Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis

Lactate dehydrogenase-5 (LDH-5) catalyses the reversible transformation of pyruvate to lactate, having a principal position in the anaerobic cellular metabolism. Induction of LDH-5 occurs during hypoxia and LDH-5 transcription is directly regulated by the hypoxia-inducible factor 1 (HIF1). Serum LDH levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy in various neoplastic diseases. The expression, however, of LDH in tumours has never been investigated in the past. In the present study, we established an immunohistochemical method to evaluate the LDH-5 overexpression in tumours, using two novel antibodies raised against the rat muscle LDH-5 and the human LDH-5 (Abcam, UK). The subcellular patterns of expression in cancer cells were mixed nuclear and cytoplasmic. In direct contrast to cancer cells, stromal fibroblasts were reactive for LDH-5 only in a minority of cases. Serum LDH, although positively correlated with, does not reliably reflect the intratumoral LDH-5 status. Lactate dehydrogenase-5 overexpression was directly related to HIF1alpha and 2alpha, but not with the carbonic anhydrase 9 expression. Patients with tumours bearing high LDH-5 expression had a poor prognosis. Tumours with simultaneous LDH-5 and HIF1alpha (or HIF2alpha) overexpression, indicative of a functional HIF pathway, had a particularly aggressive behaviour. It is concluded that overexpression of LDH-5 is a common event in non-small-cell lung cancer, can be easily assessed in paraffin-embedded material and provides important prognostic information, particularly when combined with other endogenous markers of hypoxia and acidity

Prediction and prevention of suicide in patients with unipolar depression and anxiety

Epidemiological data suggest that between 59 and 87% of suicide victims suffered from major depression while up to 15% of these patients will eventually commit suicide. Male gender, previous suicide attempt(s), comorbid mental disorders, adverse life-situations, acute psycho-social stressors etc. also constitute robust risk factors. Anxiety and minor depression present with a low to moderate increase in suicide risk but anxiety-depression comorbidity increases this risk dramatically Contrary to the traditional psychoanalytic approach which considers suicide as a retrospective murder or an aggression turned in-wards, more recent studies suggest that the motivations to commit suicide may vary and are often too obscure. Neurobiological data suggest that low brain serotonin activity might play a key role along with the tryptophan hydroxylase gene. Social factors include social support networks, religion etc. It is proven that most suicide victims had asked for professional help just before committing suicide, however they were either not diagnosed (particularly males) or the treatment they received was inappropriate or inadequate. The conclusion is that promoting suicide prevention requires the improving of training and skills of both psychiatrists and many non-psychiatrists and especially GPs in recognizing and treating depression and anxiety. A shift of focus of attention is required in primary care to detect potentially suicidal patients presenting with psychological problems. The proper use of antidepressants, after a careful diagnostic evaluation, is important and recent studies suggest that successful acute and long-term antidepressant pharmacotherapy reduces suicide morbidity and mortality

Present state and future perspectives of using pluripotent stem cells in toxicology research

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

On the geometry of regular hyperbolic fibrations

AbstractHyperbolic fibrations of PG(3,q) were introduced by Baker, Dover, Ebert and Wantz in [R.D. Baker, J.M. Dover, G.L. Ebert, K.L. Wantz, Hyperbolic fibrations of PG(3,q), European J. Combin. 20 (1999) 1–16]. Since then, many examples were found, all of which are regular and agree on a line. It is known, via algebraic methods, that a regular hyperbolic fibration of PG(3,q) that agrees on a line gives rise to a flock of a quadratic cone in PG(3,q), and conversely. In this paper this correspondence will be explained geometrically in a unified way for all q. Moreover, it is shown that all hyperbolic fibrations are regular if q is even, and (for all q) every hyperbolic fibration of PG(3,q) which agrees on a line is regular

Síndrome serotoninérgica associada ao uso de paroxetina: relato de caso Serotonin syndrome associated to the use of paroxetine: case report

Relatamos um caso de síndrome serotoninérgica pelo uso de inibidor da recaptação da serotonina, a paroxetina. Tal síndrome por esta droga, sem combinações, ainda não tinha sido descrita na literatura.<br>We report on a case of serotonin syndrome associated to the use of the paroxetine, a serotonin reuptake inhibitor drug. Serotonin syndrome related to this drug not combined with other drugs had not yet been described in literature

Novel chimeric gene promoters responsive to hypoxia and ionizing radiation

Despite being an adverse prognostic factor in radiotherapy, hypoxia represents a physiological difference that can be exploited for selective cancer gene therapy. In this study gene therapy vectors responsive to both hypoxia and ionizing radiation (IR) were developed. Gene expression was regulated by novel, synthetic promoters containing hypoxia responsive elements (HREs) from the erythropoietin (Epo), the phosphoglycerate kinase 1 (PGK1) and the vascular endothelial growth factor (VEGF) genes, and IR-responsive CArG elements from the early growth response (Egr) 1 gene. All chimeric promoters could be activated by hypoxia and/or IR-treatment, and selectively control marker gene expression in human T24 bladder carcinoma and MCF-7 mammary carcinoma cells. Importantly, enhancers containing combinations of HREs and CArG elements were able to respond to both triggering treatments, with the Epo HRE/CArG combination proving to be the most responsive and robust. The Epo HRE/CArG enhancer could effectively control a suicide gene therapy strategy by selectively sensitizing hypoxic and/or irradiated cells expressing the enzyme horseradish peroxidase (HRP) to the prodrug indole-3-acetic acid (IAA). These data indicate that the use of such chimeric promoters may effectively regulate therapeutic gene expression within the tumor microenvironment in gene therapy strategies aimed at addressing the problem of hypoxia in radiotherapy