The tyrosine phosphatase PTPROt is a suggested tumor suppressor (TS) in B-cell chronic lymphocytic leukemia (CLL), and its expression is reduced in this disease. In order to examine how reduced ...PTPROt expression affects CLL in vivo we induced CLL in PTPROt-targeted mice. Unexpectedly, loss of both Ptprot alleles delayed disease detection and progression and lengthened survival relative to mice carrying two intact alleles, indicating that PTPROt fulfills a novel tumor-promoting role in CLL. Tumor cells from mice lacking PTPROt exhibited reduced B-cell receptor (BCR)-induced signaling, as well as increased apoptosis and autophagy. Inhibition of BCR/Src signaling in CLL cells induced their apoptosis, indicating that these findings are linked causally. These results suggest a cell-autonomous mechanism for the weakened CLL phenotype of PTPROt-deficient mice and uncover non-redundant roles for PTPROt in support of BCR signaling and survival of CLL cells. In contrast, loss of only one Ptprot allele induced earlier detection and progression of CLL and reduced survival, consistent with a tumor-suppressing role for PTPROt. Tumor cells from mice lacking one or both Ptprot allele exhibited increased interleukin-10 (IL-10) expression and signaling, factors known to support CLL; cells lacking one Ptprot alleles exhibited normal BCR signaling and cell death rates. We conclude that loss of one Ptprot allele promotes CLL, most likely by activating IL-10 signaling. Loss of both Ptprot alleles also reduces BCR signaling and increases cell death rates, offsetting the IL-10 effects and reducing the severity of the disease. PTPROt thus functions as an obligate haploinsufficient TS in CLL, where its expression levels determine its role as a promoter or inhibitor of the tumorigenic process in mice. Partial loss of PTPROt generates the strongest disease phenotype, suggesting that its intermediate expression levels in CLL are selected for.
The low reproducibility rate in social sciences has produced hesitation among researchers in accepting published findings at their face value. Despite the advent of initiatives to increase ...transparency in research reporting, the field is still lacking tools to verify the credibility of research reports. In the present paper, we describe methodologies that let researchers craft highly credible research and allow their peers to verify this credibility. We demonstrate the application of these methods in a multi-laboratory replication of Bem's Experiment 1 (Bem 2011
, 407-425. (doi:10.1037/a0021524)) on extrasensory perception (ESP), which was co-designed by a consensus panel including both proponents and opponents of Bem's original hypothesis. In the study we applied direct data deposition in combination with born-open data and real-time research reports to extend transparency to protocol delivery and data collection. We also used piloting, checklists, laboratory logs and video-documented trial sessions to ascertain as-intended protocol delivery, and external research auditors to monitor research integrity. We found 49.89% successful guesses, while Bem reported 53.07% success rate, with the chance level being 50%. Thus, Bem's findings were not replicated in our study. In the paper, we discuss the implementation, feasibility and perceived usefulness of the credibility-enhancing methodologies used throughout the project.
The submitted paper proposes the possible use of integrated semi-quantitative risk assessment of groundwater resources. There are risks resulting from both natural and anthropogenic hazard sources. ...Activation of these types of hazard sources can cause damage to, or destruction of, particular hydrogeological structures and technological equipment of selected groundwater resources suitable for the emergency drinking water supply of the population. The process of risk assessment is based on the described register of hazards, including semi-quantitative assessment of the frequency with which the assessed sources of hazards are activated, the register of sensitivity together with the semi-quantitative sensitivity assessment of selected threatened elements of the assessed water resource and the determination of their criticality. The semi-quantitative risk assessment should become one of the important criteria for classifying groundwater resources which have been proposed for emergency water supply. The classification carried out on the basis of the above-mentioned principle can contribute to faster selection and effective use of groundwater resources, as well as to the enhancement of emergency and crisis planning systems when the public system is either damaged or destroyed.
The human multidrug resistance protein (MRP1) contributes to drug resistance in cancer cells. In addition to an MDR1-like core, MRP1 contains an N-terminal membrane-bound (TMD(0)) region and a ...cytoplasmic linker (L(0)), both characteristic of several members of the MRP family. In order to study the role of the TMD(0) and L(0) regions, we constructed various truncated and mutated MRP1, and chimeric MRP1-MDR1 molecules, which were expressed in insect (Sf9) and polarized mammalian (MDCKII) cells. The function of the various proteins was examined in isolated membrane vesicles by measuring the transport of leukotriene C(4) and other glutathione conjugates, and by vanadate-dependent nucleotide occlusion. Cellular localization, and glutathione-conjugate and drug transport, were also studied in MDCKII cells. We found that chimeric proteins consisting of N-terminal fragments of MRP1 fused to the N terminus of MDR1 preserved the transport, nucleotide occlusion and apical membrane routing of wild-type MDR1. As shown before, MRP1 without TMD(0)L(0) (Delta MRP1), was non-functional and localized intracellularly, so we investigated the coexpression of Delta MRP1 with the isolated L(0) region. Coexpression yielded a functional MRP1 molecule in Sf9 cells and routing to the lateral membrane in MDCKII cells. Interestingly, the L(0) peptide was found to be associated with membranes in Sf9 cells and could only be solubilized by urea or detergent. A 10-amino-acid deletion in a predicted amphipathic region of L(0) abolished its attachment to the membrane and eliminated MRP1 transport function, but did not affect membrane routing. Taken together, these experiments suggest that the L(0) region forms a distinct domain within MRP1, which interacts with hydrophobic membrane regions and with the core region of MRP1.
Multidrug resistance is frequently observed when treating cancer patients with chemotherapeutic agents. A variety of ATP binding cassette (ABC) transporters, localized in the cell membrane, cause ...this phenomenon by extruding a variety of chemotherapeutic agents from the tumor cells. However, the major physiological role of the multidrug transporters is the protection of our cells and tissues against xenobiotics, and these transporters play a key role in drug availability, metabolism and toxicity. Three major groups of ABC transporters are involved in multidrug resistance: the classical
P-glycoprotein MDR1, the multidrug resistance associated proteins (MRP1, MRP2, and probably MRP3, MRP4 and MRP5), and the ABCG2 protein, an ABC half-transporter. All these proteins were shown to catalyze an ATP-dependent active transport of chemically unrelated compounds. MDR1 (
P-glycoprotein) and ABCG2 preferentially extrude large hydrophobic, positively charged molecules, while the members of the MRP family can extrude both hydrophobic uncharged molecules and water-soluble anionic compounds. By examining the interactions of the multidrug transporters with pharmacological and toxic agents, a prediction for the cellular and tissue distribution of these compounds can be achieved. Oral bioavailability, entering the blood–brain and blood-CSF barrier, reaching the fetus through the placenta, liver and kidney secretion, cellular entry for affecting intracellular targets, are all questions, which can be addressed by basic in vitro studies on the multidrug resistance proteins. Investigation of the substrate interactions and modulation of multidrug transporters may pave the way for predictive toxicology and pharmacogenomics. Here we show that by using in vitro assay systems it is possible to measure the interactions of multidrug transporters with various drugs and toxic agents. We focus on the characterisation of the MRP1 and MRP3 proteins, their relevance in chemoresistance of cancer and in drug metabolism and toxicity.
Authors in this article emphasize the wide use of laparoscopic cholecystectomy in gall bladder surgery. Indications for laparoscopic operations are increasing. In spite of increasing practical ...experience of surgeons, availability of new instruments, advances of techniques, this problem of conversion is always actual. The question of conversion may depend on subjective and objective causes. It's the decision of the surgeon whether a conversion is necessary taking into account uncomplicated operation and postoperative state of the patient. In the Surgery clinic of FN Nitra 2078 cholecystectomies were performed in the period from 1.1.2002 to 31.1. 2007. Out of this number, there were 1535 (74%) laparoscopic operations and 543 (26%) classic operations. From the group of 1535 laparoscopic operations conversion was necessary in 89 patients (5.7%) (Tab. 4, Ref. 9).
The aim of our study is to show the clinical potential of laparoscopic treatment of pericardial effusions. In spite of the small number of the patients we want to bring to attention the benefit of ...this mininvasive procedure. The laparoscopic fenestration is indicated when the pericardial effusion persists after unsuccessful medical treatment and when clinical and echocardiografic signs of tamponade develop (Ref 13). Full Text (Free, PDF) www.bmj.sk.
As part of the Many Labs 5 project, we ran a replication of van Dijk, van Kleef, Steinel, and van Beest’s (2008) study examining the effect of emotions in negotiations. They reported that when the ...consequences of rejection were low, subjects offered fewer chips to angry bargaining partners than to happy partners. We ran this replication under three protocols: the protocol used in the Reproducibility Project: Psychology, a revised protocol, and an online protocol. The effect averaged one ninth the size of the originally reported effect and was significant only for the revised protocol. However, the difference between the original and revised protocols was not significant.
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