The Role of Kinase Inhibitors in Cancer Therapies

Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. Methods/design The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. Trial registration ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1929-0) contains supplementary material, which is available to authorized users

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Replacing the Image of the Ottoman Turk: Le Bourgeois Gentilhomme and Turquerie as Resistance

Thesis (Ph.D.)--University of Washington, 2021This dissertation examines the cultural and diplomatic clashes that happened in the 17th century between the Ottoman Empire and France beginning with an Ottoman envoy’s visit to Louis XIV’s Court in France in 1669. This visit has generally been given the labels “failed” and “scandalous” by the western scope as a result of consequent conflicts that occurred between these states’ representatives. In every moment that these representatives encountered each other, their performances reveal fascination and confusion in trying to make sense of one another. This study provides a close examination of these performative interactions which reveal that this event was not necessarily a failure, but rather a commencement of spectacular social reactions. Throughout the visit of Ambassador Müteferrika Süleyman Ağa, French officials were skeptical about the envoys’ mission and did not know how to treat them, which resulted in novel theatrical interactions such as the French foreign minister impersonating the Ottoman Grand Vizier. This haphazard attempt to gain the upper hand in diplomacy, I argue, led to the adoption of and permission to use Ottoman identifiers which developed into the practice of turquerie. Throughout the century turquerie became a tool that was used to declare either political power for its practitioner or resistance to authoritarian power. Thus, the visit, even years after it occurred, has impacted French identity and its “high” culture. This study analyzes the performativity of these events, their well-known products such as Le Bourgeois Gentilhomme and turquerie, how they shaped these states’ identities and politics, and the ways in which they still affect the scholarly approach to this period. Rather than relying solely on French sources, I re-examine this encounter by including Ottoman sources of diplomatic and cultural customs. This methodological approach reveals the French political agenda behind this interaction and why this encounter, which has historically been referred to as a diplomatic failure, may have been purposely orchestrated. I argue that giving an equal voice to the point of view of the Ottoman Empire changes our conception of this, and similar, diplomatic and artistic performances

Thermal design and analysis of a shell and tube heat exchanger integrating a geothermal based organic Rankine cycle and parabolic trough solar collectors

In this paper, the design and analysis of a shell and tube heat exchanger used to combine parabolic trough solar collectors (PTSCs) and an organic Rankine cycle (ORC) based geothermal power plant is presented. A thermal model for the PTSC was first used to find the temperature of the thermal oil entering the heat exchanger under different solar irradiation intensity. Then, a detailed thermal model for the shell and tube heat exchanger based on logarithmic mean temperature difference method was formed. A computer code was developed using Engineering Equation Solver to study the effect of some key design parameters on the heat transfer surface area of the heat exchanger and the pumping power. Furthermore, a two-stage Taguchi method was applied to find the design parameters that give the minimum heat transfer surface area and pumping power. In addition, the effect of the solar irradiation intensity on the optimum design parameters was assessed. The results show that the baffle spacing is the most dominant design parameter; and Therminol VP1 or Dowtherm A as the PTSC side fluid and R245fa or R600 as the ORC side fluid should be selected. In addition, it was found that when the solar irradiation intensity increases from 450 W/m(2) to 1000 W/m(2), the minimum heat transfer surface area increases from 2.644 m(2) to 8.681 m(2). (C) 2017 Elsevier Ltd. All rights reserved

Current evidence on the efficacy and safety of generic imatinib in CML and the impact of generics on health care costs

Since the introduction of imatinib, the management of chronic myeloid leukemia (CML) has changed considerably. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment; however, the high financial burden of TKIs can be problematic for both the patients and health care systems. After the emergence of generics, reimbursement policies of many countries have changed, and generics offered an alternative treatment option for CML patients. There are many papers published on the use of generics in CML patients with conflicting results regarding both efficacy and safety. In this paper, we systematically reviewed the current literature on generic imatinib use in CML, and 36 papers were evaluated. Both in vitro and in vivo studies of generic imatinib showed comparable results with branded imatinib in terms of bioequivalence and bioavailability. In most studies, generics were comparable with the original molecule in terms of efficacy and safety, both in newly diagnosed patients and after switching from Gleevec. Some generic studies showed contradictory findings regarding efficacy and toxicity, and these differences can be attributed to some factors including the use of different generics in different countries. Both in hypothetical models and in real life, introduction of generic imatinib caused significant reduction in health care costs. In conclusion, generics are not inferior to original imatinib in terms of efficacy with an acceptable toxicity profile. Notwithstanding the generally favorable efficacy and safety of generics worldwide to date, we most probably still need more time to draw firmer conclusions on the longer-term outcomes of generics

Thermodynamic optimisation of a hybrid solar-geothermal power plant using Taguchi method

In this paper, an exergetic optimisation of a hybrid solar-geothermal power plant based on Taguchi method is presented. The effects of ambient temperature and solar irradiance on the output parameters of the system were first studied using a thermal model. Then, an optimisation study based on Taguchi method was performed to find the values of the key design and operating parameters that maximises the net power output and the electrical and exergetic efficiencies of the system. The results of this study showed that when the solar irradiance increases, the net power output and the exergetic and electrical efficiencies increase. It was also shown that the turbine inlet and exit pressures are the most dominant factors affecting the performance of the system. In addition, the net power output and the electrical and exergetic efficiencies can be increased up to 16,773 kW, 21.63%, and 70.06%, respectively, for the case study conducted