Explore the vast range of titles available.

Adenosine 5′-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X 1 and P2X 3 , respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X 1 receptor immunoreactivity was found on detrusor muscle fibres and P2X 3 receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X 3 receptors. No clear evidence was found for the presence of P2X 3 receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X 3 receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by ≈50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G1and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.

Adenosine 5′-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X1 and P2X3, respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X1 receptor immunoreactivity was found on detrusor muscle fibres and P2X3 receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X3 receptors. No clear evidence was found for the presence of P2X3 receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X3 receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.

Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.

Key Points As cells are infected by microorganisms, they can pre-emptively die to prevent the replication and spreading of the pathogen. Cell death that is associated with the presence of pathogen-associated molecular patterns (PAMPs) can stimulate vigorous immune responses. In the absence of PAMPs, damage-associated molecular patterns (DAMPs) produced by dying cells can stimulate an immune response that can elicit the specific recognition of antigens expressed by dying cells (for example, tumour antigens). The nature of the immune response to cell death depends on which cells die, where they die, how they die, which cell engulfs them and when (or if) an associated antigen has been or will be recognized. Variations in these factors can have consequences that range from effective anti-pathogen or antitumour responses to autoimmune pathology. The simple idea that apoptosis is tolerogenic or non-immunogenic and that necrosis is immunogenic is an oversimplification. Thus, apoptosis of tumour cells that is induced by chemotherapy can prime an efficient immune response, which in turn can contribute to the efficacy of antitumour regimens. Various DAMPs contribute to the immunogenicity of apoptotic cell death. These include the surface exposure of chaperone proteins (such as calreticulin) or the release of proteins, such as high-mobility group box 1 protein (HMGB1) and SIN3A-associated protein 130 (SAP130) among others. The catabolic action of caspases and autophagy can also contribute to the immunogenicity of cell death. The tolerogenic effect of cell death depends on many factors, including the absence of T cell help, the location of the dying cells (which in part dictates their engulfment by distinct dendritic cell (DC) subtypes), the maturation state of the DC, the production of immunosuppressive factors (such as transforming growth factor-β) or the modification of DAMPs (for example, oxidation of HMGB1 that results in its inactivation). In conclusion, the mechanisms that determine the immune response to dead and dying cells are complex. Understanding (and possibly manipulating) these mechanisms can have important implications for cancer biology, infectious disease, tissue injury and autoimmunity. How should the immune system respond to a dying cell? Should it ignore it (to allow normal tissue turnover), tolerate it (to prevent autoimmunity) or respond to it (to clear pathogens or tumours)? This Review describes our current understanding of the mechanisms involved in this decision. The immune system is routinely exposed to dead cells during normal cell turnover, injury and infection. Mechanisms must exist to discriminate between different forms of cell death to correctly eliminate pathogens and promote healing while avoiding responses to self, which can result in autoimmunity. However, an effective immune response against host tissue is often needed to eliminate tumours following treatment with chemotherapeutic agents that trigger tumour cell death. Consequently, a central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent'.

Although a small number of the vast array of animal long non-coding RNAs (lncRNAs) have known effects on cellular processes examined in vitro, the extent of their contributions to normal cell processes throughout development, differentiation and disease for the most part remains less clear. Phenotypes arising from deletion of an entire genomic locus cannot be unequivocally attributed either to the loss of the lncRNA per se or to the associated loss of other overlapping DNA regulatory elements. The distinction between cis- or trans-effects is also often problematic. We discuss the advantages and challenges associated with the current techniques for studying the in vivo function of lncRNAs in the light of different models of lncRNA molecular mechanism, and reflect on the design of experiments to mutate lncRNA loci. These considerations should assist in the further investigation of these transcriptional products of the genome.

Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.

Treatment of non-small cell lung cancer is increasingly biomarker driven with multiple genomic alterations, including those in the epidermal growth factor receptor ( EGFR ) gene, that benefit from targeted therapies. We developed a set of algorithms to assess EGFR status and morphology using a real-world advanced lung adenocarcinoma cohort of 2099 patients with hematoxylin and eosin (H&E) images exhibiting high morphological diversity and low tumor content relative to public datasets. The best performing EGFR algorithm was attention-based and achieved an area under the curve (AUC) of 0.870, a negative predictive value (NPV) of 0.954 and a positive predictive value (PPV) of 0.410 in a validation cohort reflecting the 15% prevalence of EGFR mutations in lung adenocarcinoma. The attention model outperformed a heuristic-based model focused exclusively on tumor regions, and we show that although the attention model also extracts signal primarily from tumor morphology, it extracts additional signal from non-tumor tissue regions. Further analysis of high-attention regions by pathologists showed associations of predicted EGFR negativity with solid growth patterns and higher peritumoral immune presence. This algorithm highlights the potential of deep learning tools to provide instantaneous rule-out screening for biomarker alterations and may help prioritize the use of scarce tissue for biomarker testing.

Central sleep apnea is common among patients who have heart failure and increases the risk of death in this setting. In the Canadian Continuous Positive Airway Pressure trial, continuous positive airway pressure (CPAP) therapy administered to patients with heart failure was found to reduce the severity of central sleep apnea and increase the left ventricular ejection fraction, but did not improve survival. Continuous positive airway pressure therapy administered to patients with heart failure was found to reduce the severity of central sleep apnea and increase the left ventricular ejection fraction but did not improve survival. Central sleep apnea, which is present in approximately 25 to 40 percent of patients with chronic heart failure, 1 – 3 results from cyclic hyperventilation and falls in the partial pressure of arterial carbon dioxide below the apnea threshold. 4 The condition affects cardiovascular function adversely by causing tissue hypoxia, arousals from sleep, and activation of the sympathetic nervous system, and it independently increases the risk of death. 1 , 5 , 6 In short-term, single-center randomized trials lasting one to three months involving small numbers of patients who had central sleep apnea and chronic heart failure, continuous positive airway pressure (CPAP) attenuated the central sleep . . .

This trial revisited research conducted about a decade ago that showed a survival benefit with early neuromuscular blockade in patients with acute respiratory distress syndrome. The new trial did not show a benefit with neuromuscular blockade with respect to overall survival or other clinical outcomes.