Intracardiac echography-guided fluoroless ablation versus conventional fluoroscopy-guided ablation for cardiac arrhythmias: a systematic review and meta-analysis

BACKGROUND: Intracardiac echocardiography (ICE) has improved catheter ablation procedures, reducing reliance on fluoroscopy. Yet, the efficacy and safety of zero-fluoroscopy (ZF) procedures remain uncertain. METHODS: We conducted a systematic review and meta-analysis comparing ZF ablation procedures guided by ICE vs. conventional techniques regarding efficacy and safety outcomes. PubMed, Cochrane, and embase were searched. A random-effects model was used to calculate risk ratios (RRs), odds ratios (OR) and mean differences (MDs) with 95% confidence intervals (CI). RESULTS: We includedfourteen studies with 1,919 patients of whom 1,023 (58.72%) performed ZF ablation using ICE. We found a significant reduced ablation time (SMD -0.18; 95% CI -0.31;-0.04; p=0.009), procedure time (MD -7.54; 95% CI -14.68;-0.41; p=0.04), fluoroscopic time (MD -2.52; 95% CI -3.20;-1.84; p<0.001) in patients treated with ZF approach compared with NZF approach. However, there was no significant difference between the two groups in acute success rate (RR 1.00; 95% CI 0.99-1.01; p=0.85), long-term success rate (RR 0.99; 95% CI 0.93-1.05; p=0.77) and complications (RR 0.84, 95% CI: 0.48-1.46; p = 0.54). CONCLUSION: Our findings suggest that among patients undergoing arrhythmia ablation, fluoroscopy-free ICE-guided technique reduces procedure time and radiation exposure with comparable short and long-term success rates and complications.

Complete versus culprit-only revascularization for older adults with acute coronary syndromes: a meta-analysis and systematic review

BACKGROUND: Randomized studies support complete over culprit-only revascularization for patients with acute coronary syndrome (ACS) However,whether these findings extend to elderly patients has not been thoroughly explored. METHODS: We conducted a systematic review and meta-analysis comparing clinical outcomes of elderly individuals (defined as age > 75 years) with ACS and multivessel coronary artery disease submitted to complete vs. culprit-only percutaneous coronary intervention (PCI). PubMed, Embase, and Cochrane were searched. We computed pooled hazard ratios (HRs) with 95% confidence intervals (CI) to preserve time-to-event data RESULTS: We included 7 studies, of which 2 were randomized controlled trials (RCTs), comprising 7,409 patients, of whom 3225 (43.5%) underwent complete revascularization. As compared with culprit lesion only PCI, complete revascularization was associated with a lower risk of all-cause mortality (HR 0.76; 95% CI 0.68-0.85; p<0.001), cardiovascular mortality (HR 0.67; 95% CI 0.54-0.82; p<0.001), and recurrent myocardial infarction (MI) (HR 0.65; 95% CI 0.50-0.85; p=0.002). There was no significant difference between the groups regarding the risk of recurrent revascularizations (HR 0.79; 95% CI 0.54-1.16; p=0.23). CONCLUSION: Among elderly patients with ACS and multivessel CAD, complete revascularization is associated with a lower risk of all-cause mortality, cardiovascular mortality, and recurrent MI.

Cardioneuroablation for reflex syncope: a systematic review and single-arm meta-analysis

BACKGROUND: Reflex syncope reduces quality of life and leads to fall-related injuries, with no highly effective treatment. In this context, cardioneuroablation (CNA) presents as a promising therapy for these patients. METHODS: We searched PubMed, Embase and Cochrane Central for studies that evaluated safety and efficacy outcomes related to CNA procedures. Two reviewers independently performed study selection, data extraction and assessment of bias. Generalized linear mixed models was used. We performed a single-arm meta-analysis using R version 4.2.3. RESULTS: A total of 25 studies comprising 871 patients were included. The mean follow-up ranged from 8 to 40 months. Mean age ranged from 32.9 to 53.9 years and 541 (62.1%) were female. The ablation target was biatrial in 302 patients (34%), left atrium only in 433 (49%), and right atrium only in 136 (15%). The freedom from syncope was 94% (95% confidence interval (CI) 90.13-97.00; P<0.01). Left and right atrial CNA was associated with a significant higher freedom from syncope (96.03%; 95% CI 93.13-97.73) than left atrial ablation only (94.61%; 95% CI 82.88-98.45) and right ablation only (84.53%; 95% CI 74.30-91.18). Peri-procedural adverse event occurred on 1.4% (95% CI 0.44- 4.50). CONCLUSION: Our findings suggest that in patients with reflex syncope, CNA is a procedure associated with a significant reduction in syncope incidence and with low complication rates. Among the procedures used, both right and left ablation were more effective.

Cardiac myosin inhibitors in obstructive hypertrophic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Selective cardiac myosin inhibitors (CMI) are promising therapies for obstructive hypertrophic cardiomyopathy (HCM). Yet, the extent of their benefits remains unclear due to the limited population studied. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing CMI vs. placebo in patients with obstructive HCM. PubMed, Cochrane, and embase were searched. We calculated risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs) with 95% confidence intervals (CI). RESULTS: Four RCTs with 485 patients with obstructive HCM were included, of whom 261 (53.8%) were prescribed CMI (10.7% were aficamten and 89.3% were mavacamten). CMI significantly reduced resting left ventricular outflow tract (LVOT) gradient (SMD -1.4, 95% CI -1.6,-1.2, p<0.001), but also reduced left ventricular ejection fraction (LVEF) (MD -5.1%, 95% CI -7.6,-2.6, p<0,001). Patients receiving CMI had a higher rate of study-defined complete hemodynamic response (RR 16.8, CI 95% 5.5, 51.4, p<0,001; Figure 1A) with a number needed to treat (NNT) of 8; and improvement of at least one point in NYHA functional class (RR 2.29, CI 95% 1.8,2.9, p<0,001; Figure 1B). Conclusion: In this meta-analysis of RCTs including patients with obstructive HCM, CMI led to a significant reduction in LVOT gradient and symptomatic improvement. The NNT to achieve one complete hemodynamic response was 8. There was a significant, albeit modest, decrease in LVEF in the CMI group.

Effects of anabolic androgenic steroids in athletes on left ventricle systolic and diastolic function: a systematic review and meta-analysis

BACKGROUND: The use of anabolic androgenic steroids (AAS) among athletes has been linked to pathological structural and functional cardiac changes. However, the studies are small, and the results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of echocardiographic outcomes comparing athletes with prolonged use of AAS (at least 2 years of use) versus sex and age- matched athletes who were did not use AAS. PubMed, Cochrane, and embase were searched. A random-effects model was used to calculate mean differences (MDs), with 95% confidence intervals (CI). Statistical analyses were performed using Review Manager 5.4.1. RESULTS: We included 17 studies comprising 1,023 athletes, of whom 543 (53%) were AAS users. The mean age ranged to 24.2 to 43 years. Compared with non-AAS users, athletes who used AAS exhibited a significant increase in interventricular septal wall thickness (MD 1.33 mm; 95% CI [0.8,1.89], p<0.001), a reduction in left ventricular ejection fraction (MD 2.77 %; 95% CI [-4.2,-1.34], p<0.001;Figure 1B) , and worsening of global longitudinal strain (MD 3.39%; 95% CI [2.88,3.91], p<0.001;Figure 1B). Additionally, there was a significant reduction in the E/A ratio (MD -0.21; 95% CI [-0.35,-0.07], p=0.003) and an increase in the E/e' ratio (MD 1.71; 95% CI [0.96,2.46], p<0.001). CONCLUSION: Our findings suggest that prolonged use of AAS in athletes is associated with increased left ventricular wall thickness and worsening of systolic and diastolic parameters.

Ion exchange and adsorption of cadmium from aqueous media in sodium-modified expanded vermiculite.

The use of mineral clays as alternative adsorbent has received attention due to their physicochemical characteristics, superficial negative charge, abundance of vermiculite (especially in Brazil), low cost, and chemical composition, which allows the material modification to increase the adsorptive capacity. This manuscript evaluated the use of expanded vermiculite (EV) and sodium-modified vermiculite (VNa) in the adsorption and ion exchange of Cd2+ ions. The sodification was successfully carried out making the ion exchange capacity greater in the modified clay, confirmed by EDX, cation exchange capacity (CEC), DRX, and FTIR analysis. The CEC was 210 and 233 mEq/100 g for the EV and VNa, respectively, with 97.8% exchangeable ion (Na+) in the VNa. FTIR spectra showed small variations in the groups related to ion exchange and XRD analysis indicated changes in the distance of the layers with loss of crystallinity after clay modification, which was recovered after cadmium adsorption. The kinetics became faster with an equilibrium time of 10 min for VNa and 45 min for EV. Cd2+ removal by vermiculite above 99% was achieved. Pseudo-second order model best described the kinetics, in which the resistance to mass transfer in external film is the limiting step of the process and, once this resistance is overcome, the ion exchange happens quickly. Despite the decrease in surface area after sodification, the adsorptive capacity increased 158% in the sodified adsorbent, from 0.107 mmol/g for EV to 0.276 mmol/g for VNa, under the evaluated conditions.

Competition for nutritional resources masks the true frequency of bacterial mutants.

BACKGROUND: It is widely assumed that all mutant microorganisms present in a culture are able to grow and form colonies, provided that they express the features required for selection. Unlike wild-type Escherichia coli, PHO-constitutive mutants overexpress alkaline phosphatase and hence can hydrolyze glycerol-2-phosphate (G2P) to glycerol and form colonies on plates having G2P as the sole carbon source. These mutations mostly occur in the pst operon. However, the frequency of PHO-constitutive colonies on the G2P selective plate is exceptionally low. RESULTS: We show that the rate in which spontaneous PHO-constitutive mutations emerge is about 8.0 × 10-6/generation, a relatively high rate, but the growth of most existing mutants is inhibited by their neighboring wild-type cells. This inhibition is elicited only by non-mutant viable bacteria that can take up and metabolize glycerol formed by the mutants. Evidence indicates that the few mutants that do form colonies derive from microclusters of mutants on the selective plate. A mathematical model that describes the fate of the wild-type and mutant populations under these circumstances supports these results. CONCLUSION: This scenario in which neither the wild-type nor the majority of the mutants are able to grow resembles an unavoidable "tragedy of the commons" case which results in the collapse of the majority of the population. Cooperation between rare adjacent mutants enables them to overcome the competition and eventually form mutant colonies. The inhibition of PHO-constitutive mutants provides an example of mutant frequency masked by orders of magnitude due to a competition between mutants and their ancestral wild-type cells. Similar "tragedy of the commons-like" cases may occur in other settings and should be taken into consideration while estimating true mutant frequencies and mutation rates.

Phosphate uptake by the phosphonate transport system PhnCDE.

BACKGROUND: Phosphate is a fundamental nutrient for all creatures. It is thus not surprising that a single bacterium carries different transport systems for this molecule, each usually operating under different environmental conditions. The phosphonate transport system of E. coli K-12 is cryptic due to an 8 bp insertion in the phnE ORF. RESULTS: Here we report that an E. coli K-12 strain carrying the triple knockout ΔpitA Δpst Δugp reverted the phnE mutation when plated on complex medium containing phosphate as the main phosphorus source. It is also shown that PhnCDE takes up orthophosphate with transport kinetics compatible with that of the canonical transport system PitA and that Pi-uptake via PhnCDE is sufficient to enable bacterial growth. Ugp, a glycerol phosphate transporter, is unable to take up phosphate. CONCLUSIONS: The phosphonate transport system, which is normally cryptic in E. coli laboratory strains is activated upon selection in rich medium and takes up orthophosphate in the absence of the two canonical phosphate-uptake systems. Based on these findings, the PhnCDE system can be considered a genuine phosphate transport system.

Glyphosate induces the synthesis of ppGpp.

Glyphosate, the most widely used herbicide in both agricultural and urban areas is toxic for plants and for many bacterial species. The mechanism of action of glyphosate is through the inhibition of the EPSP synthase, a key enzyme in the biosynthetic pathway of aromatic amino acids. Here we show that glyphosate induces the stringent response in Escherichia coli. Bacteria treated with glyphosate stop growing and accumulate ppGpp. Both growth arrest and ppGpp accumulation are restored to normal levels upon addition of aromatic amino acids. Glyphosate-induced ppGpp accumulation is dependent on the presence of the (p)ppGpp synthetase RelA. However, unlike other cases of amino acid starvation, pppGpp could not be discerned. In a gppA background both ppGpp and pppGpp accumulated when exposed to glyphosate. Conversely, the wild-type strain and gppA mutant treated with serine hydroxamate accumulated high levels of both ppGpp and pppGpp. Altogether, the data indicate that glyphosate induces amino acid starvation resulting in a moderate accumulation of ppGpp and a reversible stringent response.

DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer.

Breast cancer is one of the most common malignancies in women worldwide. In breast cancer, the cell proliferation rate is known to influence the cancer malignancy. Recent studies have shown that DNA replication initiation/licensing factors are involved in cancer cell proliferation as well as cancer cell migration and invasion. Licensing factors have also been reported as important prognostic markers in lung, prostrate, and bladder cancers. Here, we studied the role of MCM10, a novel licensing factor, in breast cancer progression. From the public database, NCBI, we investigated six independent breast cancer patient cohorts, totaling 1283 patients. We observed a significant association between high MCM10 mRNA expression with tumor grading and patients' survival time. Most importantly, using breast cancer cohorts with available treatment information, we also demonstrated that a high level of MCM10 is associated with a better response to conventional treatment. Similarly, in in vitro studies, the expression level of MCM10 in breast cancer cell lines is significantly higher compared to paired normal breast epithelium cells. Knockdown of MCM10 expression in the cancer cell line showed significantly decreased tumorigenic properties such as cell proliferation, migration and anchorage independence. The MCF7 breast cancer cell line, after MCM10 expression knockdown, showed significantly decreased tumorigenic properties such as cell proliferation, migration, and anchorage independent growth. Mechanistically, MCM10 expression is observed to be regulated by an Estrogen Receptor (ER) signaling pathway, where its expression is suppressed by the inhibition of the ER or serum withdrawal. Our results suggest that MCM10 plays an important role in breast cancer progression and is a potential prognostic/predictive biomarker and therapeutic target for breast cancer patients.

Expression of minichromosome maintenance genes in renal cell carcinoma.

Minichromosome maintenance (MCM) proteins play an essential role in DNA replication. They have been shown to be overexpressed in various types of cancer. However, the role of this family in renal cell carcinoma (RCC) is widely unknown. In this study, we have identified a number of RCC datasets in the Gene Expression Omnibus database and also investigated the correlation between the expression levels of MCM genes and clinicopathological parameters. We found that the expression levels of MCM genes are positively correlated with one another. Expression levels of MCM2, MCM5, MCM6, and MCM7, but not of MCM3 and MCM4, were higher in RCC compared to paired adjacent normal tissue. Only the expression level of MCM4, but not of other MCMs, was positively correlated with tumor grade. In addition, a high-level expression of MCM2 in either primary tumor or metastases of RCC predicted a shorter disease-free survival time, while a high-level expression of MCM4 or MCM6 in primary tumor was also associated with poorer disease-free survival. Interestingly, we also demonstrated that patients with their primary RCC overexpressing 2 or more MCM genes had a shorter disease-free survival time, while those with RCC metastases overexpressing 3 or more MCM genes had a shorter disease-free survival. Importantly, we also demonstrated that overexpression of MCM genes is an independent predictor for survival in RCC patients. Our results suggest that MCM2-7 genes may be an important prognostic marker for patients with RCC.

A new approach by optical coherence tomography for elucidating biofilm formation by emergent Candida species.

The majority of microorganisms present a community lifestyle, establishing biofilm ecosystems. However, little is known about its formation in emergent Candida species involved in catheter-related infections. Thus, various techniques may be used in the biofilm detection to elucidate structure and clinical impact. In this context, we report the ability of emergent Candida species (Candida haemulonii, C. lusitaniae, C. pelliculosa, C.guilliermondii, C. famata and C. ciferrii) on developing well structured biofilms with cell viability and architecture, using optical coherence tomography (OCT). This new approach was compared with XTT analyses and Scanning Electron Microscopy (SEM). A positive correlation between oxidative activity (XTT) and OCT results (r = 0.8752, p < 0.0001) was observed. SEM images demonstrated cells attachment, multilayer and morphologic characteristics of the biofilm structure. C. lusitaniae was the emergent species which revealed the highest scattering extension length and oxidative metabolism when evaluated by OCT and XTT methods, respectively. Herein, information on C. ciferri biofilm structure were presented for the first time. The OCT results are independently among Candida strains and no species-specific pattern was observed. Our findings strongly contribute for clinical management based on the knowledge of pathogenicity mechanisms involving emergent yeasts.

In sickness and in health: The many roles of the minichromosome maintenance proteins.

Cell division is a tightly-regulated process that involves the contribution of a large number of proteins. Before they are able to undergo mitosis, cells must first synthesize new DNA, effectively and accurately duplicating their genome. This occurs during what is called the S-phase and requires a fine control in order to avoid replication errors. The synthesis of new DNA takes place in the origin, specific locations in the genome where the double strands of DNA are unwound and separated, allowing for the binding of proteins and complexes that will build new strands of the genomic material, using the existing ones as molds, in what is referred to as semi-conservative process. While the overall flow of the DNA synthesis process has been elucidated, its regulation and the exact role of its contributors are not yet entirely understood. It is believed that the Minichromosome Maintenance (MCM) proteins occupy a central role in DNA synthesis. Given their contribution to a central aspect in the conservation of life, further studies have been launched to understand how the MCM proteins may affect or be affected by pathologies involving cell division, such as neoplasia. In this review, we aim to give an overview on the members of the MCM family, what their functions are in a healthy environment and how they are altered in cancer.

The prognostic significance of Cdc6 and Cdt1 in breast cancer.

DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients.

The prognostic significance of DAPK1 in bladder cancer.

Bladder cancer is one of the leading causes of cancer-related death in men, however, there was only limited effective treatment for invasive bladder cancer. DAPK1 has been shown to play important role in apoptosis and autophagy to suppress cancer progression. Previous results have shown that DAPK1 promoter was hypermethylated in the majority of bladder cancer specimens, however, the prognostic significance of DAPK1 in bladder cancer has yet to be demonstrated. In the present study, we found that DAPK1 expression was negatively associated with tumor stage and a low level expression of DAPK1 in bladder cancer specimens were associated with shorter survival in bladder cancer patients in 3 independent bladder cancer datasets (n = 462). Further investigation showed that FGFR3 knockdown resulted in downregulation of DAPK1 in bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1. Further analysis of the 3 independent bladder cancer datasets have identified ACOX1, UPK2, TRAK1, PLEKHG6 and MT1X genes had their expression significantly correlated with that of DAPK1. Knockdown of DAPK1 in bladder cancer T24 cells resulted in downregulation of ACOX1, UPK2 and TRAK1. Interestingly, TRAK1, by itself, was a favorable prognostic marker in the 3 independent bladder cancer datasets. Importantly, by using connectivity mapping with DAPK1-associated gene signature, we found that vemurafenib and trametinib could possibly reverse DAPK1-associated gene signature, suggesting that inhibition of Raf/MEK pathway may be a potential therapeutic approach for bladder cancer. Indeed, treatment of vemurafenib in T24 bladder cancer cells resulted in upregulation of DAPK1 confirming our connectivity mapping, while knockdown of DAPK1 resulted in reduced sensitivity towards inhibition of Braf signaling by vemurafenib. Together, our results suggest that DAPK1 is an important prognostic marker and therapeutic target for bladder cancer and have identified possible therapeutic agents for future testing in bladder cancer models with low DAPK1 expression.

Digitoxin synergizes with sorafenib to inhibit hepatocelluar carcinoma cell growth without inhibiting cell migration.

Sorafenib is a chemotherapeutic agent approved for the treatment of hepatocellular carcinoma (HCC) in China. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers, but not in HCC. The aim of the present study was to evaluate the combinational effect of sorafenib and digitoxin on the treatment of HCC and to investigate the relevant molecular mechanisms of action that underlie these effects. The proliferation, cell death and migration of HCC cell lines, HepG2 and BEL­7402, were examined using MTT, acridine orange/ethidium bromide staining and scratch wound healing assays, respectively. In addition, alterations in the expression of phosphorylated-extracellular signal-regulated kinase (ERK), hypoxia­inducible factor 1­α (HIF­1α), hypoxia­inducible factor 2­α (HIF­2α) and vascular endothelial growth factor (VEGF) were measured prior to and following drug application using western blot analysis. Digitoxin and sorafenib synergistically inhibited cell viability, but did not inhibit migration, which was potentially mediated by suppression of ERK and hypoxia signaling. In downstream signaling pathways, the activity of ERK was synergistically suppressed by combinatorial treatment of HepG2 and BEL­7402 cells with sorafenib and digitoxin. In addition, the expression of HIF­1α, HIF­2α and VEGF was synergistically downregulated by combinational treatment.

Recent advances in the field of anti-cancer immunotherapy.

BACKGROUND: The main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index - the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein-protein interaction and deliver cytotoxic events to a tumor-specific antigen. REVIEW SCOPE: It is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy. GENERAL SIGNIFICANCE: Immunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects.

The prognostic significance of protein tyrosine phosphatase 4A2 in breast cancer.

Although PTP4A3 has been shown to be a very important factor in promoting cancer progression, the role of its close family member PTP4A2 is still largely unknown. Recent reports have shown contradicting results on the role of PTP4A2 in breast cancer progression. Considering this, we aimed to investigate the prognostic value of PTP4A2 in five independent breast cancer data sets (minimum 198 patients per cohort, totaling 1,124 patients) in the Gene Expression Omnibus Database. We found that high expression of PTP4A2 was a favorable prognostic marker in all five independent breast cancer data sets, as well as in the combined cohort, with a hazard ratio of 0.68 (95% confidence interval =0.56-0.83; P<0.001). Low PTP4A2 expression was associated with estrogen receptor-negative tumors and tumors with higher histological grading; furthermore, low expression was inversely correlated with the expression of genes involved in proliferation, including MKI67 and the MCM gene family encoding the minichromosome maintenance proteins. These findings suggest that PTP4A2 may play a role in breast cancer progression by dysregulating cell proliferation. PTP4A2 expression was positively correlated with ESR1, the gene encoding estrogen receptor-alpha, and inversely correlated with EGFR expression, suggesting that PTP4A2 may be involved in these two important oncogenic pathways. Together, our results suggest that expression of PTP4A2 is a favorable prognostic marker in breast cancer.

Ugp and PitA participate in the selection of PHO-constitutive mutants.

UNLABELLED: Mutations that cause the constitutive expression of the PHO regulon of Escherichia coli occur either in the pst operon or in the phoR gene, which encode, respectively, a high-affinity Pi transport system and a histidine kinase sensor protein. These mutations are normally selected on glycerol-2-phosphate (G2P) as the carbon source in the presence of excess Pi. The emergence of early PHO-constitutive mutants, which appear after growth for up to 48 h on selective medium, depends on the presence of phoA, which codes for a periplasmic alkaline phosphatase, while late mutants, which appear after 48 h, depend both on phoA and on the ugp operon, which encodes a glycerophosphodiester transport system. The emergence of the late mutants hints at an adaptive mutation process. PHO-constitutive phoR mutants appear only in a host that is mutated in pitA, which encodes an alternative Pi transport system that does not belong to the PHO regulon. The conserved Thr(217) residue in the PhoR protein is essential for PHO repression. IMPORTANCE: One of the principal ways in which bacteria adapt to new nutrient sources is by acquiring mutations in key regulatory genes. The inability of E. coli to grow on G2P as a carbon source is used to select mutations that derepress the PHO regulon, a system of genes involved in the uptake of phosphorus-containing molecules. Mutations in the pst operon or in phoR result in the constitutive expression of the entire PHO regulon, including alkaline phosphatase, which hydrolyzes G2P. Here we demonstrate that the ugp operon, another member of the PHO regulon, is important for the selection of PHO-constitutive mutants under prolonged nutritional stress and that phoR mutations can be selected only in bacteria lacking pitA, which encodes a secondary Pi transport system.