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Clinical Colorectal Cancer Sep 2014Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic... (Review)
Review
Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic colorectal cancer (mCRC). The approval of 3 agents that target angiogenic signaling, bevacizumab, ziv-aflibercept, and regorafenib, provides strong evidence that angiogenesis is an important process in mCRC. The addition of bevacizumab to combination chemotherapy in the first- and second-line treatment of mCRC has resulted in meaningful improvement in overall and progression-free survival. The standard of care for mCRC has evolved to incorporate cytotoxic chemotherapy as the backbone regimens (eg, FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]) with or without bevacizumab, and epidermal growth factor receptor-targeted therapies (eg, cetuximab, panitumumab) in the setting of wild-type KRAS. The development of ziv-aflibercept in combination with FOLFIRI has improved clinical efficacy in the second-line treatment of mCRC. Regorafenib, a small-molecule multikinase inhibitor, has recently been approved by the US Food and Drug Administration as single-agent therapy in the treatment of refractory and progressive mCRC. Each of these agents has been integrated into an evidence-based-albeit, still evolving-treatment continuum for initial treatment, treatment after first progression, and treatment after second progression. However, the most effective strategy for the use of these agents, and others in development remains unclear. This review provides an overview of the current clinical evidence for the use of antiangiogenic agents targeting in the treatment of mCRC.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaloacetates; Phenylurea Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retreatment; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; ras Proteins
PubMed: 24768040
DOI: 10.1016/j.clcc.2014.02.001 -
Echo Research and Practice Aug 2022The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents... (Review)
Review
The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents (UEAs) in echocardiography, based on more than two decades of experience in the use of UEAs for cardiac imaging. The protocols reflect current clinical CEUS practice in many modern echocardiography laboratories throughout the world. Specific attention is given to preparation and dosing of three UEAs that have been approved by the United States Food and Drug Administration (FDA) and additional regulatory bodies in Europe, the Americas and Asia-Pacific. Consistent with professional society guidelines (J Am Soc Echocardiogr 31:241-274, 2018; J Am Soc Echocardiogr 27:797-810, 2014; Eur Heart J Cardiovasc Imaging 18:1205, 2017), these protocols cover unapproved "off-label" uses of UEAs-including stress echocardiography and myocardial perfusion imaging-in addition to approved uses. Accordingly, these protocols may differ from information provided in product labels, which are generally based on studies performed prior to product approval and may not always reflect state of the art clinical practice or guidelines.
PubMed: 35996167
DOI: 10.1186/s44156-022-00008-3 -
Respiratory Physiology & Neurobiology Oct 2021Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in...
Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in this study. The harmonic distortion index (k) was used to assess the respiratory system nonlinearity. The analysis of variance showed difference between groups (OVA vs control) and among doses for both protocols. Bolus protocol posttest: there was a difference between OVA and control at 0.3 and 1 mg/kg doses (p<0.0001 and p<0.001) for R. Infusion: there was a difference between OVA and control at 192 μg.kg.min dose for R, G and H, (p<0.01; p<0.001; p<0.001). An increment was found in k values near to the observed peak values in bolus protocol. The bolus protocol could better differentiate inflamed and non-inflamed airway resistance, whereas the differences between OVA and control in continuous infusion protocol were associated to airway- and, mainly, parenchyma-related parameters. Moreover, the bolus protocol presented a higher nonlinear degree compared to the infusion protocol.
Topics: Animals; Asthma; Bronchoconstrictor Agents; Disease Models, Animal; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Models, Theoretical; Respiratory Mechanics
PubMed: 34062282
DOI: 10.1016/j.resp.2021.103705 -
International Journal of Molecular... Jul 2023The aim of our laboratory-based study was to investigate the extent of delayed-onset cell death after cryopreservation in endothelial and epithelial cell lines of...
The aim of our laboratory-based study was to investigate the extent of delayed-onset cell death after cryopreservation in endothelial and epithelial cell lines of ovarian origin. We found differences in percentages of vital cells directly after warming and after cultivation for 48 to 72 h. A granulosa cell line of endothelial origin (KGN) and an epithelial cell line (OvCar-3) were used. In both DMSO-containing and DMSO-free protocols, significant differences in vitality rates between the different cell lines when using open and closed vitrification could be shown (DMSO-containing: KGN open vs. OvCar open, = 0.001; KGN closed vs. OvCar closed, = 0.001; DMSO-free: KGN open vs. OvCar open, = 0.001; KGN closed vs. OvCar closed, = 0.031). Furthermore, there was a marked difference in the percentage of vital cells immediately after warming and after cultivation for 48 to 72 h; whereas the KGN cell line showed a loss of cell viability of 41% using a DMSO-containing protocol, the OvCar-3 cell loss was only 11% after cultivation. Using a DMSO-free protocol, the percentages of late-onset cell death were 77% and 48% for KGN and OvCar-3 cells, respectively. Our data support the hypothesis that cryopreservation-induced damage is cell type and cryoprotective agent dependent.
Topics: Female; Humans; Apoptosis; Cell Line, Tumor; Ovarian Neoplasms; Cryopreservation; Cryoprotective Agents; Granulosa Cells; Dimethyl Sulfoxide
PubMed: 37569601
DOI: 10.3390/ijms241512225 -
Pharmacy (Basel, Switzerland) Aug 2019Antimicrobial desensitization represents a last-line option for patients with no alternative therapies, where the benefits of this intensive process must outweigh the... (Review)
Review
Antimicrobial desensitization represents a last-line option for patients with no alternative therapies, where the benefits of this intensive process must outweigh the potential harm from drug exposure. The goal of antimicrobial desensitization procedures is to establish a temporary state of tolerance to drugs that may otherwise cause hypersensitivity reactions. While no universal antimicrobial desensitization protocols exist, this review critically analyzes previously published desensitization protocols. The purpose of this review is to provide a greater insight for clinicians and institutions to ensure desensitization procedures are efficacious while minimizing potential for patient harm. With an increasing rate of antimicrobial resistance and the critical need to preserve antimicrobial agents, desensitization may represent another option in our antimicrobial stewardship toolkit.
PubMed: 31405062
DOI: 10.3390/pharmacy7030112 -
Autonomous Agents and Multi-agent... 2021We propose a formalism to model and reason about reconfigurable multi-agent systems. In our formalism, agents interact and communicate in different modes so that they...
We propose a formalism to model and reason about reconfigurable multi-agent systems. In our formalism, agents interact and communicate in different modes so that they can pursue joint tasks; agents may dynamically synchronize, exchange data, adapt their behaviour, and reconfigure their communication interfaces. Inspired by existing multi-robot systems, we represent a system as a set of agents (each with local state), executing independently and only influence each other by means of message exchange. Agents are able to sense their local states and partially their surroundings. We extend ltl to be able to reason explicitly about the intentions of agents in the interaction and their communication protocols. We also study the complexity of satisfiability and model-checking of this extension.
PubMed: 34776761
DOI: 10.1007/s10458-021-09521-x -
International Journal of Molecular... Nov 2021Corneal cryopreservation can partially solve the worldwide concern regarding donor cornea shortage for keratoplasties. In this study, human corneas were cryopreserved...
Corneal cryopreservation can partially solve the worldwide concern regarding donor cornea shortage for keratoplasties. In this study, human corneas were cryopreserved using two standard cryopreservation protocols that are employed in the Tissue Bank of the Teresa Herrera Hospital (Spain) to store corneas for tectonic keratoplasties (TK protocol) and aortic valves (AV protocol), and two vitrification protocols, VS55 and DP6. Endothelial viability and general corneal state were evaluated to determine the protocol that provides the best results. The potential corneal cryopreservation protocol was studied in detail taking into consideration some cryopreservation-related variables and the endothelial integrity and stroma arrangement of the resulting cryopreserved corneas. TK corneas showed mostly viable endothelial cells, while the others showed few (AV) or none (DP6 and VS55). The corneal structure was well maintained in TK and AV corneas. TK corneas showed endothelial acellular areas surrounded by injured cells and a normal-like stromal fiber arrangement. Cryoprotectant solutions of the TK protocol presented an increasing osmolality and a physiological pH value. Cooling temperature rate of TK protocol was of 1 °C/min to -40 °C and 3 °C/min to -120 °C, and almost all of dimethyl sulfoxide left the tissue after washing. Future studies should be done changing cryopreservation-related variables of the TK protocol to store corneas of optical grade.
Topics: Cold Temperature; Cornea; Corneal Transplantation; Cryopreservation; Dimethyl Sulfoxide; Endothelium, Corneal; Humans; Microscopy, Electron, Scanning; Spain; Tissue Banks
PubMed: 34830446
DOI: 10.3390/ijms222212564 -
EFSA Journal. European Food Safety... Oct 2023EFSA Strategy 2027 outlines the need for fit-for-purpose protocols for EFSA generic scientific assessments to aid in delivering trustworthy scientific advice. This EFSA...
EFSA Strategy 2027 outlines the need for fit-for-purpose protocols for EFSA generic scientific assessments to aid in delivering trustworthy scientific advice. This EFSA Scientific Committee guidance document helps address this need by providing a harmonised and flexible framework for developing protocols for EFSA generic assessments. The guidance replaces the 'Draft framework for protocol development for EFSA's scientific assessments' published in 2020. The two main steps in protocol development are described. The first is problem formulation, which illustrates the objectives of the assessment. Here a new approach to translating the mandated Terms of Reference into scientifically answerable assessment questions and sub-questions is proposed: the 'APRIO' paradigm (Agent, Pathway, Receptor, Intervention and Output). Owing to its cross-cutting nature, this paradigm is considered adaptable and broadly applicable within and across the various EFSA domains and, if applied using the definitions given in this guidance, is expected to help harmonise the problem formulation process and outputs and foster consistency in protocol development. APRIO may also overcome the difficulty of implementing some existing frameworks across the multiple EFSA disciplines, e.g. the PICO/PECO approach (Population, Intervention/Exposure, Comparator, Outcome). Therefore, although not mandatory, APRIO is recommended. The second step in protocol development is the specification of the evidence needs and the methods that will be applied for answering the assessment questions and sub-questions, including uncertainty analysis. Five possible approaches to answering individual (sub-)questions are outlined: using evidence from scientific literature and study reports; using data from databases other than bibliographic; using expert judgement informally collected or elicited via semi-formal or formal expert knowledge elicitation processes; using mathematical/statistical models; and - not covered in this guidance - generating empirical evidence . The guidance is complemented by a standalone 'template' for EFSA protocols that guides the users step by step through the process of planning an EFSA scientific assessment.
PubMed: 37908452
DOI: 10.2903/j.efsa.2023.8312 -
Breast (Edinburgh, Scotland) Jun 2022The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However,... (Review)
Review
IMPORTANCE
The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease.
OBSERVATIONS
Using protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data.
CONCLUSIONS
and Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Central Nervous System Diseases; Clinical Trials, Phase III as Topic; Female; Humans; Receptor, ErbB-2; Trastuzumab
PubMed: 35344688
DOI: 10.1016/j.breast.2022.03.013 -
Leukemia & Lymphoma May 2017The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a... (Review)
Review
The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a significant advancement, HMA lead to responses in less than half of patients and for those that respond most will relapse. As such, there is a crucial need to improve frontline therapy approaches. One promising strategy involves combining azacitidine or decitabine with investigational or existing therapies with the goal of achieving synergistic activity and better patient outcomes. The purpose of this paper is to critically review the efficacy and safety of reported HMA-based combination regimens in patients with higher-risk MDS.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; DNA Methylation; Histone Deacetylase Inhibitors; Humans; Lenalidomide; Molecular Targeted Therapy; Myelodysplastic Syndromes; Protein Kinase Inhibitors; Thalidomide; Treatment Outcome
PubMed: 27654579
DOI: 10.1080/10428194.2016.1228927