Miracle-dz/UniFAR-FTUs huggingface dataset:
Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Significance How receptor for hyaluronan-mediated motility (RHAMM) expression is regulated, how statins exert anticancer effects, and what roles mevalonate and Hippo pathways play in tumors are important issues in cancer biology. We find that the two pathways converge onto Yes-associated protein (YAP)/TEAD to control RHAMM transcription leading to ERK activation and cancer metastasis, which is inhibited by simvastatin. YAP/TEAD binds RHAMM promoter at specific sites to activate RHAMM transcription, and mevalonate/simvastatin affects RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic distribution. These in vitro and in vivo findings identify a mechanism regulating RHAMM expression and cancer metastasis wherein RHAMM is a downstream effector of mevalonate/Hippo pathways, and a YAP/TEAD-transcription and simvastatin-inhibition target, revealing interesting interplay of the pathways and potential targets for cancer therapeutic agents. Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.
Benefits of Psychological Preparation for Surgery: a Meta-Analysis

There is now substantial agreement that psychological preparation for surgery is beneficial to patients. It is important, however, to establish which benefits can be achieved by psychological preparation and if all forms of preparation are equally effective. The results of randomized controlled trials of psychological methods of preparing adult patients for surgery were analyzed in terms of eight outputs (negative affect, pain, pain medication, length of stay, behavioral and clinical indices of recovery, physiological indices, and satisfaction). In order to reduce publication bias, published as well as unpublished studies were included in the meta-analysis. It was concluded that significant benefits can be obtained on all of the major outcome variables that have been explored. Procedural information and behavioral instructions show the most ubiquitous effects in improving measures of postoperative recovery. The results have implications for the improvement of patient care in surgical units.
Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle

Significance Caulobacter crescentus, a bacterium with an inherent asymmetric cell division, uses dynamic changes in chromosome methylation state to synchronize chromosome replication with cell-cycle regulation. We identified the N6-methyladenine and 5-methylcytosine methylation state of every base pair at five times in the cell cycle to show that 4,515 GANTC sites, recognized by the CcrM methyltransferase, change from full- to hemimethylation upon passage of the replication fork. Significantly, 27 of the GANTC sites are protected from methylation at all times. We also identified four previously unknown methylation motifs and the cognate methyltransferase for two of these motifs. The ability to track the state of the methylome in exquisite temporal detail will be invaluable to investigations of microbial epigenetic regulation. The Caulobacter DNA methyltransferase CcrM is one of five master cell-cycle regulators. CcrM is transiently present near the end of DNA replication when it rapidly methylates the adenine in hemimethylated GANTC sequences. The timing of transcription of two master regulator genes and two cell division genes is controlled by the methylation state of GANTC sites in their promoters. To explore the global extent of this regulatory mechanism, we determined the methylation state of the entire chromosome at every base pair at five time points in the cell cycle using single-molecule, real-time sequencing. The methylation state of 4,515 GANTC sites, preferentially positioned in intergenic regions, changed progressively from full to hemimethylation as the replication forks advanced. However, 27 GANTC sites remained unmethylated throughout the cell cycle, suggesting that these protected sites could participate in epigenetic regulatory functions. An analysis of the time of activation of every cell-cycle regulatory transcription start site, coupled to both the position of a GANTC site in their promoter regions and the time in the cell cycle when the GANTC site transitions from full to hemimethylation, allowed the identification of 59 genes as candidates for epigenetic regulation. In addition, we identified two previously unidentified N6-methyladenine motifs and showed that they maintained a constant methylation state throughout the cell cycle. The cognate methyltransferase was identified for one of these motifs as well as for one of two 5-methylcytosine motifs.
Insulin resistance and vascular dysfunction in chronic kidney disease: mechanisms and therapeutic interventions

Insulin resistance (IR) is a novel cardiovascular risk factor that has been implicated in the pathogenesis of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Beyond its metabolic effects, insulin can potentially mediate the increased risk for CVD through its vasoactive properties. This review examines key clinical data and potential mechanisms linking IR and cardiovascular risk in CKD. While lifestyle interventions and pharmacotherapies with known insulin-sensitizing properties are promising therapeutic targets to reduce the CVD burden in this population, clinical trial data on the effect of insulin sensitization on vascular function in CKD are either lacking or conflicting and are limited by small sample size and short duration of intervention. Affirming the role of IR in lowering CVD risk in CKD will require prospective randomized controlled studies with sufficient sample size and hard clinical outcomes. Future research efforts should be directed at assessing the efficacy, safety and mechanisms by which novel insulin sensitizers such as bile acid sequestrant, selective and dual peroxisome proliferator-activated receptor modulators and modulators of gut microbiota and uraemic toxins alter vascular function in patients with CKD.
The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA Registry.

BACKGROUND This study examines the time trends in incidence, prevalence, patient and kidney allograft survival and causes of death (COD) in patients receiving renal replacement therapy (RRT) in Europe. METHODS Eighteen national or regional renal registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry between 1998 and 2011 were included. Incidence and prevalence time trends between 2001 and 2011 were studied with Joinpoint and Poisson regression. Patient and kidney allograft survival and COD between 1998 and 2011 were analysed using Kaplan-Meier and competing risk methods and Cox regression. RESULTS From 2001 to 2008, the adjusted incidence of RRT rose by 1.1% (95% CI: 0.6, 1.7) annually to 131 per million population (pmp). During 2008-2011, the adjusted incidence fell by 2.2% (95% CI: -4.2, -0.2) annually to 125 pmp. This decline occurred predominantly in patients aged 45-64 years, 65-74 years and in the primary renal diseases diabetes mellitus type 1 and 2, renovascular disease and glomerulonephritis. Between 2001 and 2011, the overall adjusted prevalence increased from 724 to 1032 pmp (+3.3% annually, 95% CI: 2.8, 3.8). The adjusted 5-year patient survival on RRT improved between 1998-2002 and 2003-2007 [adjusted hazard ratio (HRa) 0.85, 95% CI: 0.84, 0.86]. Comparing these time periods, the risk of cardiovascular deaths fell by 25% (HRa 0.75, 95% CI: 0.74, 0.77). However the risk of malignant death rose by 9% (HRa 1.09, 95% CI: 1.03, 1.16) in patients ≥65 years. CONCLUSION This European study shows a declining RRT incidence, particularly in patients aged 45-64 years, 65-74 years and secondary to diabetic nephropathy. Encouragingly, the adjusted RRT patient survival continues to improve. The risk of cardiovascular death has decreased, though the risk of death from malignancy has increased in the older population.
The epidemiology of EBV and its association with malignant disease

Epstein-Barr virus (EBV) is an ancient virus, and has probably coevolved with its different hosts over the last 90–100 million years (McGeoch et al., 1995). With the ability to establish lifelong latency and intermittent reactivation after primary infection and with limited clinical symptoms in the majority of infected individuals, EBV has become ubiquitous in all human populations
Prevalence of Earth-size planets orbiting Sun-like stars

Significance A major question is whether planets suitable for biochemistry are common or rare in the universe. Small rocky planets with liquid water enjoy key ingredients for biology. We used the National Aeronautics and Space Administration Kepler telescope to survey 42,000 Sun-like stars for periodic dimmings that occur when a planet crosses in front of its host star. We found 603 planets, 10 of which are Earth size and orbit in the habitable zone, where conditions permit surface liquid water. We measured the detectability of these planets by injecting synthetic planet-caused dimmings into Kepler brightness measurements. We find that 22% of Sun-like stars harbor Earth-size planets orbiting in their habitable zones. The nearest such planet may be within 12 light-years. Determining whether Earth-like planets are common or rare looms as a touchstone in the question of life in the universe. We searched for Earth-size planets that cross in front of their host stars by examining the brightness measurements of 42,000 stars from National Aeronautics and Space Administration’s Kepler mission. We found 603 planets, including 10 that are Earth size () and receive comparable levels of stellar energy to that of Earth (). We account for Kepler’s imperfect detectability of such planets by injecting synthetic planet–caused dimmings into the Kepler brightness measurements and recording the fraction detected. We find that 11 ± 4% of Sun-like stars harbor an Earth-size planet receiving between one and four times the stellar intensity as Earth. We also find that the occurrence of Earth-size planets is constant with increasing orbital period (P), within equal intervals of logP up to ∼200 d. Extrapolating, one finds % of Sun-like stars harbor an Earth-size planet with orbital periods of 200–400 d.
The Radial Distribution Functions of Water as Derived from Radiation Total Scattering Experiments: Is There Anything We Can Say for Sure?

The present paper reviews the investigation of ambient water structure and focusses in particular on the determination of the radial distribution functions of water from total experimental radiation scattering experiments. A novel method for removing the inelastic scattering from neutron data is introduced, and the effect of Compton scattering on X-ray data is discussed. In addition the extent to which quantum effects can be discerned between heavy and light water is analysed against these more recent data. It is concluded that, with the help of modern data analysis and computer simulation tools to interrogate the scattering data, a considerable degree of consistency can be obtained between recent and past scattering experiments on water. That consistency also gives a realistic estimate of the likely uncertainties in the extracted radial distribution functions, as well as offering a benchmark against which future experiments can be judged.
Suppression of the hepcidin‐encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase‐2/TMPRSS6

Hepcidin, the master regulator of enteric iron absorption, is controlled by the opposing effects of pathways activated in response to iron excess or iron attenuation. Iron excess is regulated through a pathway involving the cell surface receptor hemojuvelin (HFE2) that stimulates expression of the hepcidin encoding gene (HAMP). Iron attenuation is countered through a pathway involving the hepatocyte‐specific plasma membrane protease matriptase‐2 encoded by TMPRSS6, leading to suppression of HAMP expression. The non‐redundant function of hemojuvelin and matriptase‐2 has been deduced from the phenotype imparted by mutations of HFE2 and TMPRSS6, which cause iron excess and iron deficiency respectively. Hemojuvelin is positioned to be the ideal substrate for matriptase‐2. To examine the relationship between hemojuvelin and matriptase‐2 in vivo, we crossed mice lacking the protease domain of matriptase‐2 with mice lacking hemojuvelin. Mice lacking functional matriptase‐2 and hemojuvelin exhibited low Hamp (Hamp1) expression, high serum and liver iron, and high transferrin saturation. Surprisingly, the double mutant mice also exhibited lower levels of iron in the heart compared to hemojuvelin‐deficient mice, demonstrating a possible cardioprotective effect resulting from the loss of matriptase‐2. This phenotype is consistent with hemojuvelin being a major substrate for matriptase‐2/TMPRSS6 protease activity.
Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate‐related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate‐related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age‐defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non‐Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms.
The vaginal colonization of Group B Streptococci in pregnants at the last trimester.

Group B Streptococcus research was conducted. Group B Streptococcus were identified by analyzing swap samples received from participants. RESULTS: Particularly affects newborn babies and can cause serious infections group B streptococci in 2 patients (4%) were determined. CONCLUSION: Regular vaginal culture in pregnant third trimester screening be done, with evaluation of risk factors and treatment practices will reduce risk of infection in infants is considered.
Impaired pneumococcal immunity in children after treatment for acute lymphoblastic leukaemia

Although the substantial risk for invasive pneumococcal disease is well recognized in children after allogeneic stem cell transplantation, little is known about the specific immunity against pneumococci in children after cytotoxic therapy for acute lymphoblastic leukaemia (ALL). We therefore assessed the spontaneous reconstitution of humoral immunity against pneumococcal antigens, of total IgG and the IgG2 subclass, and of lymphocyte subsets in a total of 53 children treated for ALL. None of the patients had received pneumococcal vaccination prior to or after therapy for ALL. At 3 and 9 months after completion of chemotherapy, most patients had levels of specific antibodies to pneumococcal antigens below the presumed threshold of protection and significantly lower than those of age‐matched unvaccinated healthy controls. In contrast, at 9 months after completion of therapy, only a minority of patients had immunoglobulin concentrations or lymphocyte subset counts below the age‐matched reference value. Our data indicate that patients with ALL who are unvaccinated against pneumococci have a selective immunodeficiency with an impaired antibody protection against pneumococci for up to 9 months after completion of therapy. Therefore, effective prevention, including chemoprophylaxis and active immunization, has to be considered in this patient population.
The fundamental contribution of William Bate Hardy to shape the concept of mast cell heterogeneity

This review article acknowledges the pioneering contribution of William Bate Hardy in shaping the concept of mast cell heterogeneity. In two outstanding papers, published in 1894 and 1895, he focussed on the ‘wandering cells’ (the modern leucocytes) in different mammalian species and distinguished two types of granular basophil cells, i.e., the coarsely granular basophil cells and the splanchnic basophil cells. These corresponded to the populations of connective tissue‐type and mucosal mast cells, respectively, described 70 years later by Enerbäck in rodents. Among the coarsely granular basophil cells, he also differentiated those cells which populated the serosal cavities – the so‐called coelomic coarsely granular basophil cells – from the common coarsely granular basophil cells, which were localized in the connective tissues. He stated that the granular basophil cells presented with different morphological and histochemical characteristics in diverse animal species as well as at different anatomical sites. Remarkably, he performed a series of functional experiments on the basophil cells as well as the other wandering cells, and suggested the view that different granular basophil cells might express functional specializations.
Minimal residual disease is a significant predictor of treatment failure in non T‐lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993

The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone‐specific immunoglobulin or T‐cell Receptor rearrangements was analysed in 161 patients with non T‐lineage Philadelphia‐negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (≥10−4) in patients treated with chemotherapy alone was associated with significantly shorter relapse‐free survival (RFS) at several time‐points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8·95 (2·85–28·09)‐fold higher in MRD‐positive (≥10−4) patients and the 5‐year RFS 15% [95% confidence interval (CI) 0–40%] compared to 71% (56–85%) in MRD‐negative (<10−4) patients (P = 0·0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5‐year RFS 25% (CI 0–55%) vs. 77% (95% CI 54–100%) in MRD‐negative/<10−4, P = 0·01] whereas in recipients of allogeneic‐SCT in first complete remission, MRD positivity pre‐transplant did not adversely affect outcome. These data provide a rationale for introducing MRD‐based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.
Barriers to Permanency Planning for Older HIV-Affected Caregivers

Abstract HIV disease is now a major reason that grandparents and other older caregivers assume custodial care of minor children whose parents have died or become incapacitated. Grandparents are becoming custodial parents for a growing number of orphaned children, either through kinship care or informal means. Although these older caregivers are raising minors again because their adult children are unavailable due to a life threatening illness, we know little about whether these older surrogate parents are planning for the eventuality of their own deaths. This exploratory, qualitative, grounded theory study explored the permanency planning experiences of older caregivers of HIV-affected and HIV-infected minor children. Five barriers emerged impeding the permanency planning process for these older caregivers: Lack of knowledge about the legal process, lack of legal authority, emotional concerns, lack of informal social support, and HIV-related stigma. Implications for gerontological social work include the need for more supportive and legal services for older HIV-affected caregivers who are raising minors, encouraging formal adoption and/or negotiations with living biological parents, and helping grandmothers to manage disclosures and HIVstigma.
Multipotent adult progenitor cell isolation and proliferation in cytokine and serum‐free medium conditioned by rat B104 cells

This report describes the isolation of rodent multipotent adult progenitor cells (MAPCs) and proliferation of these cells in both standard medium and medium without exogenous serum or growth factors conditioned by the rat cell line B104. MAPCs have exacting requirements for their proliferation in vitro but once established proliferate rapidly at low seeding density, requiring almost daily passage and media exchange. Previously published methods for growth of MAPCs in vitro all used media supplemented with serum and growth factors, which adds considerable expense.