Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable ...first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N.sup.6-methyladenosine (m.sup.6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m.sup.6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m.sup.6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m.sup.6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m.sup.6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m.sup.6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators--ZCCHC4, G3BP1, and RBMX--may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m.sup.6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m.sup.6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC. Keywords: Small-cell lung cancer, m.sup.6A regulators, Epigenetic modification, Chemotherapy resistance, Individualized medicine
The implementation of tailor-made dosage forms is currently one of the biggest challenges in the health sector. Over the last years, different approaches have been introduced to provide an individual ...and precise dispensing of the appropriate dose of an active pharmaceutical ingredient (API). A more recent approach, which has been intensively researched in the last years, is 3D-printing of medicines.
The aim of this work was to develop printing formulations free of organic solvents for a pressure-assisted microsyringe printing method (PAM), which should also be printable over several days of storage. Furthermore, the printed dosage forms should provide a sustained release of the incorporated API. A mixture of polyvinyl acetate/polyvinylpyrrolidone copolymer (PVAc-PVP), hydroxypropyl methylcellulose (HPMC) and highly dispersed silicon dioxide (SiO2) was found to be a feasible polymer matrix to achieve a sustained drug release. Levetiracetam (LEV) was used as model drug.
The printed formulations were analyzed regarding mass variation, friability and thickness. Furthermore, the dissolution behavior of freshly printed tablets and tablets printed from stored printing formulations were investigated. The dissolution profiles indicate that the dissolution of LEV could be modified by varying the amount of HPMC and by changing the infill design of tablets. Tablet-like geometries with an infill design of 0.35 mm and 5% HPMC released 50% of the incorporated drug after 4 h, while for tablets with a higher HPMC amount the release was decreased (10% HPMC: 5.5 h; 15% HPMC: 8 h). All printed tablets exhibit a friability < 0.5%, indicating that PAM printing is suitable for the manufacturing of tablets with a high structural integrity. Furthermore, this study demonstrates the ability of producing tablets with a uniform content and mass using PAM printing.
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Purpose Benign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms ...and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5α-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms. Materials and Methods A PubMed® literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5α-reductase type 2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications. Results Benign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5α-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5α-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5α-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy. Conclusions Progressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy.
During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research ...projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.
The etiology of kidney disease remains unknown in many individuals with chronic kidney disease (CKD). We created the Mayo Clinic Nephrology Genomics Clinic to improve our ability to integrate genomic ...and clinical data to identify the etiology of unexplained CKD.
Retrospective study.
An essential component of our program is the Nephrology Genomics Board which consists of nephrologists, geneticists, pathologists, translational omics scientists, and trainees who interpret the patient’s clinical and genetic data. Since September 2016, the Board has reviewed 163 cases (15 cystic, 100 glomerular, 6 congenital anomalies of kidney and urinary tract (CAKUT), 20 stones, 15 tubulointerstitial, and 13 other).
Testing was performed with targeted panels, single gene analysis, or analysis of kidney-related genes from exome sequencing. Variant classification was obtained based on the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.
A definitive genetic diagnosis was achieved for 50 families (30.7%). The highest diagnostic yield was obtained in individuals with tubulointerstitial diseases (53.3%), followed by congenital anomalies of the kidney and urological tract (33.3%), glomerular (31%), cysts (26.7%), stones (25%), and others (15.4%). A further 20 (12.3%) patients had variants of interest, and variant segregation, and research activities (exome, genome, or transcriptome sequencing) are ongoing for 44 (40%) unresolved families.
Possible overestimation of diagnostic rate due to inclusion of individuals with variants with evidence of pathogenicity but classified as of uncertain significance by the clinical laboratory.
Integration of genomic and research testing and multidisciplinary evaluation in a nephrology cohort with CKD of unknown etiology or suspected monogenic disease provided a diagnosis in a third of families. These diagnoses had prognostic implications, and often changes in management were implemented.
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Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to ...develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was conducted systematically for the continuous film coating process. A continuously working pilot-scale coating bench was used for film manufacturing and the viscosities of the polymer solutions were investigated to obtain processible formulations. The investigation of the mechanical properties of the long film was an integral part of the study, because the handling of the long film during flexible dosing differs distinctly from the handling of a single dosed ODF. The secant modulus and the yield stress were evaluated as parameters with high information value about the deformation behavior of the ODF. A long warfarin ODF was successfully produced using the pilot-scale coating bench equipped with an optical probe for in-line film thickness measurement. It was feasible to use the principle of a tape dispenser for flexible and, therefore, individualized dosing as proof of concept. Combining the long ODF with a dosing device allows individualized therapy with warfarin for all age groups manageable by the patient himself.
Abstract The objective of this article was to provide a framework for understanding the different definitions of the term “personalized medicine.” The term personalized medicine is used regularly but ...interpreted in different ways. This article approaches the term by starting with a broad view of clinical medicine, where three components can be distinguished: the questions (e.g., what is the diagnosis?), the methods used to answer them (e.g., a test), and the available actions (e.g., to give or not give a particular drug). Existing definitions of personalized medicine disagree about which questions, methods, and actions fall within its domain. Some define the term narrowly, referring to the use of a diagnostic test to predict drug response, thereby clarifying whether or not a patient will benefit from that drug. An example of this combination is the HER2/neu test to predict the effectiveness of trastuzumab in breast cancer. Many who adopt this definition associate the concept of personalized medicine with fields such as genetics, genomics, and other types of “-omics.” In contrast, others view personalized medicine as a concept that has always existed, because medicine has always considered the needs of the individual. One definition of personalized medicine that accommodates both interpretations is “the use of combined knowledge (genetic or otherwise) about a person to predict disease susceptibility, disease prognosis, or treatment response and thereby improve that person’s health.” This predictive ability can increase over time through innovations in various technologies, resulting in further improvements in health outcomes. Moreover, these developments can lead to a better understanding of the underlying causes of disease, which can eventually lead to breakthroughs in the treatment of individual patients. In that sense, a truly personalized form of medicine can also be seen as an ideal, a goal that will be achieved only after multiple advances in science. Although the term personalized medicine was rechristened somewhat recently, our ability to personalize medicine will continue to advance in unimaginable ways as we come to learn more about the heterogeneity that exists among individuals and diseases.
Advances in genomics and next-generation sequencing have provided clinical researchers with unprecedented opportunities to understand the molecular basis of human genetic disorders. This abundance of ...information places new requirements on traditional disease models, which have the potential to be used to confirm newly identified pathogenic mutations and test the efficacy of emerging therapies. The unique attributes of zebrafish are being increasingly leveraged to create functional disease models, facilitate drug discovery, and provide critical scientific bases for the development of new clinical tools for the diagnosis and treatment of human disease. In this short review and the accompanying poster, we highlight a few illustrative examples of the applications of the zebrafish model to the study of human health and disease.
Psoriasis is an incurable cutaneous illness characterized by the presence of well-delimited reddish plaques and silvery-white dry scales. So far, there is a limited understanding of its pathogenesis, ...though recent discoveries on the immunological, genetic and molecular aspects of this disease have significantly contributed to the identification of new targets and the development of novel drugs. Despite these advances, many patients are still dissatisfied, so to improve patient satisfaction, reliability, and clinical outcomes, the individualization of the treatments for this disease becomes a necessity. This review summarizes recent findings related to psoriasis pathogenesis and describes new small molecules and targets recently identified as promising for treatments. Additionally, the current status, challenges and the future directions for achieving individualized therapy for this disease and the need for more collaborative studies are discussed. The individualization of treatments for psoriasis, rather than a goal, is analyzed as a process where a dynamic integration between the needs and characteristics of the patients, the pharmacological progress, and the clinical decisions takes place.
Major depressive disorder (MDD) is projected to be a leading cause of disability globally by 2030. Only a minority of patients remit with antidepressants. If assay of polymorphisms influencing ...central nervous system (CNS) bioavailability could guide prescribers to more effectively dose patients, remission rates may improve and the burden of disease from MDD reduce. Hepatic and blood brain barrier (BBB) polymorphisms appear to influence antidepressant CNS bioavailability.
A 12-week prospective double blind randomized genetically guided versus unguided trial of antidepressant dosing in Caucasian adults with MDD (n=148) was conducted.
Subjects receiving genetically guided prescribing had a 2.52-fold greater chance of remission (95% confidence interval CI=1.71-3.73, z=4.66, p<0.0001). The number needed to genotype (NNG)=3 (95% CI=1.7-3.5) to produce an additional remission.
These data suggest that a pharmacogenetic dosing report (CNSDose(®)) improves antidepressant efficacy. The effect size was sufficient that translation to clinical care may arise if results are independently replicated.
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