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Background: Patients with chronic kidney disease (CKD) are routinely prescribed complex medication regimes. Medication reconciliation, medicine reviews, patient counselling and disease state and medication education are all key pharmacist-led interventions, which can improve medication adherence in patients with CKD., Aim: To characterize peer reviewed literature on the role of pharmacists in supporting medication adherence of patients with chronic kidney disease and highlight the impact they might have in the health outcomes for patients., Method: This review was performed in accordance with the Scoping Review Framework outlined in the Joanna Briggs Institute Reviewer's Guide. Four electronic databases were searched (Medline (Ovid), Emcare, Scopus and Web of Science) for all relevant literature published up until November 2022. A total of 32 studies were reviewed against an exclusion and inclusion criteria, with findings from each study categorized into barriers, interventions, perceptions, financial implications and outcomes., Results: Eight eligible studies were identified, where pharmacists' interventions including medication reconciliation, medicine reviews, patient counselling and disease state and medication education, were all reported to have a positive effect on medication adherence. Although pharmacy services in chronic kidney disease were acceptable to patients and pharmacists, these services were under-utilized and limited by logistical constraints, including staffing shortages and time limitations. Patient education supplemented with education tools describing disease states and medications was reported to increase patient adherence to medication regimes., Conclusions: Pharmacist-led interventions play an integral role in improving medication adherence in patients with chronic kidney disease, with their inclusion in renal care settings having the potential to improve outcomes for patients.

TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73's pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy.

Synthetic antioxidant food additives, such as BHA, BHT and TBHQ, are going through a difficult time, since these products generate a negative perception in consumers. This has generated an increased pressure on food manufacturers to search for safer natural alternatives like phytochemicals (such as polyphenols, including flavonoids, and essential oils rich in terpenoids, including carotenoids). These plant bioactive compounds have antioxidant activities widely proven in in vitro tests and in diverse food matrices (meat, fish, oil and vegetables). As tons of food are wasted every year due to aesthetic reasons (lipid oxidation) and premature damage caused by inappropriate packaging, there is an urgent need for natural antioxidants capable of replacing the synthetic ones to meet consumer demands. This review summarizes industrially interesting antioxidant bioactivities associated with terpenoids and polyphenols with respect to the prevention of lipid oxidation in high fat containing foods, such as meat (rich in saturated fat), fish (rich in polyunsaturated fat), oil and vegetable products, while avoiding the generation of rancid flavors and negative visual deterioration (such as color changes due to oxidized lipids). Terpenoids (like monoterpenes and carotenoids) and polyphenols (like quercetin and other flavonoids) are important phytochemicals with a broad range of antioxidant effects. These phytochemicals are widely distributed in fruits and vegetables, including agricultural waste, and are remarkably useful in food preservation, as they show bioactivity as plant antioxidants, able to scavenge reactive oxygen and nitrogen species, such as superoxide, hydroxyl or peroxyl radicals in meat and other products, contributing to the prevention of lipid oxidation processes in food matrices.

Coronavirus-related disease 2019 (COVID-19) became a pandemic in February 2020, and worldwide researchers try to tackle the disease with approved drugs of all kinds, or to develop novel compounds inhibiting viral spreading. Flavonoids, already investigated as antivirals in general, also might bear activities specific for the viral agent causing COVID-19, SARS-CoV-2. Microbial biotechnology and especially synthetic biology may help to produce flavonoids, which are exclusive plant secondary metabolites, at a larger scale or indeed to find novel pharmaceutically active flavonoids. Here, we review the state of the art in (i) antiviral activity of flavonoids specific for coronaviruses and (ii) results derived from computational studies, mostly docking studies mainly inhibiting specific coronaviral proteins such as the 3CL (main) protease, the spike protein or the RNA-dependent RNA polymerase. In the end, we strive towards a synthetic biology pipeline making the fast and tailored production of valuable antiviral flavonoids possible by applying the last concepts of division of labour through co-cultivation/microbial community approaches to the DBTL (Design, Build, Test, Learn) principle., (© 2020 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Objective: This study provides a series of updated, evidence-based recommendations for the management of acute stroke. We aim to lay a foundation for the development of individual centres' internal protocols, serving as a reference for nursing care., Methods: We review the available evidence on acute stroke care. The most recent national and international guidelines were consulted. Levels of evidence and degrees of recommendation are based on the Oxford Centre for Evidence-Based Medicine classification., Results: The study describes prehospital acute stroke care, the operation of the code stroke protocol, care provided by the stroke team upon the patient's arrival at hospital, reperfusion treatments and their limitations, admission to the stroke unit, nursing care in the stroke unit, and discharge from hospital., Conclusions: These guidelines provide general, evidence-based recommendations to guide professionals who care for patients with acute stroke. However, limited data are available on some aspects, showing the need for continued research on acute stroke management., (Copyright © 2020 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound-healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236-51. ©2016 AACR., (©2016 American Association for Cancer Research.)

Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that treating Ewing Sarcoma cells with JQ1(+), a BET bromodomain inhibitor, represses directly EWS-Fli1 transcription as well as its transcriptional program. Moreover, the Chromatin Immuno Precipitation experiments demonstrate for the first time that these results are a consequence of the depletion of BRD4, one of the BET bromodomains protein from the EWS-Fli1 promoter. In vitro, JQ1(+) treatment reduces the cell viability, impairs the cell clonogenic and the migratory abilities, and induces a G1-phase blockage as well as a time- and a dose-dependent apoptosis. Furthermore, in our in vivo model, we observed a tumor burden delay, an inhibition of the global vascularization and an increase of the mice overall survival. Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context., Competing Interests: Dr. Bradner is the scientific founder of Tensha Therapeutics which has licensed drug like inhibitors of BET bromodomains from the Dana-Farber Cancer Institute for clinical translation as cancer therapeutics.

One of the most important limitations of mammalian cell-based processes is the secretion and accumulation of lactate as a by-product of their metabolism. Among the cell lines commonly used in industrial bioprocesses, HEK293 has been gaining importance over the last years. Up recently, HEK293 cells were known to consume lactate in late stages of cell culture usually when glucose and/or glutamine were depleted from media. Remarkably, in both scenarios, no significant cell growth was reported. However, we have observed a different metabolic behavior regarding lactate production and consumption in HEK293 cultures. HEK293 cells were able to co-metabolize glucose and lactate simultaneously, even in exponentially growing cell cultures. Our deep study of the effects of environmental conditions on lactate metabolism revealed that pH was the key to trigger the metabolic shift from lactate production to lactate and glucose concomitant consumption. Remarkably, this shift could be triggered at will when pH was set at 6.8. Even more interesting was the fact that lowering pH to 6.6 and supplementing media with exogenous lactate resulted in co-consumption of glucose and lactate from the beginning of cell culture, without affecting cell growth or protein productivity. On the contrary, cell growth was clearly hampered at this low pH if extracellular lactate was lacking. From our results, we hypothesize that HEK293 cells metabolize extracellular lactate as a strategy for pH detoxification, by means of co-transporting extracellular protons together with lactate into the cytosol. This novel hypothesis for unraveling lactate metabolism in HEK293 cells could open a door to re-direct genetic engineering strategies in order to obtain more efficient cell lines and also to further develop animal cell technology applications.

The increasing demand for biopharmaceuticals produced in mammalian cells has lead industries to enhance bioprocess volumetric productivity through different strategies. Among those strategies, cell culture media development is of major interest. In the present work, several commercially available culture media for Human Embryonic Kidney cells (HEK293) were evaluated in terms of maximal specific growth rate and maximal viable cell concentration supported. The main objective was to provide different cell culture platforms which are suitable for a wide range of applications depending on the type and the final use of the product obtained. Performing simple media supplementations with and without animal derived components, an enhancement of cell concentration from 2 × 10(6) cell/mL to 17 × 10(6) cell/mL was achieved in batch mode operation. Additionally, the media were evaluated for adenovirus production as a specific application case of HEK293 cells. None of the supplements interfered significantly with the adenovirus infection although some differences were encountered in viral productivity. To the best of our knowledge, the high cell density achieved in the work presented has never been reported before in HEK293 batch cell cultures and thus, our results are greatly promising to further study cell culture strategies in bioreactor towards bioprocess optimization., (Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development.

In previous studies we have shown that seminal plasma (SP) proteins can prevent and repair cold-shock membrane damage to ram spermatozoa. Three proteins of approximately 14, 20 and 22kDa, mainly responsible for this protective ability, were identified in ram SP. They are exclusively synthesized in the seminal vesicles and, consequently, named RSVP14, RSVP20 and RSVP22. The aim of this study is to characterize and express the RSVP14 gene to provide new insights into the mechanisms through which SP proteins are able to protect spermatozoa. Additionally, a first approach has been made to the recombinant protein production. The cDNA sequence obtained encodes a 129 amino acid chain and presents a 25-amino acid signal peptide, one potential O-linked glycosylation site and seven phosphorylation sites on tyrosine, serine and threonine residues. The sequence contains two FN-2 domains, the signature characteristic of the bovine seminal plasma (BSP) protein family and related proteins of different species. More interestingly, it was shown that RSVP14 contains four disulphide bonds and a cholesterol recognition/interaction amino acid consensus (CRAC) domain, also found in BSP and similar proteins. Analysis of the relationships between RSVP14 and other mammalian SP proteins revealed a 76-85% identity, particularly with the BSP protein family. The recombinant protein was obtained in insect cell extracts and in Escherichia coli in which RSVP14 was detected in both the pellet and the supernatant. The results obtained corroborate the role of RSVP14 in capacitation and might explain its protective effect against cold-shock injury to the membranes of ram spermatozoa. Furthermore, the biochemical and functional similarities between RSVP14 and BSP proteins suggest that it might play a similar role in sperm functionality., (Copyright © 2013 Elsevier B.V. All rights reserved.)

As the oxygen tension of inspired air falls with increasing altitude in normal subjects, hyperventilation ensues. This acute respiratory alkalosis, induces increased renal excretion of bicarbonate, returning the pH back to normal, giving rise to compensated respiratory alkalosis or chronic hypocapnia. It seems a contradiction that so many normal people at high altitude should permanently live as chronic acid-base patients. Blood gas analyses of 1,865 subjects at 3,510 m, reported a P(a)CO(2) (arterial carbon dioxide tension ± SEM) = 29.4 ± 0.16 mmHg and pH = 7.40 ± 0.005. Base excess, calculated with the Van Slyke sea level equation, is -5 mM (milliMolar or mmol/l) as an average, suggesting chronic hypocapnia. THID, a new term replacing "Base Excess" is determined by titration to a pH of 7.40 at a P(a)CO(2) of 5.33 kPa (40 mmHg) at sea level, oxygen saturated and at 37°C blood temperature. Since our new modified Van Slyke equations operate with normal values for P(a)CO(2) at the actual altitude, a calculation of THID will always result in normal values-that is, zero.

Adaptation takes place not only when going to high altitude, as generally accepted, but also when going down to sea level. Immediately upon ascent to high altitude, the carotid body senses the lowering of the arterial oxygen partial pressure due to a diminished barometric pressure. High altitude adaptation is defined as having three stages: 1) acute, first 72 hours, where acute mountain sickness (CMS or polyerythrocythemia) can occur; 2) subacute, from 72 hours until the slope of the hematocrit increase with time is zero; here high altitude subacute heart disease can occur; and 3) chronic, where the hematocrit level is constant and the healthy high altitude residents achieve their optimal hematocrit. In the chronic stage, patients with CMS increase their hematocrit values to levels above that of normal individuals at the same altitude. CMS is due to a spectrum of medical disorders focused on cardiopulmonary deficiencies, often overlooked at sea level. In this study we measured hematocrit changes in one high altitude resident traveling several times between La Paz (3510 m) and Copenhagen (35 m above sea level) for the past 3 years. We have also studied the fall in hematocrit values in 2 low-landers traveling once from La Paz to Copenhagen. High altitude adaptation is altitude and time dependent, following the simplified equation: Adaptation=Time/Altitude where High altitude adaptation factor=Time at altitude (days)/Altitude in kilometers (km). A complete and optimal hematocrit adaptation is only achieved at around 40 days for a subject going from sea level to 3510 m in La Paz. The time in days required to achieve full adaptation to any altitude, ascending from sea level, can be calculated by multiplying the adaptation factor of 11.4 times the altitude in km. Descending from high altitude in La Paz to sea level in Copenhagen, the hematocrit response is a linear fall over 18 to 23 days.

Chronic Mountain Sickness (CMS) patients have repeatedly been found to hypoventilate. Low saturation in CMS is attributed to hypoventilation. Although this observation seems logical, a further understanding of the exact mechanism of hypoxia is mandatory. An exercise study using the Bruce Protocol in CMS (n = 13) compared to normals N (n = 17), measuring ventilation (VE), pulse (P), and saturation by pulse oximetry (SaO(2)) was performed. Ventilation at rest while standing, prior to exercise in a treadmill was indeed lower in CMS (8.37 l/min compared with 9.54 l/min in N). However, during exercise, stage one through four, ventilation and cardiac frequency both remained higher than in N. In spite of this, SaO(2) gradually decreased. Although CMS subjects increased ventilation and heart rate more than N, saturation was not sustained, suggesting respiratory insufficiency. The degree of veno-arterial shunting of blood is obviously higher in the CMS patients both at rest and during exercise as judged from the SaO(2) values. The higher shunt fraction is due probably to a larger degree of trapped air in the lungs with uneven ventilation of the CMS patients. One can infer that hypoventilation at rest is an energy saving mechanism of the pneumo-dynamic and hemo-dynamic pumps. Increased ventilation would achieve an unnecessary high SaO(2) at rest (low metabolism). This is particularly true during sleep.

Chronic mountain sickness (CMS) is a condition in which hematocrit is increased above the normal level in residents at high altitude. In this article we take issue with the "Consensus Statement On Chronic And Subacute High Altitude Diseases" of 2005 on two essential points: using a questionnaire to evaluate the symptoms of CMS to use the term "loss of adaptation" as opposed to "adaptation to disease in the hypoxic environment". We opine that CMS is rather an adaptive reaction to an underlying malfunction of some organs and no specific symptoms could be quantified. To substantiate our line of reasoning we reviewed 240 CMS cases seen at the High Altitude Pathology Institute in La Paz. Patients who had a high hematocrit (<58%) underwent pulmonary function studies in search for the cause of hypoxia: hypoventilation, diffusion alteration, shunts, and uneven ventilation-perfusion. The tests included arterial blood gas tests, chest x-rays, spirometry, hyperoxic tests, flow-volume curves, ventilation studies at rest and during exercise, ECG, exercise testing and doppler color echocardiography to assess heart structure and function. When correlated with clinical history these results revealed that CMS is practically always secondary to some type of anomaly in cardio-respiratory or renal function. Therefore, a questionnaire that tries to catalog symptoms common to many types of diseases that lead to hypoxia is flawed because it leads to incomplete diagnosis and inappropriate treatment. CMS, once again, was shown to be an adaptation of the blood transport system to a deficient organs' function due to diverse disease processes; the adaptation aimed at sustaining normoxia at the cellular level in the hypoxic environment at high altitude.

Pulse oximetry during breath-holding (BH) in normal residents at high altitude (3510 m) shows a typical graph pattern. Following a deep inspiration to total lung capacity (TLC) and subsequent breath-holding, a fall in oxyhemoglobin saturation (SaO(2) is observed after 16 s. The down-pointed peak in SaO(2) corresponds to the blood circulation time from the alveoli to the finger where the pulse oximeter probe is placed. This simple maneuver corroborates the measurement of circulation time by other methods. This phenomenon is even observed when the subject breathes 88% oxygen (PIO(2) = 403 mmHg for a barometric pressure of 495 mmHg). BH time is, as expected, prolonged under these circumstances. Thus the time delay of blood circulation from pulmonary alveoli to a finger is measured non-invasively. In the present study we used this method to compare the circulation time in 20 healthy male high altitude residents (Group N with a mean hematocrit of 50%) and 17 chronic mountain sickness patients (Group CMS with a mean hematocrit of 69%). In the two study groups, the mean circulation time amounted to 15.94 +/-2.57 s (SD) and to 15.66 +/-2.74 s, respectively. The minimal difference was not significant. We conclude that the CMS patients adapted their oxygen transport rate to the rise in hematocrit and blood viscosity.