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1
Cosway, B., V. Paleri, and J. Wilson. "Biomarkers predicting chemotherapy response in head and neck squamous cell carcinoma: a review." Journal of Laryngology & Otology 129, no. 11 (October 2, 2015): 1046–52. http://dx.doi.org/10.1017/s0022215115002479.
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AbstractBackground:Biomarkers are increasingly being used in many cancers to select patients for oncological treatment paradigms based on their inherent genetic properties. However, in head and neck cancers, there are no personalised therapies available outside the context of a clinical trial. A number of studies suggest there are intrinsic tumour properties of head and neck cancers that affect their response to chemotherapeutic agents. This paper aimed to review their evidence base.Method:A narrative review was conducted following a search of the PubMed database.Results and conclusion:The review identified a number of biomarkers predicting response to chemotherapy in head and neck cancers. The paper discusses these in detail, and explores where future research could be directed in order to deliver personalised therapies for patients with head and neck cancers.
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Gisbert, Javier P., and María Chaparro. "Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice." Journal of Crohn's and Colitis 14, no. 5 (November 28, 2019): 694–709. http://dx.doi.org/10.1093/ecco-jcc/jjz195.
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Abstract Background Inflammatory bowel diseases [IBD]―ulcerative colitis and Crohn’s disease―are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. Aim The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. Methods We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. Results For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. Conclusion In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
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Wang, Rui, Wentao Li, Esmée M. Bordewijk, Richard S. Legro, Heping Zhang, Xiaoke Wu, Jingshu Gao, et al. "First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis." Human Reproduction Update 25, no. 6 (October 23, 2019): 717–32. http://dx.doi.org/10.1093/humupd/dmz029.
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Abstract BACKGROUND Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment–covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17–1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23–1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38–2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01–1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00–1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00–1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87–1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01–1.06). WIDER IMPLICATIONS In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.
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GODOY, DANIELA, and ANALÍA AMANDI. "COLLABORATIVE WEB SEARCH BASED ON USER INTEREST SIMILARITY." International Journal of Cooperative Information Systems 17, no. 04 (December 2008): 495–521. http://dx.doi.org/10.1142/s0218843008001907.
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The motivation behind personal information agents resides in the enormous amount of information available on the Web, which has created a pressing need for effective personalized techniques. In order to assists Web search these agents rely on user profiles modeling information preferences, interests and habits that help to contextualize user queries. In communities of people with similar interests, collaboration among agents fosters knowledge sharing and, consequently, potentially improves the results of individual agents by taking advantage of the knowledge acquired by other agents. In this paper, we propose an agent-based recommender system for supporting collaborative Web search in groups of users with partial similarity of interests. Empirical evaluation showed that the interaction among personal agents increases the performance of the overall recommender system, demonstrating the potential of the approach to reduce the burden of finding information on the Web.
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Rattrout, Amjad, Rasha Assaf, and Ali Al-Dahoud. "Personalizing the dynamic information resources in a self organized web system using CAS and MAS." Computer Science and Information Systems 7, no. 4 (2010): 883–905. http://dx.doi.org/10.2298/csis090608023r.
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The Web is a constantly growing dynamic environment where the components are changed in non-linear ways. These components represent the targets to researches in order to better understand the behavior of the Web, where the owners and the users in this environment exist as out factors. Web page Usage information is the term which describes ways and methods of using the Web. Various factors affect the use of the diversity of the resources in the Web, The non-linear way of its growth, and the evolution in the methods for how we build the Web pages which eventually leads to reflecting the users? interests. Personalizing the results of search engines are created to meet the users need for information on the Web. Generally, the researchers seek user?s satisfaction through utilizing these search engines to serve the user. One of the most efficient methods in this domain is the use of semantic measure algorithms to personalize and recognize the outputs of the information resources according to the users' needs. The Web is represented as three aspects: Content, Structure, and Usage. Three components can lead to a personalized Web in order to reinforce the semantic value. This paper will present a model that uses new Web Usage information to see the effects on the semantic values, and how it will help us achieve a robust well personalized and organized Web. It will consider the Usage space as the field of our research as we will simulate this environment in the MAS ?Multi Agents System? and CAS ?Complex Adaptive System ?paradigm.
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Kocaballi, Ahmet Baki, Shlomo Berkovsky, Juan C. Quiroz, Liliana Laranjo, Huong Ly Tong, Dana Rezazadegan, Agustina Briatore, and Enrico Coiera. "The Personalization of Conversational Agents in Health Care: Systematic Review." Journal of Medical Internet Research 21, no. 11 (November 7, 2019): e15360. http://dx.doi.org/10.2196/15360.
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Background The personalization of conversational agents with natural language user interfaces is seeing increasing use in health care applications, shaping the content, structure, or purpose of the dialogue between humans and conversational agents. Objective The goal of this systematic review was to understand the ways in which personalization has been used with conversational agents in health care and characterize the methods of its implementation. Methods We searched on PubMed, Embase, CINAHL, PsycInfo, and ACM Digital Library using a predefined search strategy. The studies were included if they: (1) were primary research studies that focused on consumers, caregivers, or health care professionals; (2) involved a conversational agent with an unconstrained natural language interface; (3) tested the system with human subjects; and (4) implemented personalization features. Results The search found 1958 publications. After abstract and full-text screening, 13 studies were included in the review. Common examples of personalized content included feedback, daily health reports, alerts, warnings, and recommendations. The personalization features were implemented without a theoretical framework of customization and with limited evaluation of its impact. While conversational agents with personalization features were reported to improve user satisfaction, user engagement and dialogue quality, the role of personalization in improving health outcomes was not assessed directly. Conclusions Most of the studies in our review implemented the personalization features without theoretical or evidence-based support for them and did not leverage the recent developments in other domains of personalization. Future research could incorporate personalization as a distinct design factor with a more careful consideration of its impact on health outcomes and its implications on patient safety, privacy, and decision-making.
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Savinova, A. R., and I. G. Gataullin. "Personalized approach to the ovarian cancer treatment." Kazan medical journal 97, no. 3 (June 15, 2016): 388–93. http://dx.doi.org/10.17750/kmj2016-388.
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The aim of the review is to summarize the modern views on etiopathogenesis and treatment of ovarian cancer, as well as to search for ways for a more personalized approach to the management of patients with this oncological disease. Despite the limited number of patients participating in clinical trials of ovarian cancer, there are obvious results of gradual evolution in its diagnosis and treatment. Studies of etiopathogenesis led to a better understanding of the ovarian cancer genesis mechanisms, whereas evolution in treatment was marked by combination of secondary cytoreductive surgery with the most effective chemotherapeutic drugs and biological agents. The introduction of biomarkers, particularly CA125 (cancer antigen 125), in the diagnostic algorithm for both primary and recurrent ovarian cancer has opened up new horizons for the application of effective methods of treatment at the disease earliest stages. However, in the landmark study of G.J. Rustin et al. there was no a statistically significant difference in disease-free and overall survival among female patients with immediate treatment of recurrent ovarian cancer based only on elevated CA125 and female patients in whom chemotherapy was initiated after the clinical symptoms manifestation. Conducting clinical trials in small cohorts of patients with certain ovarian cancer histotype will help to select one or another effective combination of chemotherapy and/or biological agents administered not only intravenously, but also intraperitoneally, and thereby provide the personalized approach to the treatment of this disease.
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Snoch, Wojciech, Dawid Wnuk, Tomasz Witko, Jakub Staroń, Andrzej J. Bojarski, Ewelina Jarek, Francisco J. Plou, and Maciej Guzik. "In Search of Effective Anticancer Agents—Novel Sugar Esters Based on Polyhydroxyalkanoate Monomers." International Journal of Molecular Sciences 22, no. 13 (July 5, 2021): 7238. http://dx.doi.org/10.3390/ijms22137238.
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Cancer is one of the deadliest illness globally. Searching for new solutions in cancer treatments is essential because commonly used mixed, targeted and personalized therapies are sometimes not sufficient or are too expensive for common patients. Sugar fatty acid esters (SFAEs) are already well-known as promising candidates for an alternative medical tool. The manuscript brings the reader closer to methods of obtaining various SFAEs using combined biological, chemical and enzymatic methods. It presents how modification of SFAE’s hydrophobic chains can influence their cytotoxicity against human skin melanoma and prostate cancer cell lines. The compound’s cytotoxicity was determined by an MTT assay, which followed an assessment of SFAEs’ potential metastatic properties in concentrations below IC50 values. Despite relatively high IC50 values (63.3–1737.6 μM) of the newly synthesized SFAE, they can compete with other sugar esters already described in the literature. The chosen bioactives caused low polymerization of microtubules and the depolymerization of actin filaments in nontoxic levels, which suggest an apoptotic rather than metastatic process. Altogether, cancer cells showed no propensity for metastasis after treating them with SFAE. They confirmed that lactose-based compounds seem the most promising surfactants among tested sugar esters. This manuscript creates a benchmark for creation of novel anticancer agents based on 3-hydroxylated fatty acids of bacterial origin.
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Abdulrahman, Amal, and Deborah Richards. "In Search of Embodied Conversational and Explainable Agents for Health Behaviour Change and Adherence." Multimodal Technologies and Interaction 5, no. 9 (September 18, 2021): 56. http://dx.doi.org/10.3390/mti5090056.
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Conversational agents offer promise to provide an alternative to costly and scarce access to human health providers. Particularly in the context of adherence to treatment advice and health behavior change, they can provide an ongoing coaching role to motivate and keep the health consumer on track. Due to the recognized importance of face-to-face communication and establishment of a therapist-patient working alliance as the biggest single predictor of adherence, our review focuses on embodied conversational agents (ECAs) and their use in health and well-being interventions. The article also introduces ECAs who provide explanations of their recommendations, known as explainable agents (XAs), as a way to build trust and enhance the working alliance towards improved behavior change. Of particular promise, is work in which XAs are able to engage in conversation to learn about their user and personalize their recommendations based on their knowledge of the user and then tailor their explanations to the beliefs and goals of the user to increase relevancy and motivation and address possible barriers to increase intention to perform the healthy behavior.
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Nebbioso, Marcella, Alessandro Lambiase, Alberto Cerini, Paolo Giuseppe Limoli, Maurizio La Cava, and Antonio Greco. "Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules." International Journal of Molecular Sciences 20, no. 7 (April 4, 2019): 1693. http://dx.doi.org/10.3390/ijms20071693.
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The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy.
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Gao, Ke Lian, Yan Xia Cao, and Hai Yan Zhao. "Research on Network Fitness Service System Based on Multi-Agent Technology." Advanced Materials Research 926-930 (May 2014): 2394–97. http://dx.doi.org/10.4028/www.scientific.net/amr.926-930.2394.
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This paper uses Agent technology into the application of network fitness service system, and establishes the network fitness service system model based on multi-agent. Each agent in the model takes charge of different work, which is like client interest modeling, information search, information push and client interaction. Each agent is independent with others. Agents cooperate together, and complete personalized service to change the traditional passive service to active service. This can improve use ratio of network fitness service system and users satisfaction effectively.
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Pallio, Giovanni, Federica Mannino, Natasha Irrera, Ali H. Eid, Francesco Squadrito, and Alessandra Bitto. "Polymorphisms Involved in Response to Biological Agents Used in Rheumatoid Arthritis." Biomolecules 10, no. 9 (August 19, 2020): 1203. http://dx.doi.org/10.3390/biom10091203.
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Rheumatoid arthritis (RA) is a systemic disease that leads to joint destruction. During the last decade, the therapy of RA has been principally based on biological drugs. Although the efficacy of biological therapy has been established, patients demonstrated a high heterogeneity in clinical response to treatment. Several genetic polymorphisms play a part in the different response to biological drugs. This review summarizes the pharmacogenetics of biological agents approved for clinical RA treatment. We reviewed PubMed papers published over the past 20 years (2000–2020), inserting as the search term “rheumatoid arthritis and polymorphisms”. Despite some studies showing important correlations between genetic polymorphisms and response to biological therapy in RA patients, most of these findings are still lacking and inconsistent. The personalized treatment according to a pharmacogenetics approach is promising but the available pharmacogenetics data on biological treatment in RA are not adequate and reliable to recommend pharmacogenetic tests before starting biological therapy in RA patients.
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Schwaederle, Maria, Melissa Zhao, J. Jack Lee, Alexander M. Eggermont, Richard L. Schilsky, John Mendelsohn, Vladimir Lazar, and Razelle Kurzrock. "Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials." Journal of Clinical Oncology 33, no. 32 (November 10, 2015): 3817–25. http://dx.doi.org/10.1200/jco.2015.61.5997.
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Purpose The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate. Methods We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not. Results Multivariable analysis (both weighted multiple linear regression and random effects meta-regression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P < .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P < .001) and OS (13.7 v 8.9 months, respectively; P < .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P < .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P < .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P ≤ .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P < .001). Conclusion Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.
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Ji, Zhi Gang. "The Study on Personalized Guidance in Intelligent Library Based on Multi-Agent." Advanced Materials Research 143-144 (October 2010): 18–22. http://dx.doi.org/10.4028/www.scientific.net/amr.143-144.18.
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The system integrated RFID technique, wireless and mobile phone which apply in the intelligent guidance and book management of large scale of library, and to collate the real time information by different functional mobile agents to provide customized information and service, according to the favorite of each reader. Meanwhile, to display forgoing information by multimedia video of book introduction for readers to replace traditional looking for some particular book provide the customized knowledge search style and effective book introduction. In addition, our article set forth System Environment Aware and Recommending Mechanism which bring up considerations for customized information, besides to analyzing personal favorite, should think about the environmental factors in the library, such as, moving path of readers, service and so on such synthetic factors to have a complete analysis and consideration, so as to know what the most appropriate guided service and information is for readers and to make it as a customized intellectual guided service.
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Smith, Sonali M. "What Is the Best Strategy for Incorporating New Agents into the Current Treatment of Follicular Lymphoma?" American Society of Clinical Oncology Educational Book, no. 32 (June 2012): 481–87. http://dx.doi.org/10.14694/edbook_am.2012.32.38.
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Overview: Although there is increasing knowledge about the pathobiology of follicular lymphoma (FL), the incorporation of new agents is challenged by the long clinical course and inherent heterogeneity of the disease. Furthermore, a longstanding concept in FL is that although most patients have an indolent initial phase of disease, this is typically followed by sequentially shorter remission durations and justifies the continued intense search for new rationally designed agents. Ideally, there would be personalized prognostic tools, preemptive target identification, and means to predict response in individual patients. Short of having these tools, one conceptual approach is to consider FL as a series of clinical disease states divided between treatment-naïve (low tumor burden and high tumor burden), relapsed (typically still chemoimmunotherapy-sensitive), and multiply relapsed (usually chemoimmunotherapy-resistant) disease. By applying what is known about the biology of FL along with the available agents, new treatment options can be better defined and tested within these clinical contexts. During the last few years, novel chemotherapeutics, biologic agents, monoclonal antibodies, antibody drug conjugates, and maintenance strategies are all either replacing or adding onto existing strategies. These new agents and approaches challenge the notion of inevitably shorter response durations, and offer hope of improved clinical outcomes compared with traditional sequential cytotoxic therapy.
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Gaudreau, Pierre-Olivier, John Stagg, Denis Soulières, and Fred Saad. "The Present and Future of Biomarkers in Prostate Cancer: Proteomics, Genomics, and Immunology Advancements." Biomarkers in Cancer 8s2 (January 2016): BIC.S31802. http://dx.doi.org/10.4137/bic.s31802.
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Prostate cancer (PC) is the second most common form of cancer in men worldwide. Biomarkers have emerged as essential tools for treatment and assessment since the variability of disease behavior, the cost and diversity of treatments, and the related impairment of quality of life have given rise to a need for a personalized approach. High-throughput technology platforms in proteomics and genomics have accelerated the development of biomarkers. Furthermore, recent successes of several new agents in PC, including immunotherapy, have stimulated the search for predictors of response and resistance and have improved the understanding of the biological mechanisms at work. This review provides an overview of currently established biomarkers in PC, as well as a selection of the most promising biomarkers within these particular fields of development.
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Kantemirova, B. I., E. A. Orlova, O. S. Polunina, E. N. Chernysheva, M. A. Abdullaev, and D. A. Sychev. "PHARMACOGENETIC BASES OF INDIVIDUAL SENSITIVITY AND PERSONALIZED ADMINISTRATION OF ANTIPLATELET THERAPY IN DIFFERENT ETHNIC GROUPS." Pharmacy & Pharmacology 8, no. 6 (May 17, 2021): 392–404. http://dx.doi.org/10.19163/2307-9266-2020-8-6-392-404.
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Cardiovascular diseases (CVDs) are the leading cause of disability and mortality worldwide. Increased thrombosis is the trigger point for the development of various CVDs and their complications, and therefore, therapy with P2Y12-receptor inhibitors is always pathogenetically justified and vital. However, according to the various data, 10-25% of patients treated with clopidogrel have “resistance” to antiplatelet therapy. The causes for the formation of resistance are still not clear. There is no generally accepted, standard methodology for determining resistance to antiplatelet agents. In addition, there are no methodological approaches to identify the patients with resistance to antiplatelet drugs, and standardized schemes for correcting a low sensitivity to these drugs.The aim of this review was to summarize the available results of foreign and domestic studies devoted to the investigation of the effectiveness and safety problems of antiplatelet drugs administration from the point of view of the genetic predisposition to changes in their metabolism.Materials and methods. For the review, the following information from scientific literature represented in open and accessible sources for the period of 1996-2020, was used: pharmgkb.org, PubMed, Scopus, Web of Science Core Collection, Elibrary. Search queries – “Genetic features+antiplatelet therapy+ethnic groups”, “CYP2C19+clopidogrel+antiplatelet therapy effectiveness”; “Stent retrombosis+CYP2C19 polymorphism+ residual platelet reactivity” and “CYP2C19 polymorphism+ethnic groups+clopidogrel resistance” in both Russian and English equivalents. All these data are placed in electronic databases.Results. Currently, the problem of the resistance formation to antiplatelet drugs is studied insufficiently. The best thought-out issue is the research of the effect of the polymorphic alleles carriage of the CYP2C19 gene on the residual platelet reactivity in the patients administrated with dual antiplatelet treatment, including clopidogrel. In general, the analysis of open literature sources indicates the presence of a statistically significant association between the carrier of slow alleles of the CYP2C19 gene and the residual platelet reactivity, clinically manifested by thrombosis and adverse cardiovascular events. The occurrence frequency of polymorphic carriage of the CYP2C19 gene varies in different ethnic groups, so it cannot be extrapolated to individual subjects, peculiar in the ethnic diversity.Conclusion. To develop preventive and predictive measures aimed at overcoming resistance to antiplatelet agents, as well as working out methodological approaches to personalized prescribtion of this group drugs, a further investigation with the expansion of the search for causes and the study of the other genes participation of the cytochrome P450 system, is required.
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OHTANI, TAKESHI, SIMON CASE, NADER AZARMI, and MARCUS THINT. "AN INTELLIGENT SYSTEM FOR MANAGING AND UTILIZING INFORMATION RESOURCES OVER THE INTERNET." International Journal on Artificial Intelligence Tools 11, no. 01 (March 2002): 117–38. http://dx.doi.org/10.1142/s0218213002000800.
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The Internet is a vast, semi-structured information repository that is expanding ever-faster with two alarming results. First, finding information is becoming increasingly difficult, and second, the management of such information resources is also becoming more complex. We have developed an Intelligent Distributed Information Management System (IDIoMS) to solve these problems. IDIoMS provides a comprehensive set of tools for personalized information delivery, and a platform that enables straightforward management of distributed information resources using agent technologies. These agents enable the sharing, management, search, and presentation of useful information that is widely distributed over a network such as the Internet. IDIoMS benefits users through the automatic provision of timely and relevant information with minimal need for users to search for that information. In addition, the system also benefits service providers through the plug-and-play provision of information services that minimizes the overhead needed to make their service widely available. This paper describes the concept and the architecture of IDIoMS and discusses its utility through three field trials.
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Aardoom, Martine A., Gigi Veereman, and Lissy de Ridder. "A Review on the Use of Anti-TNF in Children and Adolescents with Inflammatory Bowel Disease." International Journal of Molecular Sciences 20, no. 10 (May 23, 2019): 2529. http://dx.doi.org/10.3390/ijms20102529.
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Inflammatory bowel disease (IBD) presents with disabling symptoms and may lead to insufficient growth and late pubertal development in cases of disease onset during childhood or adolescence. During the last decade, the role of anti-tumor necrosis factor (TNF) in the treatment of paediatric-onset IBD has gained more ground. The number of biologicals presently available for children and adolescents with IBD has increased, biosimilars have become available, and practices in adult gastroenterology with regards to anti-TNF have changed. The aim of this study is to review the current evidence on the indications, judicious use, effectiveness and safety of anti-TNF agents in paediatric IBD. A PubMed literature search was performed and included articles published after 2000 using the following terms: child or paediatric, Crohn, ulcerative colitis, inflammatory bowel disease, anti-TNF, TNF alpha inhibitor, infliximab, adalimumab, golimumab and biological. Anti-TNF agents, specifically infliximab and adalimumab, have proven to be effective in moderate and severe paediatric IBD. Therapeutic drug monitoring increases therapy effectiveness and safety. Clinical predictors for anti-TNF response are currently of limited value because of the variation in outcome definitions and follow-ups. Future research should comprise large cohorts and clinical trials comparing groups according to their risk profile in order to provide personalized therapeutic strategies.
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Morris, Stephanie A., Sharon Gaheen, Michal Lijowski, Mervi Heiskanen, and Juli Klemm. "Experiences in supporting the structured collection of cancer nanotechnology data using caNanoLab." Beilstein Journal of Nanotechnology 6 (July 21, 2015): 1580–93. http://dx.doi.org/10.3762/bjnano.6.161.
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The cancer Nanotechnology Laboratory (caNanoLab) data portal is an online nanomaterial database that allows users to submit and retrieve information on well-characterized nanomaterials, including composition, in vitro and in vivo experimental characterizations, experimental protocols, and related publications. Initiated in 2006, caNanoLab serves as an established resource with an infrastructure supporting the structured collection of nanotechnology data to address the needs of the cancer biomedical and nanotechnology communities. The portal contains over 1,000 curated nanomaterial data records that are publicly accessible for review, comparison, and re-use, with the ultimate goal of accelerating the translation of nanotechnology-based cancer therapeutics, diagnostics, and imaging agents to the clinic. In this paper, we will discuss challenges associated with developing a nanomaterial database and recognized needs for nanotechnology data curation and sharing in the biomedical research community. We will also describe the latest version of caNanoLab, caNanoLab 2.0, which includes enhancements and new features to improve usability such as personalized views of data and enhanced search and navigation.
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Janardhan, Sridhara, Varvara Dubovskaja, Alexey Lagunin, Batchu Venkateswara Rao, Garikapati Narahari Sastry, and Vladimir Poroikov. "Recent Advances in the Development of Pharmaceutical Agents for Metabolic Disorders: A Computational Perspective." Current Medicinal Chemistry 25, no. 39 (January 17, 2019): 5432–63. http://dx.doi.org/10.2174/0929867324666171002120647.
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Background: Metabolic disorders comprise a set of different disorders varying from epidemic diseases such as diabetes mellitus to inborn metabolic orphan diseases such as phenylketonuria. Despite considerable evidence showing the importance of the computational methods in discovery and development of new pharmaceuticals, there are no systematic reviews outlining how they are utilized in the field of metabolic disorders. This review aims to discuss the necessity of the development of web-based tools and databases by integration of available information for solving Big Data problems in network pharmacology of metabolic disorders. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. Results: The alterations in metabolic pathways cause various cardiovascular, hematological, neurological, gastrointestinal, immune disorders and cancer. In this regard, informatics, Big Data and modeling techniques aid in the design of novel therapeutic agents for metabolic diseases by addressing various Big Data problems in the network polypharmacology (drugs/pharmaceutical agents, proteins, genes, diseases, bioassays, ADMET and metabolic pathways), identification of privileged scaffolds, developing new diagnostic biomarkers, understanding the pathophysiology of disease and progress in personalized medicine. Conclusion: The recent advances of developing pharmaceutical agents for various metabolic disorders by considering their pathogenesis, mechanisms of action, therapeutic and adverse effects have been summarized. We have highlighted the role of computational techniques, drug repurposing, and network-based polypharmacological approaches in the identification of new/existing medicines with improved drug-likeness properties for the rare metabolic disorders.
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Benfaremo, Devis, Valentino Paci, Michele Maria Luchetti, and Armando Gabrielli. "Novel Therapeutic Approaches and Treatment Targets for Psoriatic Arthritis." Current Pharmaceutical Biotechnology 22, no. 1 (December 31, 2020): 85–98. http://dx.doi.org/10.2174/1389201021666200928095521.
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Background: Psoriatic Arthritis (PsA) is the most common extracutaneous manifestation of psoriasis. This chronic inflammatory arthritis is burdened with significant morbidity, leading to irreversible joint damage and disability. In recent years, a deeper understating of its pathogenesis has led to the development of several new drugs targeting different pathways. Objectives: This review aims to highlight the clinical efficacy and safety of the novel agents that have become recently available for the treatment of PsA, as well as new promising therapeutic targets that are being evaluated in clinical trials. Methods: For the purpose of this narrative review, we searched in the MEDLINE and ClinicalTrials. gov databases. Results: After the introduction of the first biological drugs targeting Tumor Necrosis Factor (TNF), several other drugs with different targets have been developed, including anti-Interleukin (IL) 12/23p40, anti-IL17, and, more recently, anti-IL23p19 agents. Conclusions: Data supporting the efficacy of different agents in the major domains of PsA, as well as their safety issues, are summarized here. Finally, the current pipeline, including several novel nonbiological small molecules, such as Janus kinase (JAK) inhibitors, that are currently being evaluated in clinical trials are also presented. Discussion: The availability of newer therapeutic agents has substantially changed the treatment strategy for PsA. In the future, a personalized treatment approach will probably achieve better control of disease manifestations.
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Rosenkranz, A. A., and T. A. Slastnikova. "Epidermal Growth Factor Receptor: Key to Selective Intracellular Delivery." Biochemistry (Moscow) 85, no. 9 (September 2020): 967–93. http://dx.doi.org/10.1134/s0006297920090011.
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Abstract Epidermal growth factor receptor (EGFR) is an integral surface protein mediating cellular response to a number of growth factors. Its overexpression and increased activation due to mutations is one of the most common traits of many types of cancer. Development and clinical use of the agents, which block EGFR activation, became a prime example of the personalized targeted medicine. However, despite the obvious success in this area, cancer cure remains unattainable in most cases. Because of that, as well as the result of the search for possible ways to overcome the difficulties of treatment, a huge number of new treatment methods relying on the use of EGFR overexpression and its changes to destroy cancer cells. Modern data on the structure, functioning, and intracellular transport of EGFR, its natural ligands, as well as signaling cascades triggered by the EGFR activation, peculiarities of the EGFR expression and activation in oncological disorders, as well as applied therapeutic approaches aimed at blocking EGFR signaling pathway are summarized and analyzed in this review. Approaches to the targeted delivery of various chemotherapeutic agents, radionuclides, immunotoxins, photosensitizers, as well as the prospects for gene therapy aimed at cancer cells with EGFR overexpression are reviewed in detail. It should be noted that increasing attention is being paid nowadays to the development of multifunctional systems, either carrying several different active agents, or possessing several environment-dependent transport functions. Potentials of the systems based on receptor-mediated endocytosis of EGFR and their possible advantages and limitations are discussed.
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Ribaldone, Davide Giuseppe, Selvaggia Brigo, Michela Mangia, Giorgio Maria Saracco, Marco Astegiano, and Rinaldo Pellicano. "Oral Manifestations of Inflammatory Bowel Disease and the Role of Non-Invasive Surrogate Markers of Disease Activity." Medicines 7, no. 6 (June 16, 2020): 33. http://dx.doi.org/10.3390/medicines7060033.
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Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), can be associated with several extra-intestinal manifestations requiring a multidisciplinary management both in terms of work-up and therapy. Oral lesions are common in patients with IBD, with a prevalence ranging from 5% to 50%. These can represent an oral location of IBD as well as a side-effect of drugs used to treat the intestinal disease. Oral manifestations, occurring in patients with IBD, can be divided in nonmalignant, specific, and non-specific ones, and malignant lesions. While there is undoubtedly a need to search for an IBD in patients with oral lesions associated with intestinal symptoms, the work-up of those with an exclusive oral lesion should be personalized. Fecal calprotectin is a non-invasive marker of intestinal inflammation and may be used to select which patients need to undergo endoscopic examination, thereby avoiding unnecessary investigations. The pharmacological armamentarium to treat oral lesions associated with IBD includes topical or systemic corticosteroids, immunosuppressive agents, and biologic drugs.
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Jones, Christopher R., Barnaby F. Flower, Ella Barber, Bryony Simmons, and Graham S. Cooke. "Treatment optimisation for hepatitis C in the era of combination direct-acting antiviral therapy: a systematic review and meta-analysis." Wellcome Open Research 4 (September 6, 2019): 132. http://dx.doi.org/10.12688/wellcomeopenres.15411.1.
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Background: Prior to direct-acting antiviral (DAA) therapy, personalised medicine played an important role in the treatment of hepatitis C virus (HCV). Whilst simplified treatment strategies are central to treatment scale-up, some patients will benefit from treatment optimisation. This systematic review and meta-analysis explores treatment optimisation strategies in the DAA era. Methods: We systematically searched Medline, Embase, and Web of Science for studies that adopted a stratified or personalised strategy using a licensed combination DAA regimen, alone or with additional agents. We performed a thematic analysis to classify optimisation strategies and a meta-analysis of sustained virologic response rates (SVR), exploring heterogeneity with subgroup analyses and meta-regression. Results: We included 64 studies (9450 participants). Thematic analysis found evidence of three approaches: duration, combination, and/or dose optimisation. We separated strategies into those aiming to maintain SVR in the absence of predictors of failure, and those aiming to improve SVR in the presence of predictors of failure. Shortened duration regimens achieve pooled SVR rates of 94.2% (92.3-95.9%) for 8 weeks, 81.1% (75.1-86.6%) for 6 weeks, and 63.1% (39.9-83.7%) for ≤4 weeks. Personalised strategies (100% vs 87.6%; p<0.001) and therapy shortened according to ≥3 host/viral factors (92.9% vs 81.4% or 87.2% for 1 or 2 host/viral factors, respectively; p=0.008) offer higher SVR rates when shortening therapy. Hard-to-treat HCV genotype 3 patients suffer lower SVR rates despite treatment optimisation (92.6% vs 98.2%; p=0.001). Conclusions: Treatment optimisation for individuals with multiple predictors of treatment failure can offer high SVR rates. More evidence is needed to identify with confidence those individuals in whom SVR can be achieved with shortened duration treatment.
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Wu, Catherine J. "Checkpoint Blockade with Neoantigen Cancer Vaccines for Personalized Immunotherapy." Blood 126, no. 23 (December 3, 2015): SCI—9—SCI—9. http://dx.doi.org/10.1182/blood.v126.23.sci-9.sci-9.
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Methods for harnessing the exquisite specificity of the immune system to eliminate tumors have been under development since the start of the 20th century, with numerous studies in animal models and trials in humans. Despite accumulating evidence, there has been widespread skepticism in the cancer community about whether tumors could be controlled by spontaneous immunity, and whether effective immunotherapy would be feasible to develop. However, the field has now passed an inflection point as new results have quelled these doubts, including: (i) several large clinical studies that have identified infiltrating CD8+ T cells as one of the best predictors of overall survival in human cancers, with strong validation in a large study of colorectal cancers; (ii) adoptive T cell therapy that effectively eradicates some types of B cell leukemias and (iii) novel checkpoint blockade (CPB) therapies inducing unprecedented long-term cures for patients with solid tumors, and more recently with blood malignancies. With the availability of these novel immunologic agents, the priority has shifted to understanding the mechanisms of and predicting responses to each treatment. Fundamental to this endeavor is the understanding of the crosstalk between tumor cells and immune cell populations within the tumor microenvironment and the selective pressure they mutually exert on each other. At the heart of cancer and host immune cell coevolution is the tumor antigen and host antigen-specific T cell interaction. The cytotoxic T cell-cognate antigen interaction forms the mechanistic basis for immune-mediated recognition and the killing of malignant cells, and provides selective pressure on the cancer cell to evolve. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. With the recent availability of next-generation sequencing, systematic approaches to identify mutations leading to amino acid changes have become feasible. This development, together with the improved sensitivity of well-validated neural network/machine learning-based algorithms that predict binding to class I MHC, has enabled the implementation of neoantigen discovery pipelines. Recent studies by us and others in humans and mice have leveraged these tools to demonstrate evidence of protective immunity when targeting tumor neoantigens. We have further incorporated this approach to discover antigen targets to generate a multi-epitope personalized therapeutic cancer vaccine, that we are now testing in phase I clinical trials. Altogether, effective targeting of tumor neoantigens occurs spontaneously and during CPB, and offers prospects of a powerful, new immunotherapy. Disclosures No relevant conflicts of interest to declare.
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Morales, Enrique, Maria Galindo, Hernando Trujillo, and Manuel Praga. "Update on Lupus Nephritis: Looking for a New Vision." Nephron 145, no. 1 (November 4, 2020): 1–13. http://dx.doi.org/10.1159/000511268.
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Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), affecting approximately 40% of patients with lupus. It represents a major risk factor for morbidity and mortality, and 10% of patients with LN will develop end-stage kidney disease (ESKD). Therefore, there are a number of areas for improvement in the field of LN such as the search for new clinical biomarkers with a more accurate correlation with lupus activity and the redefinition of the histological classification into different subgroups in order to guide a personalized treatment. Although the role of protocol repeat kidney biopsies in LN is controversial, recent publications suggest that repeat histological assessment can be useful in guiding therapeutic decisions that may yield toward precision medicine. In the last decade, LN therapy has remained largely unchanged, with a probability of achieving complete or partial remission not exceeding 60–70%. Thus, optimization of old treatment strategies and search for new agents are urgently needed in order to improve outcomes such as mortality or development of ESKD. Future trials should focus in addressing unanswered issues such as the appropriate dose and duration of immunosuppressive treatment, timing of steroid withdrawal, and drug toxicity. In addition, data are still lacking regarding pregnancy and kidney transplantation in LN and knowledge about these important areas is essential for the management of a subset of patients with SLE. In summary, several major gaps are still present in the therapeutic approach and follow-up of patients with LN. The development of new clinical trial designs will be crucial in the search to improve long-term outcomes.
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Trainer, Alison H., Bettina Meiser, Kaaren Watts, Gillian Mitchell, Kathy Tucker, and Michael Friedlander. "Moving Toward Personalized Medicine: Treatment-Focused Genetic Testing of Women Newly Diagnosed With Ovarian Cancer." International Journal of Gynecologic Cancer 20, no. 5 (June 2010): 704–16. http://dx.doi.org/10.1111/igc.0b013e3181dbd1a5.
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Objectives:The presence of a germline BRCA mutation defines a genotype-specific group of women whose invasive ovarian cancer is associated with an increasingly well-defined prognostic and chemosensitivity biological profile. To determine the criteria that may be used to select patients for BRCA treatment-focused genetic testing, we performed a systemic literature search of studies that assessed BRCA1 and BRCA2 mutation frequency in women with ovarian cancer unselected for family history. The results are discussed with regard to the added clinical value gained by identifying a germline BRCA mutation at the time of the ovarian cancer diagnosis.Methods:BRCA-related studies were identified in the CD-ROM databases PubMed (including MEDLINE), PsychINFO, and CINAHL and included in the review if they met the following criteria: they (a) assessed mutation frequency in women with ovarian cancer who were unselected for family history and ethnicity, (b) were published in a peer-review journal, (c) between January 1997 and October 2009, and (d) in the English language.Results:Studies investigating the prevalence of BRCA1 or BRCA2 mutations in ovarian cancer patients unselected for family history or ethnicity have found a pathological BRCA mutation rate of approximately 3% to 17%. Without a significant family history, specific features that may be used to target treatment-focused BRCA testing in the ovarian cancer setting include young age at onset (<50 years), high-grade serous tumor histology, and specific ethnicity associated with known BRCA founder mutations.Conclusions:We believe that given the growing appreciation of the prognostic significance of BRCA mutations and the differential chemosensitivity shown by these tumors, as well as the potential of novel agents such as poly(ADP-ribose) polymerase inhibitors, the identification of a germline BRCA mutation concurrent with a new diagnosis of ovarian cancer will significantly impact on tailoring personalized ovarian management in the future.
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Shrivastava, Garima, Hamid A. Bakshi, Alaa A. Aljabali, Vijay Mishra, Faruck L. Hakkim, Nitin B. Charbe, Prashant Kesharwani, Dinesh K. Chellappan, Kamal Dua, and Murtaza M. Tambuwala. "Nucleic Acid Aptamers as a Potential Nucleus Targeted Drug Delivery System." Current Drug Delivery 17, no. 2 (March 12, 2020): 101–11. http://dx.doi.org/10.2174/1567201817666200106104332.
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Background: Nucleus targeted drug delivery provides several opportunities for the treatment of fatal diseases such as cancer. However, the complex nucleocytoplasmic barriers pose significant challenges for delivering a drug directly and efficiently into the nucleus. Aptamers representing singlestranded DNA and RNA qualify as next-generation highly advanced and personalized medicinal agents that successfully inhibit the expression of certain proteins; possess extraordinary gene-expression for manoeuvring the diseased cell's fate with negligible toxicity. In addition, the precisely directed aptamers to the site of action present a tremendous potential to reach the nucleus by escaping the ensuing barriers to exhibit a better drug activity and gene expression. Objective: This review epigrammatically highlights the significance of targeted drug delivery and presents a comprehensive description of the principal barriers faced by the nucleus targeted drug delivery paradigm and ensuing complexities thereof. Eventually, the progress of nucleus targeting with nucleic acid aptamers and success achieved so far have also been reviewed. Method: Systematic literature search was conducted of research published to date in the field of nucleic acid aptamers. Conclusion: The review specifically points out the contribution of individual aptamers as the nucleustargeting agent rather than aptamers in conjugated form.
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Choi, Woncheol, Hyunsik Jung, Kyungsuk Kim, Sookyung Lee, Seongwoo Yoon, Jaehyun Park, Sehyun Kim, Seongha Cheon, Wankyo Eo, and Sanghun Lee. "Rhus vernicifluaStokes against Advanced Cancer: A Perspective from the Korean Integrative Cancer Center." Journal of Biomedicine and Biotechnology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/874276.
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Active anticancer molecules have been searched from natural products; many drugs were developed from either natural products or their derivatives following the conventional pharmaceutical paradigm of drug discovery. However, the advances in the knowledge of cancer biology have led to personalized medicine using molecular-targeted agents which create new paradigm. Clinical benefit is dependent on individual biomarker and overall survival is prolonged through cytostatic rather than cytotoxic effects to cancer cell. Therefore, a different approach is needed from the single lead compound screening model based on cytotoxicity. In our experience, theRhus vernicifluastoke (RVS) extract traditionally used for cancer treatment is beneficial to some advanced cancer patients though it is herbal extract not single compound, and low cytotoxic in vitro. The standardized RVS extract's action mechanisms as well as clinical outcomes are reviewed here. We hope that these preliminary results would stimulate different investigation in natural products from conventional chemicals.
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Doeleman, Martijn J. H., Erik M. van Maarseveen, and Joost F. Swart. "Immunogenicity of biologic agents in juvenile idiopathic arthritis: a systematic review and meta-analysis." Rheumatology 58, no. 10 (February 26, 2019): 1839–49. http://dx.doi.org/10.1093/rheumatology/kez030.
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Abstract Objective The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation. Methods PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed. Results A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52). Conclusion The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.
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Mitikiri, Nirupama Devi, Emily S. Reese, Arif Hussain, Ebere Onukwugha, Daryl Pritchard, Robert W. Dubois, and C. Daniel Mullins. "Heterogeneity of treatment effects (HTE) in stage IV prostate cancer (S4PC)." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 180. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.180.
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180 Background: HTE occurs when individual patient factors modify a treatment’s effect on health outcomes in a non-random and predictable manner. HTE results in specific subgroups of patients in the same study having different responses to the same treatment due to interactions between their individual factors and the treatment. Methods: A systematic literature review was conducted of articles published between 1946 and 2011. Inclusion criteria required that articles examine the impact of HTE factors on survival outcomes (OS, TTP, PFS) or QOL among S4PC patients, in the context of a specific treatment. The quality of evidence was graded as good, fair or poor, per AHRQ guidelines. Results: The search identified 2,659 articles of which 92 met study inclusion criteria. Most articles (46%) were post-hoc analyses of randomized clinical trials. PC treatments included chemotherapy, radiation, hormonal therapy (74%) and bone-modifying agents. HTE in S4PC was identified for both biologic and non-biologic factors. Factors related to clinical signs/symptoms, laboratory tests and disease severity have been extensively studied in the literature (Table). Age and race seldom showed any correlation with PC outcomes. Conclusions: Current evidence reveals diverse factors contributing to HTE in S4PC. Ultimately, such knowledge can help oncologists prescribe more personalized medicine, help patients make more informed treatment choices, and inform policy making and treatment coverage decisions. [Table: see text]
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Collins, Anne T., and Shona H. Lang. "A systematic review of the validity of patient derived xenograft (PDX) models: the implications for translational research and personalised medicine." PeerJ 6 (November 21, 2018): e5981. http://dx.doi.org/10.7717/peerj.5981.
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Patient-derived xenograft (PDX) models are increasingly being used in oncology drug development because they offer greater predictive value than traditional cell line models. Using novel tools to critique model validity and reliability we performed a systematic review to identify all original publications describing the derivation of PDX models of colon, prostate, breast and lung cancer. Validity was defined as the ability to recapitulate the disease of interest. The study protocol was registered with the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Searches were performed in Embase, MEDLINE and Pubmed up to July 2017. A narrative data synthesis was performed. We identified 105 studies of model validations; 29 for breast, 29 for colon, 25 for lung, 23 for prostate and 4 for multiple tissues. 133 studies were excluded because they did not perform any validation experiments despite deriving a PDX. Only one study reported following the ARRIVE guidelines; developed to improve the standard of reporting for animal experimentation. Remarkably, half of all breast (52%) and prostate (50%) studies were judged to have high concern, in contrast to 16% of colon and 28% of lung studies. The validation criteria that most commonly failed (evidence to the contrary) were: tissue of origin not proven and histology of the xenograft not comparable to the parental tumour. Overall, most studies were categorized as unclear because one or more validation conditions were not reported, or researchers failed to provide data for a proportion of their models. For example, failure to demonstrate tissue of origin, response to standard of care agents and to exclude development of lymphoma. Validation tools have the potential to improve reproducibility, reduce waste in research and increase the success of translational studies.
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Aksenenko, M. B., A. V. Komina, N. V. Palkina, A. S. Averchuk, Yu A. Rybnikov, Yu A. Dyhno, and T. G. Ruksha. "TRANSCRIPTOMIC ANALYSIS OF MELANOMA CELLS EXTRACTED FROM DIFFERENT SITES OF THE PRIMARY TUMOR." Siberian journal of oncology 17, no. 4 (September 4, 2018): 59–66. http://dx.doi.org/10.21294/1814-4861-2018-17-4-59-66.
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Introduction.Intratumor heterogeneity is a characteristic feature for most malignant tumors, including cutaneous melanoma. This property represents one of the main obstacles for effective targeted therapy, due to the different sensitivity to chemotherapeutic agents on various tumor cells subclones. Treatment of malignant tumors requires an individual approach to choose the most appropriate treatment regimen.The purposeof the study was to evaluate differences in melanoma tissue samples obtained from different parts of one patient’s primary tumor at the transcriptomic level.Material and Methods. Melanoma cell cultures obtained from both central and peripheral parts of the primary tumor of two patients were used in the study.Results. Subclones from different parts of the first patient’s tumor were similar, whereas the second patient demonstrated significant differences at the transcriptomic level (in 2953 transcripts out of 48226). In the cells of the central zone of the second patient’s tumor, an increase in mRNA of the genes encoding proteins associated with tumor-specific immune response, as well as ABC-family transport proteins and cytokine signaling molecules, were noted. In the cells from the peripheral area of the same tumor, a more intensive transcription of genes encoding extracellular matrix and inflammatory response proteins was observed. Taken all round, the differences between the subclones of the second patient’s cells were relevant to some signaling cascades playing a leading role in oncogenesis (MAPK, PI3K-Akt-mTOR, VEGFA-VEGFR2, etc.).Conclusion. The study allowed evaluation of differences between cancer cells within a tumor at the transcriptional level in order to search for further approaches to personalized melanoma therapy.
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Artieta-Pinedo, Isabel, Carmen Paz-Pascual, Paola Bully, and Maite Espinosa. "Design of the Maternal Website EMAeHealth That Supports Decision-Making During Pregnancy and in the Postpartum Period: Collaborative Action Research Study." JMIR Formative Research 5, no. 8 (August 9, 2021): e28855. http://dx.doi.org/10.2196/28855.
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Background Despite the benefit maternal education has for women, it needs new tools to increase its effectiveness and scope, in tune with the needs of current users. Objective We attempted to develop a multifunctional personalized eHealth platform aimed at the self-management of health in relation to maternity, which can be considered a flexible and adaptable maternal education tool. Methods The International Patient Decision Aid Standards (IPDAS) were applied. A website prototype was developed for implementation in the public health system using a collaborative action research process, in which experts and patients participate, with qualitative research techniques, as well as focus groups, prioritization, and consensus techniques. Results We have proposed a website that includes (1) systematically updated information related to clinical practice guidelines, (2) interaction between peers and users/professionals, (3) instruments for self-assessment of health needs as a basis for working on counseling, agreement on actions, help in the search for resources, support in decision-making, and monitoring and evaluation of results, and (4) access for women to their clinical data and the option of sharing the data with other health agents. These components, with different access requirements, would be reviewed through iterative cycles depending on the frequency and effectiveness resulting from their use and would be accessible from any digital device. Conclusions A website that supports maternal education should contain not only information, but also resources for individual attention and social support. Its usefulness for the health and satisfaction of women should be evaluated in various different environments.
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Qadi, Olla, Nakawala Lufumpa, Nicola Adderley, Danai Bem, Tom Marshall, and Farina Kokab. "Patients’ and health professionals’ attitudes and perceptions towards the initiation of preventive drugs for primary prevention of cardiovascular disease: a systematic review of qualitative studies." BJGP Open 4, no. 5 (October 20, 2020): bjgpopen20X101087. http://dx.doi.org/10.3399/bjgpopen20x101087.
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BackgroundStatins and antihypertensive agents are recommended for primary prevention of cardiovascular disease (CVD), but they are not always prescribed to eligible patients.Design & settingA systematic review of qualitative studies.AimTo explore health professionals’ and patients’ attitudes towards cardiovascular preventive drugs.MethodMEDLINE, Embase, PsychINFO, CINAHL, ASSIA, HMIC, Conference Proceedings Citation Index, and Open Grey were searched for studies of qualitative design without restrictions on date or language. Two reviewers performed study selection, data extraction, quality assessment, and thematic synthesis.ResultsIn total, 2585 titles and abstracts were screened, yielding 27 studies, of which five met eligibility criteria on full text assessment. These included 62 patients and 47 health professionals. Five themes emerged about patient attitudes: questioning preventive drugs; perceived benefit and risks, such as improving quality of life; patient preferences; trust in health professional judgement; and family, friends, and media influences. Five themes emerged about health professional attitudes: addressing patient concerns and information; duty as a health professional to prescribe; uncertainty about preventive drug prescribing; recognising consequences of prescribing, such as unnecessary medicalisation; and personalised treatment.ConclusionThe attitudes of patients and health professionals regarding drug initiation for primary prevention reflect the complexity of the patient–health professional encounter in primary practice. For prescribing to be more adherent to guidelines, research should further investigate the patient–health professional relationship and the appropriate communication methods required when discussing drug initiation, specifically for primary prevention.
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Bucy, Taylor, John Zoscak, Motomi Mori, Vinayak Prasad, and Uma Borate. "Proportion of Patients with FLT3 Positive AML Required to Enroll on Clinical Trials to Satisfy the Recruitment Needs of FLT3 Inhibitor Trials: Are We Running out of Patients?" Blood 132, Supplement 1 (November 29, 2018): 713. http://dx.doi.org/10.1182/blood-2018-99-120142.
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Abstract Introduction. The push for personalized medicine in oncology has generated an influx of therapies targeting similar pathways, despite only 5% of clinically tested agents receiving FDA approval (Mattina 2017). Acute myeloid leukemia (AML) is a malignancy where identification of prognostically significant mutations suggests growing potential for therapeutic inhibition. FMS-like tyrosine kinase 3 (FLT3) mutations are deemed one of few "actionable" mutations and include 30% of de novo AML cases (25% ITD, 5% TKD) (Garcia 2017; Fathi 2016). In 2017 there will be approximately 21000 new AML cases, roughly 6000 of these patients will be FLT3+ (ACS 2017). In line with prior research in melanoma elucidating the growing number of trials aimed at personalized medicine, we sought to identify the total number of therapeutic trials studying FLT3 inhibitors (Tang 2018). We analyzed the total number of FLT3+ patients required for recruitment to these trials to ensure successful completion compared to incidence of this molecular abnormality within the AML patient population. Methods.A systematic review of therapeutic clinical trials focusing on adult FLT3+ AML from 2000-2017 was conducted using the PRISMA 2009 guidelines (Figure 1). We identified 78 therapeutic trials of FLT3 targeted therapies by cross-referencing ClinicalTrials.gov (66) and PubMed publications (12). Assuming constant accrual rate over the duration of each trial and constant rate of FLT3 mutations at 30% since 2000, statistical analysis was performed using the study start dates and primary completion dates of all trials from ClinicalTrials.gov. Incidence data was collected from the CDC, SEER database, and literature review (De Kouchkovsky 2016; ASCO 2018). Projections of discrepancies between anticipated clinical trial enrollment were provided using consistently cited rates of adult participation of 1%, 3% and 5% versus participant enrollment needed to satisfy current projected trends (Rinde 2018; Unger 2016). Results. Twenty-four therapeutic FLT3 inhibitors being investigated were identified in 78 distinct clinical trials. Pharmaceutical versus cooperative group support was 2.23:1, with 29 different pharmaceutical sponsors and 13 cooperative group/non-profit/academic sponsors(Table 1). Thirty-eight (48.7%) trials/publications accrued in the US only, 21 (26.9%) at international sites only, 15 (19.2%) accrued in both the US and internationally, and 4 (5.1%) had no location listed at time of search. Only one study (NCT03258931) proposed a head-to-head comparison of midostaurin versus crenolanib. The number of patients needed to satisfy enrollment began to surpass the upper bound of estimated participation in 2010, dropping slightly from 2013-2014 and noticeably surpassing projected participation rates from 2015-2016 (Figures 2 & 3). In 2017, approximately 21380 patients were diagnosed with AML, roughly 6414 were FLT3 positive. Assuming 5% participation rate, 320.7 FLT3 positive patients would be expected to enroll in clinical trials. However, the total number of patients needed to satisfy enrollment in 2017 was 1235; after excluding international and completed trials, the total number needed is 844.49 patients. Based on statistical analyses, we estimate that 13.2% of all US patients with FLT3 pos AML would have to enroll to satisfy eligibility in 2017; roughly 3 times the upper level of historical clinical trial participation rates in the US. Conclusions. The current clinical trial process investigating targeted therapies in AML requires an unusually high and unsustainable enrollment, given the discrepancy between the incidence of AML patients with targetable mutations and the number of pharmaceutical agents being studied for these small patient populations. This discrepancy becomes even more startling when considering barriers to enrollment, including insurance market restrictions, geographical, socioeconomic, and demographic factors. Most of these trials do not compare available agents to identify the drug that may provide the most patient benefit. Whether this method of finding new therapies eventually leading to FDA approval continues to be sustainable or whether such duplicative trials dilute the valuable resource of AML patients with rare, targetable mutations, thus impeding development of the most effective therapeutic agents, must considered by the research and regulatory community. Disclosures Borate: Novartis: Consultancy; Agios: Consultancy.
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Heakal, Yasser, Mark Kester, and Scott Savage. "Vemurafenib (PLX4032): An Orally Available Inhibitor of Mutated BRAF for the Treatment of Metastatic Melanoma." Annals of Pharmacotherapy 45, no. 11 (October 25, 2011): 1399–405. http://dx.doi.org/10.1345/aph.1q363.
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Objective: To summarize the preclinical and clinical data on vemurafenib, approved by the Food and Drug Administration (FDA) on August 17, 2011, and discuss the drug's clinical advantages and limitations. Data Sources: An English-language literature search of MEDLINE/PubMed (1966-August 2011), using the terms PLX4032, RG7204, R05185426, vemurafenib, and metastatic melanoma, was conducted. In addition, information and data were obtained from meeting abstracts, clinical trial registries, and news releases from the FDA. Study Selection and Data Extraction: All relevant published articles and abstracts on vemurafenib were included. Clinical trial registries and meeting abstracts were used to obtain information regarding ongoing trials. All peer-reviewed articles containing information regarding the clinical safety and efficacy of vemurafenib were evaluated for inclusion. Data Synthesis: Before the recent approval (March 2011) of ipilimumab, there was no first-line standard-of-care therapy, with proven overall survival benefit, for the treatment of malignant metastatic melanoma. Unlike ipilimumab, which acts through immune-modulation, vemurafenib is a novel, molecularly targeted therapeutic with preferential efficacy toward a specific mutated oncogenic BRAF-signaling mediator. In recently published results of a Phase 3 clinical trial comparing dacarbazine with vemurafenib, vemurafenib prolonged progression-free and overall survival, with confirmed objective response rate of 48% (95% CI 42 to 55) versus 5% (95% CI 3 to 9) for patients who received dacarbazine (p < 0,001) Conclusions: Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF, Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.
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Bossi, Paolo, Paolo Delrio, Annalisa Mascheroni, and Michela Zanetti. "The Spectrum of Malnutrition/Cachexia/Sarcopenia in Oncology According to Different Cancer Types and Settings: A Narrative Review." Nutrients 13, no. 6 (June 9, 2021): 1980. http://dx.doi.org/10.3390/nu13061980.
Full textAbstract:
Nutritional status in oncological patients may differ according to several modifiable and non-modifiable factors. Knowledge of the epidemiology of malnutrition/cachexia/sarcopenia may help to manage these complications early in the course of treatment, potentially impacting patient quality of life, treatment intensity, and disease outcome. Therefore, this narrative review aimed to critically evaluate the current evidence on the combined impact of tumor- and treatment-related factors on nutritional status and to draw some practical conclusions to support the multidisciplinary management of malnutrition in cancer patients. A comprehensive literature search was performed from January 2010 to December 2020 using different combinations of pertinent keywords and a critical evaluation of retrieved literature papers was conducted. The results show that the prevalence of weight loss and associated symptoms is quite heterogeneous and needs to be assessed with recognized criteria, thus allowing a clear classification and standardization of therapeutic interventions. There is a large range of variability influenced by age and social factors, comorbidities, and setting of cures (community-dwelling versus hospitalized patients). Tumor subsite is one of the major determinants of malnutrition, with pancreatic, esophageal, and other gastroenteric cancers, head and neck, and lung cancers having the highest prevalence. The advanced stage is also linked to a higher risk of developing malnutrition, as an expression of the relationship between tumor burden, inflammatory status, reduced caloric intake, and malabsorption. Finally, treatment type influences the risk of nutritional issues, both for locoregional approaches (surgery and radiotherapy) and for systemic treatment. Interestingly, personalized approaches based on the selection of the most predictive malnutrition definitions for postoperative complications according to cancer type and knowledge of specific nutritional problems associated with some new agents may positively impact disease course. Sharing common knowledge between oncologists and nutritionists may help to better address and treat malnutrition in this population.
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van Mackelenbergh, Stroes, Spijker, van Eijck, Wilmink, Bijlsma, and van Laarhoven. "Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis." Cancers 11, no. 5 (April 26, 2019): 588. http://dx.doi.org/10.3390/cancers11050588.
Full textAbstract:
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90–1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26–1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
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Schaap, Mirjam J., Finola M. Bruins, Xuehui He, Kadri Orro, Malou Peppelman, Piet E. J. van Erp, Elke M. G. J. de Jong, Hans J. P. M. Koenen, Ellen H. van den Bogaard, and Marieke M. B. Seyger. "Skin Surface Protein Detection by Transdermal Analysis Patches in Pediatric Psoriasis." Skin Pharmacology and Physiology 34, no. 5 (2021): 271–80. http://dx.doi.org/10.1159/000516110.
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<b><i>Introduction:</i></b> Transdermal analysis patches (TAPs) noninvasively measure soluble proteins in the stratum corneum. Ultimately, such local protein profiles could benefit the search for biomarkers to improve personalized treatment in psoriasis. This study aimed to explore the patient friendliness and protein detection by TAP in pediatric psoriasis in daily clinical practice. <b><i>Methods:</i></b> In this observational study, TAPs measuring CXC chemokine ligand (CXCL)-1/2, CC chemokine ligand (CCL)-27, interleukin (IL)-1RA, IL-23, IL-1α, IL-8, IL-4, IL-22, IL-17A, vascular endothelial growth factor (VEGF), human beta-defensin (hBD)-2, hBD-1, and kallikrein-related peptidase (KLK)-5 were applied on lesional, peri-lesional, and non-lesional skin sites of psoriasis patients aged >5 to <18 years. Discomfort during TAP removal as an indicator for patient friendliness was assessed by visual analogue scale (VAS; range 0–10). <b><i>Results:</i></b> Thirty-two patients (median age 14.0 years) were included, of which 19 were treated with solely topical agents and 13 with systemic treatment. The median VAS of discomfort during TAP removal was 1.0 (interquartile range 1.0). Significantly higher levels in lesional versus non-lesional skin were found for IL-1RA, VEGF, CXCL-1/2, hBD-2, and IL-8, whereas lower levels were found for IL-1α. Skin surface proteins were measured in both treatment groups, with significant higher lesional levels of KLK-5, IL-1RA, hBD-2, IL-1α, IL-23, and CCL-27 in the systemic treatment group. <b><i>Conclusion:</i></b> The TAP platform holds the potential for patient-friendly and noninvasive monitoring of skin-derived proteins in pediatric psoriasis patients in daily clinical practice.
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Hoell, Jessica I., Sebastian Ginzel, Cornelia Eckert, Michael Gombert, Ute Fischer, Martin Stanulla, Martin Schrappe, et al. "Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia Relapsing after Allogeneic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 601. http://dx.doi.org/10.1182/blood.v128.22.601.601.
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Abstract The prognosis of children with acute lymphoblastic leukemia (ALL) relapsing following allogeneic hematopoietic stem cell transplantation (allo-SCT) is still dismal. Within the framework of the ALL-REZ BFM 2002/ALL-SZT BFM 2003 trials, we performed whole-exome sequencing (WES) of ten patients relapsing after allo-SCT with the aim to thoroughly characterize the spectrum of acquired mutations and to identify potentially druggable targets, thus laying the ground for future personalized treatment strategies. Patients' age at initial diagnosis ranged from <12 months to 10 years. Two patients were diagnosed with T-ALL and 8 with pre-B-ALL. Time from initial disease to relapse ranged from 13 to 40 months. Patients underwent allo-SCT 3 to 6 months after diagnosis of relapse, donors were either HLA-matched unrelated volunteers (n=6), HLA-identical siblings (n=1) or HLA-haploidentical family donors (n=1). Time from SCT to relapse ranged from 3 to 21 months. Treatment following the post allo-SCT relapse varied considerably (from palliative care to a second allo-SCT). Only 2/10 patients are still alive, with one recently having been diagnosed with subsequent relapse following a second SCT. To investigate the mutational landscape of relapsed ALL following high-dose chemotherapeutic and immunologic attack both provided by an allo-SCT, five samples per patient were analyzed: initial leukemia (INIT), remission (REMI) after front-line chemotherapy representing patient germline, first relapse (RLPS), full donor-chimeric remission post allo-SCT (TREMI) representing donor germline, and relapse post allo-SCT (TRLPS). For comparative analyses, we defined the following three "oncogenomes" (OGs): OG1 (initial leukemia, SNVs in INIT minus REMI)), OG2 (first relapse, SNVs in RLPS minus REMI), OG3 (post allo-SCT relapse, SNVs in TRPLS minus REMI or TREMI). Median numbers of leukemia-specific SNVs in OG1-3 were 8.5, 34 and 37.5. We detected a median of 0.18 mutations per megabase (MB) in OG1, 0.67 mutations/MB in OG2 and 0.74 mutations/MB in OG3 (p= 0.005 for OG2/3 vs. OG1 [Wilcoxon test]). Although the mutational spectrum was highly diverse between individual patients and within the oncogenomes, we also identified several recurrent alterations: in OG1, five genes had recurrent SNVs (IGSF3, TTN, NOTCH1, CTBP2, NRAS). Seven genes were recurrently affected in three OG2s, including IKZF1, NOTCH1, NRAS, NT5C2. In OG3 we detected eleven recurrently mutated genes in three patients, among which were NRAS, FLT4, and TP53. Notably, TP53 was mutated in 5/10 patients. One patient carried a TP53 germline mutation, one patient had one unique SNV each in OG2 as well as OG3 and three patients had TP53 mutations only present in their OG3s. All but one SNV (resulting in a premature stop codon) were non-synonymously coding and were predicted to be deleterious for protein function. Of particular note, leukemic blasts showed profound plasticity concerning the mutational status of the nucleoside exporter NT5C2, mutations of which were previously shown to drive chemotherapy resistance in relapsed childhood ALL. While NT5C2 alterations were completely absent in OG1, 4 SNVs were detected in the OG2s of 3/10 patients. However, these NT5C2 mutations disappeared again in the OG3s once selection pressure of maintenance chemotherapy employing nucleoside analogues had been withdrawn. To identify novel treatment options in the desperate clinical scenario of post allo-SCT relapse, we searched OG3 for genetic lesions in genes known to be either targeted directly (a certain gene) or indirectly (a certain pathway) by currently approved therapeutic agents. To our surprise, nine out of ten patients exhibited such SNVs, for which additional targeted therapies are already available. Those therapeutic agents comprise small molecules inhibitors as well as antibodies such as Dasatinib, Erlotinib, Ibrutinib, Pazopanib, Tocilizumab, and Trastuzumab. Conclusion: Our comprehensive genetic analysis of ten children with ALL relapsing post allo-SCT revealed profound leukemic cell plasticity (e.g. loss of acquired NT5C2 mutations) as well as identified several recurrent genetic alterations (e.g. NOTCH1, NRAS, IKZF1) including TP53 (5/10 patients). Most importantly, we identified alterations in genes amenable to targeted treatment approaches in 9/10 patients thus potentially opening new therapeutic avenues. Disclosures Bader: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Medac: Consultancy, Research Funding. Peters:Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy; Medac: Consultancy.
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Ahmad, Muhaddis Ejaz, Muhammad Abdullah Yousaf, Abdul Rafae, Mustafa Nadeem Malik, Tariq Iqtidar Sadiq Syed, Syed Maaz Abdullah, Maimoona Khan, et al. "Melphalan Based Regimens for Treatment of Newly Diagnosed Amyloidosis, Lessons from Clinical Literature: A Systematic Review." Blood 134, Supplement_1 (November 13, 2019): 5561. http://dx.doi.org/10.1182/blood-2019-127192.
Full textAbstract:
Introduction: Melphalan causes cross linkage between DNA, causes cytotoxicity in both dividing and non-dividing tumor cells. Our objective is to analyze and summarize the published literature for the efficacy of melphalan based regimen used for the treatment of newly diagnosed Amyloidosis (ND-AL). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after June 2006, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 649 articles were identified initially and after detailed screening, we finalized 10 studies involving 616 ND-AL patients. Results: Melphalan (M), Bortezomib (V) and dexamethasone (d)/prednisone (p): A retrospective study by Zhao et al., included 123 ND-AL patients (pts) were given M, V, and d. Overall hematological response (OHR) was 100% with complete response (CR) in 44% and partial response (PR) in 38.9% pts. Median overall survival (mOS) was 38 months (mo) and 3-yr survival ranged from 41-72%. Organ response (OR) was 25%. In a study by Lee et al., with 19 pts who received M, V, and p demonstrated OHR of 84% (Table 1). Melphalan (M) and dexamethasone (d): Sanchorawala et al. (n=70) reported patients treated with M and d showed OHR of 69%, with CR in 13% and PR in 25%. Similarly, a study by Lebovic et al. reported 40 pts who were given M, d. OHR was 58% and 13% pts showed CR (Table 1). High dose Melphalan/Stem Cell Transplant (HDM/SCT) with and without induction: In study by Cowan et al., (n=45) pts in group A (n=21) were given novel induction using agents like protease inhibitor (PI), cyclophosphamide, bortezomib and dexamethasone (CyBorD), Lenalidomide (L), dexamethasone (d) prior to high-dose melphalan (HDM). CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given frontline HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. In a study by Scott et. al., 31 pts were categorized in 3 groups who received HDCT either with no induction, induction with V-based regimen and induction with other regimens including lenalidomide/dexamethasone (len/dex), melphalan/dexamethasone (mel/dex) and thalidomide/dexamethasone (Thal/dex). OHR in mel/dex cohort (n=3) was 67% (Table 1). In a study by Huang, X. et al., 56 pts were divided in two groups of 28 pts each. Pts in group A received Vd+HDM/SCT demonstrated CR in 67.9%, VGPR in 7.1%, PR in 10 .7 % and no response (NR) in 7.1 % pts. In group B, pts received with HDM/SCT upfront demonstrated CR in 35.7%, VGPR in 10.7%, PR in 2.1 % and no response NR in 21.4 % pts (Table 1). Randomized Standard dose Melphalan (SDM) versus HDM: In a study by Jaccard et al., there were two groups. The OHR was 68% in group A pts who were given SDM and high-dose dexamethasone (HD-dex) with CR in 31% and PR in 36% pts. The OHR was 67% in group B pts who were given HDM+ASCT with CR in 40% and PR in 25% pts (Table 1). Melphalan with Total body irradiaton (TBI): Vesole et al., reported 107 pts who were given M and TBI. OHR was 32% with CR in 16% and PR in 16% pts. mOS was 47.2 mo (Table 1). Melphalan (M), dexamethasone (d), Lenalidomide (L): In a clinical trial (NCT00890552) involving 25 pts M, d, and lenalidomide were give. CR, VGPR and PR were observed in 8%, 16% and 33%. 37.5% pts showed no-response (Table 1). Conclusion: Despite heterogeneity in the AL patient population and various regimens used in published literature, melphalan based regimens are very effective for treatment. Induction regimens and supportive care have evolved over the years. Novel combination regimens used for induction followed by HD-Melphalan consolidation along with careful selection of patients for high dose chemotherapy consolidation and stem cell transplantation in routine clinical practice is the best approach for personalized therapy selection for AL amyloidosis. Cytopenias of three cell lines are the major side effects reported with Mel therapy. Just like melphalan use for treatment of multiple myeloma in novel combination regimens, future randomized prospective trials are needed to better understand the efficacy and safety profile of melphalan based newer combination regimens for AL amyloidosis treatment. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
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Preddie, Martha Ingrid. "Canadian Public Library Users are Unaware of Their Information Literacy Deficiencies as Related to Internet Use and Public Libraries are Challenged to Address These Needs." Evidence Based Library and Information Practice 4, no. 4 (December 14, 2009): 58. http://dx.doi.org/10.18438/b8sp7f.
Full textAbstract:
A Review of:
Julien, Heidi and Cameron Hoffman. “Information Literacy Training in Canada’s Public Libraries.” Library Quarterly 78.1 (2008): 19-41.
Objective – To examine the role of Canada’s public libraries in information literacy skills training, and to ascertain the perspectives of public library Internet users with regard to their experiences of information literacy.
Design – Qualitative research using semi-structured interviews and observations.
Setting – Five public libraries in Canada.
Subjects – Twenty-eight public library staff members and twenty-five customers.
Methods – This study constituted the second phase of a detailed examination of information literacy (IL) training in Canadian public libraries. Five public libraries located throughout Canada were selected for participation. These comprised a large central branch of a public library located in a town with a population of approximately two million, a main branch of a public library in an urban city of about one million people, a public library in a town with a population of about 75,000, a library in a town of 900 people and a public library located in the community center of a Canadian First Nations reserve that housed a population of less than 100 persons. After notifying customers via signage posted in the vicinity of computers and Internet access areas, the researchers observed each patron as they accessed the Internet via library computers. Observations focused on the general physical environment of the Internet access stations, customer activities and use of the Internet, as well as the nature and degree of customer interactions with each other and with staff. Photographs were also taken and observations were recorded via field notes. The former were analyzed via qualitative content analysis while quantitative analysis was applied to the observations.
Additionally, each observed participant was interviewed immediately following Internet use. Interview questions focused on a range of issues including the reasons why customers used the Internet in public libraries, customers’ perceptions about their level of information literacy and their feelings with regard to being information literate, the nature of their exposure to IL training, the benefits they derived from such training, and their desire for further training. Public service librarians and other staff were also interviewed in a similar manner. These questions sought to ascertain staff views on the role of the public library with regard to IL training; perceptions of the need for and expected outcomes of such training; as well as the current situation pertinent to the provision of IL skills training in their respective libraries in terms of staff competencies, resource allocation, and the forms of training and evaluation. Interviews were recorded and transcribed. Data were interpreted via qualitative content analysis through the use of NVivo software.
Main Results – Men were more frequent users of public library computers than women, outnumbering them by a ratio ranging from 2:1 to 3.4:1. Customers appeared to be mostly under the age of 30 and of diverse ethnicities. The average income of interviewed customers was less than the Canadian average.
The site observations revealed that customers were seen using the Internet mainly for the purposes of communication (e.g., e-mail, instant messaging, online dating services). Such use was observed 78 times in four of the libraries. Entertainment accounted for 43 observations in all five sites and comprised activities such as online games, music videos, and movie listings. Twenty-eight observations involved business/financial uses (e.g., online shopping, exploration of investment sites, online banking). The use of search engines (25 observations), news information (23), foreign language and forum websites (21), and word processing were less frequently observed. Notably, there were only 20 observed library-specific uses (e.g., searching online catalogues, online database and library websites). Customers reported that they used the Internet mainly for general web searching and for e-mail.
It was also observed that in general the physical environment was not conducive to computer use due to uncomfortable or absent seating and a lack of privacy. Additionally, only two sites had areas specifically designated for IL instruction.
Of the 25 respondents, 19 reported at least five years experience with the Internet, 9 of whom cited experience of 10 years or more. Self-reported confidence with the Internet was high: 16 individuals claimed to be very confident, 7 somewhat confident, and only 2 lacking in confidence. There was a weak positive correlation between years of use and individuals’ reported levels of confidence.
Customers reported interest in improving computer literacy (e.g., keyboarding ability) and IL skills (ability to use more sources of information). Some expressed a desire “to improve certain personal attitudes” (30), such as patience when conducting Internet searches. When presented with the Association of College and Research Libraries’ definition of IL, 13 (52%) of those interviewed claimed to be information literate, 8 were ambivalent, and 4 admitted to being information illiterate. Those who professed to be information literate had no particular feeling about this state of being, however 10 interviewees admitted feeling positive about being able to use the Internet to retrieve information. Most of those interviewed (15) disagreed that a paucity of IL skills is a deterrent to “accessing online information efficiently and effectively” (30). Eleven reported development of information skills through self teaching, while 8 cited secondary schools or tertiary educational institutions. However, such training was more in terms of computer technology education than IL. Eleven of the participants expressed a desire for additional IL training, 5 of whom indicated a preference for the public library to supply such training. Customers identified face-to-face, rather than online, as the ideal training format. Four interviewees identified time as the main barrier to Internet use and online access.
As regards library staff, 22 (78.6%) of those interviewed posited IL training as an important role for public libraries. Many stated that customers had been asking for formal IL sessions with interest in training related to use of the catalogue, databases, and productivity software, as well as searching the web. Two roles were identified in the context of the public librarian as a provider of IL: “library staff as teachers/agents of empowerment and library staff as ‘public parents’” (32). The former was defined as supporting independent, lifelong learning through the provision of IL skills, and the latter encompassing assistance, guidance, problem solving, and filtering of unsuitable content.
Staff identified challenges to IL training as societal challenges (e.g., need for customers to be able to evaluate information provided by the media, the public library’s role in reducing the digital divide), institutional (e.g., marketing of IL programs, staff constraints, lack of budget for IL training), infrastructural (e.g., limited space, poor Internet access in library buildings) and pedagogical challenges, such as differing views pertinent to the philosophy of IL, as well as the low levels of IL training to which Canadian students at all levels had been previously exposed.
Despite these challenges library staff acknowledged positive outcomes resulting from IL training in terms of customers achieving a higher level of computer literacy, becoming more skillful at searching, and being able to use a variety of information sources. Affective benefits were also apparent such as increased independence and willingness to learn. Library staff also identified life expanding outcomes, such as the use of IL skills to procure employment.
In contrast to customer self-perception, library staff expressed that customers’ IL skills were low, and that this resulted in their avoidance of “higher-level online research” and the inability to “determine appropriate information sources” (36). Several librarians highlighted customers’ incapacity to perform simple activities such as opening an email account. Library staff also alluded to customer’s reluctance to ask them for help.
Libraries in the study offered a wide range of training. All provided informal, personalized training as needed. Formal IL sessions on searching the catalogue, online searching, and basic computer skills were conducted by the three bigger libraries. A mix of librarians and paraprofessional staff provided the training in these libraries. However, due to a lack of professional staff, the two smaller libraries offered periodic workshops facilitated by regional librarians.
All the libraries lacked a defined training budget. Nonetheless, the largest urban library was well-positioned to offer IL training as it had a training coordinator, a training of trainers program, as well as technologically-equipped training spaces. The other libraries in this study provided no training of trainers programs and varied in terms of the adequacy of spaces allocated for the purpose of training. The libraries also varied in terms of the importance placed on the evaluation of IL training. At the largest library evaluation forms were used to improve training initiatives, while at the small town library “evaluations were done anecdotally” (38).
Conclusion – While Internet access is available and utilized by a wide cross section of the population, IL skills are being developed informally and not through formal training offered by public libraries. Canadian public libraries need to work to improve information literacy skills by offering and promoting formal IL training programs.
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Budge, Eleanor J., Muhammad AA Khalil Allam, Imogen Mechie, Marie Scully, Obi Agu, and Chung Sim Lim. "Venous malformations: Coagulopathy control and treatment methods." Phlebology: The Journal of Venous Disease, December 6, 2020, 026835552097291. http://dx.doi.org/10.1177/0268355520972918.
Full textAbstract:
Venous malformations (VMs) are ectatic channels which arise as a result of vascular dysmorphogenesis, commonly caused by activating mutations in the endothelial tyrosine kinase receptor (TIE2)/phosphatidylinositol 3-kinase (PI3Kinase) pathway. With a prevalence of 1% in the general population, and a diverse clinical presentation depending on site, size and tissue involvement, their treatment requires a personalised and multidisciplinary approach. Larger lesions are complicated by local intravascular coagulopathy (LIC) causing haemorrhagic and/or thrombotic complications which can progress to disseminated intravascular coagulopathy (DIC). Methods We performed a literature review using a PubMed® search and identified 15 articles to include. References of these texts were examined to further expand the literature review. Principle findings: Several treatment options have been explored, including compression, sclerotherapy, laser therapy, cryoablation and surgery in addition to the management of LIC with low-molecular-weight-heparin (LMWH) and other anticoagulants. Targeted molecular therapies acting on the phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are newly emerging. Conclusion Despite a wealth of literature, larger, multi-centric, randomised and prospective trails are required to offer further clarification on the therapeutic management of coagulopathy control and to provide symptomatic benefit to patients with VMs. There should be efforts to provide long term follow up and to use standardised risk stratification tools and quality of life (QOL) questionnaires to aid comparison of agents and treatment protocols.
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Zhu, Dengya, Shastri Lakshman Nimmagadda, Torsten Reiners, and Amit Rudra. "An Integrated Search Framework for Leveraging the Knowledge-Based Web Ecosystem." Australasian Journal of Information Systems 24 (October 19, 2020). http://dx.doi.org/10.3127/ajis.v24i0.2331.
Full textAbstract:
The explosion of information constrains the judgement of search terms associated with Knowledge-Based Web Ecosystem (KBWE), making the retrieval of relevant information and its knowledge management challenging. The existing information retrieval (IR) tools and their fusion in a framework need attention, in which search results can effectively be managed. In this article, we demonstrate the effective use of information retrieval services by a variety of users and agents in various KBWE scenarios. An innovative Integrated Search Framework (ISF) is proposed, which utilises crawling strategies, web search technologies and traditional database search methods. Besides, ISF offers comprehensive, dynamic, personalized, and organization-oriented information retrieval services, ranging from the Internet, extranet, intranet, to personal desktop. In this empirical research, experiments are carried out demonstrating the improvements in the search process, as discerned in the conceptual ISF. The experimental results show improved precision compared with other popular search engines.
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Oksana, Movchan. "Molecular Aspects of Cancer Research Endometrium – The Prospect of Personalized Treatment." Journal of Pharmaceutical Research International, September 6, 2021, 346–56. http://dx.doi.org/10.9734/jpri/2021/v33i43a32496.
Full textAbstract:
Aims: Endometrial cancer is the most common gynaecological cancer, and there is a growing interest in identifying the molecular pathways involved and developing molecular-targeted treatment to prevent it. Present study was aimed to give an overview of the molecular processes involved in endometrial cancer development and treatment options.
Methods: We conducted a comprehensive systematic literature review and meta-analysis. For that purpose, PubMed database was searched for related studies till June 2021 and a through selection process was adopted to select the eligible studies.
Results: Endometrial malignancies are complicated molecularly, and their focused therapy has a wide range of outcomes, with median progressive survival rates ranging from 2.3 to 18 months.
Conclusions: The effective treatment and therapy need a detailed understanding of the molecular mechanisms underlying the creation and progression of endometrial cancer, as well as the development of innovative targeted therapeutic agents.
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Oz, Merve Demirbugen, Fezile Ozdemir, and Halit Sinan Suzen. "The influence of genetic variations and drug interactions based on metabo-lism of antidepressants and anticonvulsants." Current Drug Metabolism 21 (November 25, 2020). http://dx.doi.org/10.2174/1389200221999201125211058.
Full textAbstract:
Background:: Antidepressant (AD) and anticonvulsants (AC) medications are widely prescribed to treat neuro-psychiatric disorders and a broad range of other comorbidities. Interpatient variability in response to a given drug is a large challenge in psychiatry and neurology. Clinically similar patient’s often experience vastly different outcomes (higher or lower levels than the therapeutic range and/or adverse effects) from the same drug at similar doses. The variability in drug response is highly complex and can be attributed to the polymedication, genetic polymorphisms modulating drug-metabolizing enzyme activities (cytochromes P450, CYP), physiological and environmental factors. These identified sources of variability in drug responses makes biotransformation center of personalized treatment strategies. Objective:: The main objective of this review is deeply discuss the role of biotransformation in the occurrence of antidepres-sant and anticonvulsant induced inter individual variabilities with the focus of genetic variations and drug interactions. Methods:: We conducted an extensive search of the literature related to biotransformation of the antidepressant and anticon-vulsant agents available on relationships between genetic differences and interactions on available databases. Results:: In the present review, we provided an overview of documented clinically significant pharmacokinetic drug interac-tions, physiological and environmental differences. We further discuss the significance of genetic variations in drug metabo-lizing enzymes to underline the need for using information on both genotype and drug interactions towards implementing better clinical outcomes through personalized medicine in neurology and psychiatry. Conclusions:: The genetic variations in drug metabolizing enzymes underline the need for using information on both geno-type and drug interactions towards implementing better clinical outcomes through personalized medicine in neurology and psychiatry.
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Fong, Winnie, and Kenneth K. W. To. "Repurposing Chloroquine Analogs as an Adjuvant Cancer Therapy." Recent Patents on Anti-Cancer Drug Discovery 15 (January 6, 2021). http://dx.doi.org/10.2174/1574892815666210106111012.
Full textAbstract:
Background: Drug repurposing is emerging as an attractive strategy with lower attrition rate, lower cost and shorter timeframe than traditional drug discovery methods. Chloroquine (CQ) and its analogs are old drugs originally indicated for malaria treatment. Serendipitous discovery in early years revealed its anti-inflammatory properties, thus allowing its repositioned use in autoimmune diseases. Recent evidence also suggested its potential therapeutic use for anticancer therapy. Objective: This article reviews the molecular mechanisms, clinical evaluation and recent patents of CQ analogs in cancer therapy. Methods: Literature and patent searches were conducted using PubMed database and Google Patent/USPTO Patent Search database, respectively. The keywords including “chloroquine”, “hydroxychloroquine”, “chloroquine analogs”, “chloroquine derivatives”, “repurposing”, “autophagy”, and “cancer” were used. Results: CQ analogs have been reported to elicit their anticancer effects by modulating autophagy, inducing apoptosis, eliminating cancer stem cells, normalizing tumor vasculature and modulating antitumor immunity. As documented by recent patents and clinical trials, CQ analogs have been repurposed as an adjuvant therapy and combined with other anticancer agents for synergistic enhancement of treatment efficacy. However, most clinical trials on CQ only demonstrated modest improvement in anti-cancer efficacy. Conclusion: Given that CQ loses its anticancer activity in acidic and hypoxic environment within a tumor, novel CQ analogs and/or their formulations are under active investigation to improve their physicochemical properties and biological activity. On the other hand, identification of new biomarkers for better patient selection has been advocated in future trials in order to realize the repurposing of CQ analogs for cancer treatment in a personalized manner.
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Fong, Winnie, and Kenneth K. W. To. "Repurposing Chloroquine Analogs as an Adjuvant Cancer Therapy." Recent Patents on Anti-Cancer Drug Discovery 15 (January 6, 2021). http://dx.doi.org/10.2174/1574892815666210106111012.
Full textAbstract:
Background: Drug repurposing is emerging as an attractive strategy with lower attrition rate, lower cost and shorter timeframe than traditional drug discovery methods. Chloroquine (CQ) and its analogs are old drugs originally indicated for malaria treatment. Serendipitous discovery in early years revealed its anti-inflammatory properties, thus allowing its repositioned use in autoimmune diseases. Recent evidence also suggested its potential therapeutic use for anticancer therapy. Objective: This article reviews the molecular mechanisms, clinical evaluation and recent patents of CQ analogs in cancer therapy. Methods: Literature and patent searches were conducted using PubMed database and Google Patent/USPTO Patent Search database, respectively. The keywords including “chloroquine”, “hydroxychloroquine”, “chloroquine analogs”, “chloroquine derivatives”, “repurposing”, “autophagy”, and “cancer” were used. Results: CQ analogs have been reported to elicit their anticancer effects by modulating autophagy, inducing apoptosis, eliminating cancer stem cells, normalizing tumor vasculature and modulating antitumor immunity. As documented by recent patents and clinical trials, CQ analogs have been repurposed as an adjuvant therapy and combined with other anticancer agents for synergistic enhancement of treatment efficacy. However, most clinical trials on CQ only demonstrated modest improvement in anti-cancer efficacy. Conclusion: Given that CQ loses its anticancer activity in acidic and hypoxic environment within a tumor, novel CQ analogs and/or their formulations are under active investigation to improve their physicochemical properties and biological activity. On the other hand, identification of new biomarkers for better patient selection has been advocated in future trials in order to realize the repurposing of CQ analogs for cancer treatment in a personalized manner.