPA induced expression of multiple antiviral ISGs, including interferon regulatory factor 1 (IRF1). Cotreatment of MPA with IFN‐α resulted in additive effects on ISG expression and enhanced IFN‐induced luciferase reporter activity. Knockdown of IRF1, but not IFITM3, significantly attenuated the inhibition of HCV replication by MPA. Conclusion: MPA exerts a potent anti‐HCV effect in vitro and in mice and acts in synergy with IFN‐α. MPA's antiviral activity partially depends on IMPDH but also involves stimulation of ISGs, providing a molecular basis for its synergy with IFN‐α. (HEPATOLOGY 2012;55:1673–1683)
THE INHIBITORY ACTIVITY OF THE EXTRACTS OF POPULAR MEDICINAL HERBS ON CYP 1 A 2 , 2 C 9 , 2 C 19 AND 3 A 4 AND THE IMPLICATIONS FOR HERB-DRUG INTERACTION

Background: Studies have suggested an increasing practice of concurrent herb-drug consumption. One of the major clinical risks of such concomitant herb-drug use is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes. The aim of this study was to investigate the potential of the crude aqueous extracts of three popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes. Materials and Methods: The extracts of Bowiea volubilis, Spirostachys africana and Tulbaghia violacea were incubated with human liver microsomes (HLM) to monitor the phenacetin O-deethylation, diclofenac 4’-hydroxylation, S-mephenytoin 4’-hydroxylation and testosterone 6βhydroxylation as respective probe reactions for CYP1A2, CYP2C9, CYP2C19 and CYP3A4. The inhibitory activity, where observed, was profiled against the extract concentration. Results: Extracts of Bowiea volubilis inhibited the metabolic activity of CYP1A2 and CYP3A4 with IC50 values of 92.3 ± 5.5 g/mL and 8.1 ± 0.6 g/mL respectively. Similar observation with Spirostachys africana showed inhibitory activity against CYP1A2 and CYP3A4 with respective IC50 values of 14.3 ± 0.6 g/mL and 47.4 ± 2.4 g/mL. Tulbaghia violacea demonstrated relatively weak inhibitory activity against CYP1A2 (767.4 ± 10.8 g/mL) and CYP2C9 (921 ± 15.3 g/mL). Conclusion: The results suggest the potential for HDI between the herbs and the substrates of the affected enzymes, if sufficient in vivo concentration is attained.
Effective Factors in Urinary Tract Infection Prevention among Children: Application of Health Belief Model

Urinary Tract Infection (UTI) is one of the most common bacterial infections among children using preventive manipulations, especially among children less than 6 years old. This study aimed at exploring factors which could affect urinary tract infection prevention among children. A descriptive analytical study was conducted on 70 mothers who had children less than 6 years old in 2013. Multistage cluster sampling method was utilized in which each kindergarten was considered as a cluster and data were collected by a researcher-made questionnaire designed based on Health Belief Model (HBM). Validity and reliability of questionnaire were confirmed by a pilot study. ANOVA and Pearson Correlation Coefficient were conducted using SPSS, version 18. The mean and standard deviation of knowledge and practice were 6.96 ± 2.14 and 15.47 ± 1.54 respectively. Means and standard deviation of Health Belief Model constructs (perceived susceptibility, perceived severity, perceived benefits, perceived barriers and self-efficacy) were 17.64 ± 2.50, 22.02 ± 2.55, 20.90 ± 2.38, 27.56 ± 5.20 and 21.49 ± 3.18 respectively. More participants were in the moderate levels of knowledge (74.3%) and practice (45.7%). These findings revealed a significant relation between practice and perceived susceptibility (p = 0.02), perceived barriers (p = 0.001), self-efficacy (p = 0.014) and cues to action (p = 0.016). Based on the current study, the intervention based on Health Belief Model can be useful to improve preventive behaviors of Urinary Tract Infection.
Prevention of depression in at-risk adolescents: longer-term effects.

IMPORTANCE Adolescent offspring of depressed parents are at high risk for experiencing depressive disorders themselves. OBJECTIVE To determine whether the positive effects of a group cognitive-behavioral prevention (CBP) program extended to longer-term (multiyear) follow-up. DESIGN A 4-site randomized clinical trial with 33 months of follow-up was conducted. Recruitment of participants was from August 2003 through February 2006. SETTING The study settings included a health maintenance organization, university medical centers, and a community mental health center. PARTICIPANTS Three hundred sixteen adolescent (aged 13-17 years) offspring of parents with current and/or prior depressive disorders; adolescents had histories of depression, current elevated depressive symptoms, or both but did not currently meet criteria for a depressive disorder. INTERVENTIONS The CBP program consisted of 8 weekly 90-minute group sessions followed by 6 monthly continuation sessions. Adolescents were randomly assigned to either the CBP program or usual care (UC). MAIN OUTCOMES AND MEASURES The primary outcome was a probable or definite episode of depression (Depression Symptom Rating score ≥4) for at least 2 weeks through the month 33 follow-up evaluation. RESULTS Over the 33-month follow-up period, youths in the CBP condition had significantly fewer onsets of depressive episodes compared with those in UC. Parental depression at baseline significantly moderated the intervention effect. When parents were not depressed at intake, CBP was superior to UC (number needed to treat, 6), whereas when parents were actively depressed at baseline, average onset rates between CBP and UC were not significantly different. A 3-way interaction among intervention, baseline parental depression, and site indicated that the impact of parental depression on intervention effectiveness varied across sites. CONCLUSIONS AND RELEVANCE The CBP program showed significant sustained effects compared with UC in preventing the onset of depressive episodes in at-risk youth over a nearly 3-year period. Important next steps will be to strengthen the CBP intervention to further enhance its preventive effects, improve intervention outcomes when parents are currently depressed, and conduct larger implementation trials to test the broader public health impact of the CBP program for preventing depression in youth. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00073671.
The Medicago truncatula DMI1 Protein Modulates Cytosolic Calcium Signaling1[W][OA]

In addition to establishing symbiotic relationships with arbuscular mycorrhizal fungi, legumes also enter into a nitrogen-fixing symbiosis with rhizobial bacteria that results in the formation of root nodules. Several genes involved in the development of both arbuscular mycorrhiza and legume nodulation have been cloned in model legumes. Among them, Medicago truncatula DMI1 (DOESN'T MAKE INFECTIONS1) is required for the generation of nucleus-associated calcium spikes in response to the rhizobial signaling molecule Nod factor. DMI1 encodes a membrane protein with striking similarities to the Methanobacterium thermoautotrophicum potassium channel (MthK). The cytosolic C terminus of DMI1 contains a RCK (regulator of the conductance of K+) domain that in MthK acts as a calcium-regulated gating ring controlling the activity of the channel. Here we show that a dmi1 mutant lacking the entire C terminus acts as a dominant-negative allele interfering with the formation of nitrogen-fixing nodules and abolishing the induction of calcium spikes by the G-protein agonist Mastoparan. Using both the full-length DMI1 and this dominant-negative mutant protein we show that DMI1 increases the sensitivity of a sodium- and lithium-hypersensitive yeast (Saccharomyces cerevisiae) mutant toward those ions and that the C-terminal domain plays a central role in regulating this response. We also show that DMI1 greatly reduces the release of calcium from internal stores in yeast, while the dominant-negative allele appears to have the opposite effect. This work suggests that DMI1 is not directly responsible for Nod factor-induced calcium changes, but does have the capacity to regulate calcium channels in both yeast and plants.
The WALTHAM International Nutritional Sciences Symposia Foraging and Feeding Ecology of the Gray Wolf (Canis lupus): Lessons from Yellowstone National Park, Wyoming, USA

The foraging and feeding ecology of gray wolves is an essential component to understanding the role that top carnivores play in shaping the structure and function of terrestrial ecosystems. In Yellowstone National Park (YNP), predation studies on a highly visible, reintroduced population of wolves are increasing our understanding of this aspect of wolf ecology. Wolves in YNP feed primarily on elk, despite the presence of other ungulate species. Patterns of prey selection and kill rates in winter have varied seasonally each year from 1995 to 2004 and changed in recent years as the wolf population has become established. Wolves select elk based on their vulnerability as a result of age, sex, and season and therefore kill primarily calves, old cows, and bulls that have been weakened by winter. Summer scat analysis reveals an increased variety in diet compared with observed winter diets, including other ungulate species, rodents, and vegetation. Wolves in YNP hunt in packs and, upon a successful kill, share in the evisceration and consumption of highly nutritious organs first, followed by major muscle tissue, and eventually bone and hide. Wolves are adapted to a feast-or-famine foraging pattern, and YNP packs typically kill and consume an elk every 2–3 d. However, wolves in YNP have gone without fresh meat for several weeks by scavenging off old carcasses that consist mostly of bone and hide. As patterns of wolf density, prey density, weather, and vulnerability of prey change, in comparision with the conditions of the study period described here, we predict that there will also be significant changes in wolf predation patterns and feeding behavior. J. Nutr. 136: 1923S–1926S, 2006.
Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population.

OBJECT In this study the authors analyzed the relationship of intraventricular hemorrhage (IVH) to in-hospital complications and clinical outcome in a large population of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS Data from 3539 patients with aneurysmal SAH were evaluated, and these data were obtained from four prospective, randomized, double-blind, placebo-controlled trials of tirilazad that had been conducted between 1991 and 1997. Clinical characteristics, in-hospital complications, and outcome at 3 months post-SAH (Glasgow Outcome Scale score) were analyzed with regard to the presence or absence of IVH. RESULTS Patients with SAH and IVH differ in demographic and admission characteristics from those with SAH but without IVH and are more likely to suffer in-hospital complications and a worse outcome at 3 months post-SAH. CONCLUSIONS The presence of IVH in patients with SAH has an important predictive value with regard to these aspects.
T Cell Activation-Induced CrkII Binding to the Zap70 Protein Tyrosine Kinase Is Mediated by Lck-Dependent Phosphorylation of Zap70 Tyrosine 3151

The Zap70 protein tyrosine kinase controls TCR-linked signal transduction pathways and is critical for T cell development and responsiveness. Following engagement of TCR, the Zap70 undergoes phosphorylation on multiple tyrosine residues that are implicated in the regulation of its catalytic activity and interaction with signaling effector molecules downstream of the TCR. We have shown previously that the CT10 regulator of kinase II (CrkII) adapter protein interacts with tyrosine-phosphorylated Zap70 in TCR-engaged T cells, and now extend these studies to show that Tyr315 in the Zap70 interdomain B region is the site of interaction with CrkII. A point mutation of Tyr315 (Y315F) eliminated the CrkII-Zap70 interaction capacity. Phosphorylation of Tyr315 and Zap70 association with CrkII were both dependent upon the Lck protein tyrosine kinase. Previous studies demonstrated the Tyr315 is the Vav-Src homology 2 (SH2) binding site, and that replacement of Tyr315 by Phe impaired the function of Zap70 in TCR signaling. However, fluorescence polarization-based binding studies revealed that the CrkII-SH2 and the Vav-SH2 bind a phosphorylated Tyr315-Zap70-derived peptide with affinities of a similar order of magnitude (Kd of 2.5 and 1.02 μM, respectively). The results suggest therefore that the biological functions attributed to the association of Zap70 with Vav following T cell activation may equally reflect the association of Zap70 with CrkII, and further support a regulatory role for CrkII in the TCR-linked signal transduction pathway.
The effect of ICAD-S on the formation and intracellular distribution of a nucleolytically active caspase-activated DNase.

We show here that co-expression of murine CAD with either ICAD-L or ICAD-S in Escherichia coli as well as mammalian cells leads to a functional DFF complex, which after caspase-3 activation releases a nucleolytically active DNase. The chaperone activity of ICAD-S is between one and two orders of magnitude less effective than that of ICAD-L, as deduced from cleavage experiments with different activated recombinant DFF complexes produced in E.coli. With nucleolytically active EGFP fusion proteins of CAD it is demonstrated that co-expression of ICAD-S, which lacks the C-terminal domain of ICAD-L, including the NLS, leads to a homogeneous intracellular distribution of the DNase in transfected cells, whereas co-expression of human or murine ICAD-L variants lacking the NLS leads to exclusion of EGFP-CAD from the nuclei in approximately 50% of cells. These results attribute a particular importance of the NLS in the long isoform of the inhibitor of CAD for nuclear accumulation of the DFF complex in living cells. It is concluded that ICAD-L and ICAD-S in vivo might function as tissue-specific modulators in the regulation of apoptotic DNA degradation by controlling not only the enzymatic activity but also the amount of CAD available in the nuclei of mammalian cells.
Zolmitriptan Orally Disintegrating Tablet is Effective in the Acute Treatment of Migraine

A new formulation of zolmitriptan has been developed that dissolves on the tongue without the need for additional fluid intake. In this double-blind, parallel study, 471 patients were randomized to receive the zolmitriptan orally disintegrating tablet 2.5 mg(n=231) or matching placebo (n=240) to treat a single moderate or severe migraine. Headache relief following zolmitriptan 2.5 mg (63%) was significantly greater than with placebo (22%) at 2 h post-dose (primary endpoint; P < 0.0001). The zolmitriptan orally disintegrating tablet was also significantly more effective than placebo for 1-, 2- and 4-h pain-free response (8% vs. 3%, P =0.0207, 27% vs. 7%, P < 0.0001, and 37% vs. 11%, P < 0.0001, respectively). Of those patients stating a preference, 70% of patients preferred the orally disintegrating tablet to a conventional tablet. Zolmitriptan orally disintegrating tablets are an effective and convenient alternative to a conventional tablet, allowing migraine attacks to be treated anytime a migraine strikes, which can facilitate earlier treatment.
Molecular diagnostics for tuberculosis

Summary The phenotypic methods of smear microscopy, culture and indirect drug susceptibility testing (DST) remain the ‘gold standard’ diagnostics for tuberculosis (TB) in 2015. However, this review demonstrates that genotypic methods are in the ascendancy. Current-generation nucleic acid amplification tests (NAATs) are important supplementary tests for the rapid direct detection of (multidrug-resistant) TB in specific clinical settings. Genotypic detection is already the preferred method of detecting rifampicin and pyrazinamide resistance. Next-generation NAATs able to detect about 10 colony forming units/mL of sputum could replace culture as the initial test for detecting TB. Whole genome sequencing could also plausibly replace phenotypic DST but much work is required in method standardisation, database development and elucidation of all resistance gene determinants. The challenge then will be to rollout these increasingly complex and expensive diagnostics in the low-income countries where TB is prevalent.
Why (or why not), when and how to replicate research

© in this web service Cambridge University Press www.cambridge. org 21 The importance and prevalence of replication research varies greatly depending on the discipline and research area. In the so-called hard or pure sciences , for example, replication studies are common, and play an integral role in the process of testing and demonstrating the generalizability of crucial fi ndings. Gross ( 1997 ) notes two issues that support the need for replication studies in scientifi c disciplines. First, replication studies check the probability of error in the testing of null hypotheses, or the likelihood of a Type I or Type II error having been made. For instance, the probability for error in rejecting or accepting null hypotheses might have been affected by unrepresentative sampling or low numbers of participants. Thus, testing additional samples of the target population with the same methods provides supporting or contradictory evidence regarding the existence of a phenomenon. Second, replication studies are necessary to more effectively control for extraneous variables that might have confound ed the original fi ndings. As a result, replication contributes to increasing the explanatory power and generalizability of previous fi ndings in the “pure” sciences . In social sciences, such as sociology, psychology, and economics, as well as linguistics, conducting replication research contributes to “the essence of the scientifi c method” involving “observations that can be repeated and verifi ed by others” (American Psychological Association , 2010 : 4). Within social science research, some scholars believe a study is not complete until it has been replicated (Muma , 1993 : 927), yet results often prove diffi cult to reproduce. For example, according to Schneider , “a major problem in educational research is that investigators fi nd it diffi cult or are unable to replicate their work or that of their peers” (2004: 1472). This scarcity of replication and re-analysis of previous fi ndings undermines “the community’s ability to accumulate knowledge” (ibid.: 1473). Although calls have been made for more replications in many areas of the social sciences, including areas related to applied linguistics, such as speech and hearing research (Muma , 1993 ), research into how second languages are learned has only recently begun to be incorporated in replication studies. Why (or why not), when, and how to replicate research
The Effects of Sentiment on Market Return and Volatility and The Cross-Sectional Risk Premium of Sentiment-affected Volatility

We construct investor sentiment of UK stock market using the procedure of principal component analysis. Using sentiment-augmented EGARCH component model, we analyse the impacts of sentiment on market excess return, the permanent component of market volatility and the transitory component of market volatility. Bullish sentiment leads to higher market excess return while bearish sentiment leads to lower excess return. Sentiment-augmented EGARCH component model compares favourably to the original EGARCH component model which does not take investor sentiment into account. Furthermore, we test the cross-sectional risk premia of the permanent and transitory components of sentiment-affected volatility in the framework of ICAPM.
Androgen Deprivation Therapy and Future Alzheimer's Disease Risk.

PURPOSE To test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer's disease risk. METHODS We used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer's disease using 1:5 propensity score-matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer's disease risk. RESULTS There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow-up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score-matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer's disease risk. We also observed a statistically significant increased risk of Alzheimer's disease with increasing duration of ADT (P = .016). CONCLUSION Our results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer's disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence.