Well-proven Strategy Research Articles

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

P2518Failure of completion of post-myocardial infarction rehabilitation programme - Who and why? Single center experience with novel Coordinated Comprehensive Care program in Poland

Abstract Background Rehabilitation after acute myocardial infarction is a well-proven strategy to improve outcomes and reduce complications rate. Poland recently introduced a novel, fully-reimbursed Coordinated Comprehensive Care (CCC) program after myocardial infarction, a significant portion of which comprises access to free-of-charge cardiac rehabilitation. Purpose The purpose of the study was to analyze all patients qualified for the Coordinated Comprehensive Care Program and evaluate reasons for not completing rehabilitation. We compared two groups of patients - those who completed the rehabilitation and those that did not - in terms of clinical, demographic and laboratory characteristics. Methods All patients (n=169) referred from the cardiology department for the CCC program were included in the study. They were divided into two groups, depending on single, strict criterium of completion or non-completion of the rehabilitation program. Demographic, clinical and laboratory data were collected and analyzed. Results The majority of the patients (n=100, 59.2%) did not undergo cardiac rehabilitation. 61 of them were not qualified for rehabilitation programme by the consortium of doctors: 33 of them due to the need for further invasive treatment, the remainder 28 were disqualified due to severe comorbidities. 32 patients did not commence the program despite referral and encouragement, mostly (n=25) due to personal reasons, 7 patients did not specify reasons for not participating in the rehabilitation. 7 patients were lost to follow-up. Patients who completed rehabilitation (n=69, 40.8%) were younger that those who did not (64.4±9.8 vs. 67.1±9.5 years, respectively; p=0.076), had significantly higher baseline LVEF (49.1±9.4 vs. 44.7±11.9%, p<0.03), and had lower serum creatinine level (0.99±0.28 vs. 1.15±0.59 mg/dl; p<0.03). There were more patients with LVEF<35% (n=23; 23%) in the no-rehabilitation, than in the other group (n=5; 7.25%; p<0.01). Rehabilitation completed (n=69) Rehabilitation NOT completed (n=100) p Gender – male 40 (35.4%) 73 (64.6%) <0.05 LVEF- % 49.12 (±9.43) 44.69 (±11.97) <0.03 No. of patients with EF <35% 5 (7.25%) 23 (23%) <0.01 Conclusion Although fully-reimbursed cardiac rehabilitation is provided for all patients following acute myocardial infarction, there is a significant number of patients who fail to complete the programme. This group comprises more male patients with worse clinical and laboratory test results, especially LVEF and renal function. Efforts should be made to address the problem and modify the programme accordingly.

A simple graphical method to pinpoint local pseudosymmetries inZ′ > 1 cases

An intuitive method is presented for detecting pseudosymmetries in Z' > 1 cases as a complement to well-proven strategies already available in the literature. It is based in the simple idea that the mid-points between equivalent atoms in symmetrically related molecules are disposed according to simple well-known patterns, which are easily recognizable by optical inspection. A number of Z'= 4 cases in the literature are analyzed, which allows some of the potentialities of the method to be revealed.

Performance of a Code Migration for the Simulation of Supersonic Ejector Flow to SMP, MIC, and GPU Using OpenMP, OpenMP+LEO, and OpenACC Directives

A serial source code for simulating a supersonic ejector flow is accelerated using parallelization based on OpenMP and OpenACC directives. The purpose is to reduce the development costs and to simplify the maintenance of the application due to the complexity of the FORTRAN source code. This research follows well-proven strategies in order to obtain the best performance in both OpenMP and OpenACC. OpenMP has become the programming standard for scientific multicore software and OpenACC is one true alternative for graphics accelerators without the need of programming low level kernels. The strategies using OpenMP are oriented towards reducing the creation of parallel regions, tasks creation to handle boundary conditions, and a nested control of the loop time for the programming in offload mode specifically for the Xeon Phi. In OpenACC, the strategy focuses on maintaining the data regions among the executions of the kernels. Experiments for performance and validation are conducted here on a 12-core Xeon CPU, Xeon Phi 5110p, and Tesla C2070, obtaining the best performance from the latter. The Tesla C2070 presented an acceleration factor of 9.86X, 1.6X, and 4.5X compared against the serial version on CPU, 12-core Xeon CPU, and Xeon Phi, respectively.

Strategies to Improve Recovery in Acute Ischemic Stroke Patients: Iberoamerican Stroke Group Consensus

Stroke is not only a leading cause of death worldwide but also a main cause of disability. In developing countries, its burden is increasing as a consequence of a higher life expectancy. Whereas stroke mortality has decreased in developed countries, in Latin America, stroke mortality rates continue to rise as well as its socioeconomic dramatic consequences. Therefore, it is necessary to implement stroke care and surveillance programs to better describe the epidemiology of stroke in these countries in order to improve therapeutic strategies. Advances in the understanding of the pathogenic processes of brain ischemia have resulted in development of effective therapies during the acute phase. These include reperfusion therapies (both intravenous thrombolysis and interventional endovascular approaches) and treatment in stroke units that, through application of management protocols directed to maintain homeostasis and avoid complications, helps to exert effective brain protection that decreases further cerebral damage. Some drugs may enhance protection, and besides, there is increasing knowledge about brain plasticity and repair mechanisms that take place for longer periods beyond the acute phase. These mechanisms are responsible for recovery in certain patients and are the focus of basic and clinical research at present. This paper discusses recovery strategies that have demonstrated clinical effect, or that are promising and need further study. This rapidly evolving field needs to be carefully and critically evaluated so that investment in patient care is grounded on well-proven strategies.

Personalized Medicine in Oncology: Where Have we Come From and Where are we Going?

Current advances in the biology of cancer and emergence of new tools for genome analysis have opened clinical perspectives in oncology, generally termed as 'personalized medicine'. This broad term must encompass previous well-proven strategies, such as pharmacogenetics- and pharmacokinetics-based dosing, with more recently introduced pharmacogenomics approaches, all applied as a means to tailor treatment to a given patient presenting with a given tumor. Despite outstanding results in lung cancer, colorectal cancer and melanoma, only a few predictive biomarkers are currently justified in routine clinical practice. Overall, there is a persistent gap between the growing number of identified deregulated pathways or genetic mutations, both at the tumor and the constitutional levels, and their actual implementation at the bedside as part of clinical routine. This article underlines these limitations and covers several issues that may explain the discrepancy between the plethora of published data about emerging biomarkers, and the relative scarcity of tests eventually reaching a clinically validated application. The main identified difficulties concern invasive and costly prospective biomarker studies and the issue of tumor heterogeneity. Finally, early trial designs for targeted therapies as well as those for conventional cytotoxics may not necessarily address the right questions by skipping critical end points. Proposed solutions point out the use of liquid biopsies and systems biology approaches, for an easier implementation of personalized medicine at the bedside.

ISM for the inhibitors of service supply chain: a case study in a safety health environment and risk consultancy service sector

This paper discusses the practical contribution of ISM to model the inhibitors of a safety health environment and risk (SHER) service supply chain in the Indian context. ISM is a well-proven strategy for analysing the synergic influences of various attributes which affect the overall system under study. The unique feature of ISM is that it analyses the attributes based on their driving power and dependence. In the current study, the ISM model has been developed for a leading industrial safety service provider operating in various global regions having its headquarters in the UK. The inhibitors in the service supply chain were identified and subjected to ISM based analysis. Initial reachability metrics and final reachability metrics were made. This paper illustrates the hierarchy of various inhibitors based on the outcomes of the final reachability metrics. The digraphs were constructed. Finally, MICMAC analysis was carried out to categorise the inhibitors into four clusters. The paper is concluded with action plans and scope for future work.

A review of prevention and control of heifer mastitis via non-antibiotic strategies

Clinical and subclinical mastitis is a significant problem in primiparous dairy cattle (heifers) with a higher prevalence and incidence in heifers than cows, especially early in lactation. Differences in management (e.g. nutrition, pasturing, no use of dry cow therapy) as well as differences in physiological status (e.g. continuing growth in heifers) are likely contribute to the observed differences between heifers and cows. These differences may result in the requirement for different approaches for mastitis management in heifers than for cows. Mastitis is a multifactorial disease, hence control requires an understanding of the risk factors before effective interventions can be defined. Control strategies are aimed at reducing the incidence of new intramammary infections and eliminating existing infections. Potential strategies can include improved environmental and animal hygiene, application of internal and external teat sealants, prepartum application of teat antiseptics, prepartum milking and control of horn fly in environments where it acts as vector. Other less well-proven strategies to control heifer mastitis include management of heifers as a physically separate group from older cows and not feeding mastitic milk to calves. It is concluded that several well-proven strategies are available to manage heifer mastitis. However, further research is likely to improve understanding of heifer mastitis and lead to novel managerial approaches to mastitis control in this age group.

A cost-effective design for a neutrino factory

The design of a neutrino factory based on a muon storage ring draws upon several tried and tested technologies, upon existing design work for other accelerator projects, e.g. neutron spallation sources, but it also depends on the development of technical solutions to certain specific requirements. These include the efficient capture of muons in a large volume of phase-space, some reduction in overall phase-space volume by ionization cooling, fast acceleration to the desired energy to avoid unacceptable decay losses and storage in a decay ring optimized for its purpose as a neutrino source. There is no obvious single combination of machines to achieve this aim. Here we present a scenario which relies to a large extent upon known technologies together with a relatively unambitious mix of new schemes. Some will be tried and tested during design and construction; others during the early operational phase of the facility leading to a staged upgrade path – a well-proven strategy in the development of accelerator complexes.

Modified Smith predictor for extruded diameter control

An overview is given of an adaptive strategy for controlling output dimensions from a plastic-on-wire extrusion process, using gain-scheduled PI control in a Smith predictor control scheme. Process behaviour is most easily understood and predicted by developing a process model, and hence the article details the problem of modelling the extrusion process, with the objective of developing a standardised routine for tuning dimensional control systems. The article describes the model of diameter measurement on a cable extrusion process which was used to provide the basis for further analysis and simulation. Next, three alternative control strategies for the diameter control problem are reviewed and compared, illustrating that a combination of well-proven strategies can give significant performance improvements.