Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F. hepatica. We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation- all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1. Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni. Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro. In summary, this work demonstrates that the proliferating cells of F. hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.

Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.

Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Operating on the Mesentery in Robotic Colonic Surgery-General Techniques.

During colorectal surgery the mesentery is the organ on which the greatest amount of operating time is focused. It has recently gained increasing attention. This technical review focuses on the mesentery during robotic colonic procedures. Specifically, we focus upon how to access, dissect, and divide the mesentery using the robotic platform. We also touch on the management of bleeding and some specific disease etiologies.

What Is Wrong with the International Holocaust Remembrance Alliance's Definition of Antisemitism?

The International Holocaust Remembrance Alliance (IHRA) developed a 'Working Definition of Antisemitism' in 2016. Whilst the definition has received a significant amount of media attention, we are not aware of any comprehensive philosophical analysis. This article analyses this definition. We conclude that the definition and its list of examples ought to be rejected. The urgency to do so stems from the fact that pro-Israel activists can and have mobilised the IHRA document for political goals unrelated to tackling antisemitism, notably to stigmatise and silence critics of the Israeli government. This causes widespread self-censorship, has an adverse impact on freedom of speech, and impedes action against the unjust treatment of Palestinians. We also identify intrinsic problems in the way the definition refers to criticism of Israel similar 'to that leveled against any other country', ambiguous wording about 'the power of Jews as a collective', lack of clarity as to the Jewish people's 'right to self-determination', and its denial of obvious racism. We consider alternative definitions and prefer one like the Oxford English Dictionary (OED) definition, 'hostility to or prejudice against Jews', with the addition of the words 'as Jews'. We recognise that the Jerusalem Declaration on Antisemitism (JDA) can play a useful purpose in illustrating the shortcomings of the IHRA definition. However, we do not advocate promoting it as the prime international definition. Indeed, we question the efficacy of using complex new definitions to combat racism against Jews or other groups, and instead advocate combatting it through collective action across societies.

Formulating RALA/Au nanocomplexes to enhance nanoparticle internalisation efficiency, sensitising prostate tumour models to radiation treatment.

BACKGROUND: Gold nanoparticles (AuNP) are effective radiosensitisers, however, successful clinical translation has been impeded by short systemic circulation times and poor internalisation efficiency. This work examines the potential of RALA, a short amphipathic peptide, to enhance the uptake efficiency of negatively charged AuNPs in tumour cells, detailing the subsequent impact of AuNP internalisation on tumour cell radiation sensitivity. RESULTS: RALA/Au nanoparticles were formed by optimising the ratio of RALA to citrate capped AuNPs, with assembly occurring through electrostatic interactions. Physical nanoparticle characteristics were determined by UV-vis spectroscopy and dynamic light scattering. Nano-complexes successfully formed at w:w ratios > 20:1 (20 µg RALA:1 µg AuNP) yielding positively charged nanoparticles, sized < 110 nm with PDI values < 0.52. ICP-MS demonstrated that RALA enhanced AuNP internalisation by more than threefold in both PC-3 and DU145 prostate cancer cell models, without causing significant toxicity. Importantly, all RALA-AuNP formulations significantly increased prostate cancer cell radiosensitivity. This effect was greatest using the 25:1 RALA-AuNP formulation, producing a dose enhancement effect (DEF) of 1.54 in PC3 cells. Using clinical radiation energies (6 MV) RALA-AuNP also significantly augmented radiation sensitivity. Mechanistic studies support RALA-AuNP nuclear accumulation resulting in increased DNA damage yields. CONCLUSIONS: This is the first study to demonstrate meaningful radiosensitisation using low microgram AuNP treatment concentrations. This effect was achieved using RALA, providing functional evidence to support our previous imaging study indicating RALA-AuNP nuclear accumulation.

Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50, significantly decreased colony formation, induced apoptosis and slowed spheroid growth in vitro. In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up and in vivo application. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.

Prenatal stress enhances NNK-induced lung tumors in A/J mice.

Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.

TET1 regulates DNA repair in human glial cells.

Glioblastomas are the most aggressive of malignant brain cancers with a median patient survival of approximately 18 months. We recently demonstrated that Tet methylcytosine dioxygenase 1(TET1) is involved in cellular responses to ionizing radiation (IR) in glial-, glioblastoma-, and non-tumor-derived cells. This study used a lentiviral-mediated knockdown of TET1 to further dissect the contribution of TET1 to the DNA damage response in glial cell lines by evaluating its role in DNA repair. TET1-deficient glial cell lines displayed attenuated cytotoxicity compared to non-targeted knockdown after treatment with IR but these differences were not observed between control and TET1 deficient in response to inhibitors of Na+/K+-ATPase. Additionally, the percentage of glial cells displaying γH2A.x foci was greatly reduced in TET1-deficient glial cells compared to non-targeted knockdown conditions in response to IR and topoisomerase inhibitors. We also observed a lower percentage and a delay in 53BP1 foci formation, a marker of non-homologous end-joining, in response to IR and topoisomerase inhibitors in TET1-deficient glial cells. DNA-PK, another marker of non-homologous end-joining, was also lower in TET1-deficient glial cell lines. Interestingly, TET1-deficient glial cells displayed higher numbers of DNA strand breaks compared to control cells and repaired DNA breaks less efficiently in Comet assays. We suggest that attenuated DNA repair in TET1 deficient gliomas leads to genomic instability, which underlies poor patient survival.

Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer.

Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model.Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 × 8 Gy)±local HT, mild (HTM, 43 °C/20 min) or partially ablative (HTAbl, 45 °C/5 min plus 43 °C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 × 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases.Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT + HTM+IT, RT + HTAbl+IT and RT + HTAbl had similar or smaller tumors. These cohorts showed more infiltration of CD3+ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT + IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment.Conclusions: Single-fraction MION HT added to RT + IT improved local tumor control and recruitment of CD3+ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT + IT showed potential to increase metastatic dissemination to lungs.

Association of White Matter Hyperintensities With Short-Term Outcomes in Patients With Minor Cerebrovascular Events.

BACKGROUND AND PURPOSE: White matter lesions (WML) are associated with cognitive decline, increased stroke risk, and disability in old age. We hypothesized that superimposed acute cerebrovascular occlusion on chronic preexisting injury (leukoaraiosis) leads to worse outcome after minor cerebrovascular event, both using quantitative (volumetric) and qualitative (Fazekas scale) assessment, as well as relative total brain volume. METHODS: WML volume assessment was performed in 425 patients with high-risk transient ischemic attack (TIA; motor/speech deficits >5 minutes) or minor strokes from the CATCH study (CT and MRI in the Triage of TIA and Minor Cerebrovascular Events to Identify High Risk Patients). Complete baseline characteristics and outcome assessment were available in 412 patients. Primary outcome was disability at 90 days, defined as modified Rankin Scale score of >1. Secondary outcomes were stroke progression, TIA recurrence, and stroke recurrence. Analysis was performed using descriptive statistics and regression models including interaction terms. RESULTS: Median age was 69 years, 39.8% were female. Sixty-two patients (15%) had unfavorable outcome with disability at 90 days (modified Rankin Scale score >1). Higher Fazekas scores were strongly correlated with higher WML volume (r=0.79). Both higher Fazekas score and higher WMH volume were associated with disability at 90 days in univariate regression (odds ratio 1.22; 95% confidence interval, 1.04-1.43 and odds ratio, 1.25 per milliliter increase; 95% confidence interval, 1.02-1.54, respectively) but not with stroke progression, TIA recurrence, or stroke recurrence. In multivariable-adjusted analyses, additive interaction terms were associated with unfavorable outcome (adjusted odds ratio 3.99, 95% confidence interval, 1.87-8.49). CONCLUSIONS: Our data suggest that quantitative and qualitative WML assessments are highly correlated and comparable in TIA/minor stroke patients. WML burden is associated with short-term outcome of patients with good prestroke function in the presence of intracranial stenosis/occlusion.

Unraveling the cell-type dependent radiosensitizing effects of gold through the development of a multifunctional gold nanoparticle.

The radiosensitizing efficacy of gold is well established, however, there remain several significant barriers to the successful clinical translation of nano-sized gold particles (AuNPs). These barriers include: retaining stability in relevant biological sera, demonstrating effectiveness at clinically relevant AuNP concentrations and identifying the biological context where significant benefit is most likely to be achieved. Herein we have developed a AuNP preparation, stress-tested to provide effective protection from salt and serum mediated agglomeration. Furthermore, the core AuNP is co-functionalized with two biologically derived peptides designed to enhance endocytosis and promote endosomal escape, thus maximizing intracellular AuNP surface area. In summary, these investigations demonstrate restored AuNP internalization using the co-functionalized preparation that generated significant radiosensitization, in both in vitro and in vivo models, at clinically viable treatment concentrations. Furthermore, we have identified an underpinning biological mechanism in the inherent radical scavenging capacity that could be used to predict radiosensitizing efficacy.

A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation.

MicroRNAs (miRNAs) have been implicated in DNA repair pathways through transcriptional responses to DNA damaging agents or through predicted miRNA regulation of DNA repair genes. We hypothesized that additional DNA damage regulating miRNAs could be identified by screening a library of 810 miRNA mimetics for the ability to alter cellular sensitivity to ionizing radiation (IR). A prostate cancer Metridia luciferase cell model was applied to examine the effects of individual miRNAs on IR sensitivity. A large percentage of miRNA mimetics were found to increase cellular sensitivity to IR, while a smaller percentage were protective. Two of the most potent IR sensitizing miRNAs, miR-890 and miR-744-3p, significantly delayed IR induced DNA damage repair. Both miRNAs inhibited the expression of multiple components of DNA damage response and DNA repair. miR-890 directly targeted MAD2L2, as well as WEE1 and XPC, where miR-744-3p directly targeted RAD23B. Knock-down of individual miR-890 targets by siRNA was not sufficient to ablate miR-890 radiosensitization, signifying that miR-890 functions by regulating multiple DNA repair genes. Intratumoral delivery of miR-890 mimetics prior to IR therapy significantly enhanced IR therapeutic efficacy. These results reveal novel miRNA regulation of DNA repair and identify miR-890 as a potent IR sensitizing agent.

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

BACKGROUND: Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS: GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS: GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS: The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis.

Bromopyridone Nucleotide Analogues, Anoxic Selective Radiosensitizing Agents That Are Incorporated in DNA by Polymerases.

Ionizing radiation is frequently used to kill tumor cells. However, hypoxic solid tumor cells are more resistant to this treatment, providing the impetus to develop molecules that sensitize cells to ionizing radiation. 5-Bromo-2'-deoxyuridine (BrdU) has been investigated as a radiosensitizing agent in the lab and clinic for almost 5 decades. Recent reports that BrdU yields DNA interstrand cross-links (ICLs) in non-base-paired regions motivated us to develop radiosensitizing agents that generate cross-links in duplex DNA selectively under anoxic conditions. 4-Bromo- and 5-bromopyridone analogues of BrdU were synthesized and incorporated into oligonucleotides via solid-phase synthesis. Upon irradiation, these molecules yield DNA interstrand cross-links under anaerobic conditions. The respective nucleotide triphosphates are substrates for some DNA polymerases. ICLs are produced upon irradiation under anoxic conditions when the 4-bromopyridone is present in a PCR product. Because the nucleoside analogue is a poor phosphorylation substrate for human deoxycytidine kinase, a pro-nucleotide form of the 4-bromopyridone was used to incorporate this analogue into cellular DNA. Despite these efforts, the 4-bromopyridone nucleotide was not detected in cellular DNA. Although these molecules are improvements over previously reported nucleotide analogues designed to be hypoxic radiosensitizing agents, additional advances are needed to create molecules that function in cells.

Hydroquinone increases 5-hydroxymethylcytosine formation through ten eleven translocation 1 (TET1) 5-methylcytosine dioxygenase.

DNA methylation regulates gene expression throughout development and in a wide range of pathologies such as cancer and neurological disorders. Pathways controlling the dynamic levels and targets of methylation are known to be disrupted by chemicals and are therefore of great interest in both prevention and clinical contexts. Benzene and its metabolite hydroquinone have been shown to lead to decreased levels of DNA methylation, although the mechanism is not known. This study employs a cell culture model to investigate the mechanism of hydroquinone-mediated changes in DNA methylation. Exposures that do not affect HEK293 cell viability led to genomic and methylated reporter DNA demethylation. Hydroquinone caused reactivation of a methylated reporter plasmid that was prevented by the addition of N-acetylcysteine. Hydroquinone also caused an increase in Ten Eleven Translocation 1 activity and global levels of 5-hydroxymethylcytosine. 5-Hydroxymethylcytosine was found enriched at LINE-1 prior to a decrease in both 5-hydroxymethylcytosine and 5-methylcytosine. Ten Eleven Translocation-1 knockdown decreased 5-hydroxymethylcytosine formation following hydroquinone exposure as well as the induction of glutamate-cysteine ligase catalytic subunit and 14-3-3σ. Finally, Ten Eleven Translocation 1 knockdown decreased the percentage of cells accumulating in G2+M following hydroquinone exposure, indicating that it may have a role in cell cycle changes in response to toxicants. This work demonstrates that hydroquinone exposure leads to active and functional DNA demethylation in HEK293 cells in a mechanism involving reactive oxygen species and Ten Eleven Translocation 1 5-methylcytosine dioxygenase.

Induction of a trophoblast-like phenotype by hydralazine in the p19 embryonic carcinoma cell line.

Chemicals that affect cellular differentiation through epigenetic mechanisms have potential utility in treating a wide range of diseases. Hydralazine decreases DNA methylation in some cell types but its effect on differentiation has not been well explored. After five days of exposure to hydralazine, P19 embryocarcinoma cells displayed a giant cell morphology and were binucleate, indicative of a trophoblast-like morphology. Other trophoblast-like properties included the intermediary filament Troma-1/cytokeratin 8 and the transcription factor Tead4. A decrease in CpG methylation at three sites in the TEAD4 promoter and the B1 repeated sequence was observed. Knocking down expression of Tead4 with siRNA blocked the increase in Troma-1/cytokeratin 8 and over expression of Tead4 induced the expression of Troma-1/cytokeratin 8. Cells treated for 5days with hydralazine were no longer capable of undergoing retinoic acid-mediated neuronal differentiation. An irreversible loss of the pluripotent transcription factor Oct-4 was observed following hydralazine exposure. In summary, hydralazine induces P19 cells to assume a trophoblast-like phenotype by upregulating Tead4 expression through a mechanism involving DNA demethylation.

Acute ischaemic stroke or transient ischaemic attack and the need for inpatient echocardiography.

OBJECTIVES: To determine the diagnostic yield of echocardiography and its utility in changing medical management; and to derive a risk score to guide its use in patients with in-hospital stroke or transient ischaemic attack (TIA). METHODS: We carried out a retrospective chart review from January 2009 to June 2010 of patients with acute ischaemic stroke or TIA who had undergone transthoracic echocardiography (TTE) or transoesophageal echocardiography (TOE). Clinical and imaging findings at baseline were noted and 'potential clinically relevant findings' identified on TTE and TOE. A multivariable logistic regression was used to identify predictors of potential clinically relevant findings on TTE or TOE and derive a risk score. RESULTS: Of 370 patients, 307 (83.0%) had TTE and 63 (17.0%) had additional TOE. Potential clinically relevant findings on echocardiography were noted in 28 (7.6%) patients. Change in medical management was noted in 19/307 (6.2%) patients on TTE and in 7/63 (11.1%) patients on TOE. Male sex (OR 3.05, 95% CI 1.19 to 7.84; p=0.021), abnormal admission ECG (OR 4.39, 95% CI 1.79 to 10.79; p=0.001), and embolic pattern imaging at baseline (OR 2.38, 95% CI 1.05 to 5.40; p=0.038) were independent predictors of findings on TTE or TOE. A risk score including these three variables had modest discrimination (c-statistic 0.69, 95% CI 0.59 to 0.80). CONCLUSIONS: Echocardiography detected potential clinically relevant findings in a minority of patients (7.6%), but these findings changed medical management 90.5% of the time. A risk score using sex, ECG abnormality, and embolic pattern imaging at baseline could help predict which patients are more likely to have these echo findings.

High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells.

Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 contribute to the ability of breast cancer cells to tolerate this aneuploidy. Reducing Mps1 levels in cultured human breast cancer cells by RNAi resulted in aberrant mitoses, induction of apoptosis, and decreased ability of human breast cancer cells to grow as xenografts in nude mice. Remarkably, breast cancer cells that survive reductions in levels of Mps1 have relatively less aneuploidy, as measured by copies of specific chromosomes, compared with cells that have constitutively high levels of Mps1. Thus, high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy.

A systematic review and meta-analysis assessing the use of tranexamic acid (TXA) in acute gastrointestinal bleeding.

INTRODUCTION: Gastrointestinal bleeding results in significant morbidity, cost and mortality. TXA, an antifibrinolytic agent, has been proposed to reduce mortality; however, many studies report conflicting results. METHODS: The aim of the study was to perform the first systematic review and meta-analysis of RCTs to evaluate the efficacy TXA for both upper and lower gastrointestinal bleeding. This was performed per PRISMA guidelines. PubMed, EMBASE, Cochrane and Scopus databases were searched for RCTs. Dichotomous variables were pooled as risk ratios (RR) with 95% confidence intervals (CI) using the MH method with random effects modelling. RESULTS: Fourteen RCTs were identified with 14,338 patients and mean age of 58.4 years. 34.9% (n = 5008) were female and 65.1% (n = 9330) male. There was no significant difference in mortality between TXA and placebo (RR 0.86 95% CI (0.74 to 1.00), P: 0.05). The secondary outcomes, similarly, did not yield significant results. These included rebleeding, need for surgical intervention (RR: 0.75 95% CI (0.53, 1.07)), endoscopic intervention (RR: 0.92 95% CI (0.70, 1.22)), transfusion requirement (RR: 1.01 95% CI (0.94, 10.7)) and length of stay (RR: 0.03 95% CI (- 0.03, 0.08)). There was no increased risk of VTE, RR: 1.29 95% CI (0.53, 3.16). One trial (n = 12,009) reported an increased risk of seizure in the TXA group, RR: 1.73 95% CI (1.03-2.93). CONCLUSION: TXA does not reduce mortality in patients with acute upper or lower gastrointestinal bleeding and may confer an increased risk of seizures. The authors do not recommend the use of TXA in acute gastrointestinal bleeding.