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This multicenter study evaluated the efficacy and safety of cycloserine and measured its effects on explicit and implicit memory tests in patients with Alzheimer's disease (AD). Four hundred ten patients with AD, aged 50 years or older, were enrolled in this parallel-group, double-blind, placebo-controlled, randomized trial of 5, 15, or 50 mg cycloserine or placebo twice daily, and 403 entered the double-blind treatment phase. Two hundred sixty-five patients completed the entire 26-week treatment phase. There were no baseline differences among the four treatment groups. Cognitive Drug Research (CDR) efficacy assessments showed no differences between active treatments and placebo from baseline to study weeks 2, 6, 14, or 26. Patients receiving 15 mg of cycloserine improved significantly on one section of an implicit memory test. No differences among treatments were observed for any other assessment scales evaluated. The incidence and severity of adverse events were similar across treatment groups. Cycloserine was well tolerated but did not demonstrate consistent evidence of efficacy during the course of therapy. Higher doses may be necessary to achieve efficacy in the AD population and do not appear to be precluded by the adverse event profile seen in this study. [ABSTRACT FROM AUTHOR]

It is becoming increasingly apparent that cancer drug therapies can only reach their full potential through appropriate patient selection. Matching drugs and cancer patients has proven to be a complex challenge, due in large part to the substantial molecular heterogeneity inherent to human cancers. This is not only a major hurdle to the improvement of the use of current treatments but also for the development of novel therapies and the ability to steer them to the relevant clinical indications. In this commentary we discuss recent studies from Kuo et al., published this month in BMC Medicine, in which they used a panel of cancer cell lines as a model for capturing patient heterogeneity at the genomic and proteomic level in order to identify potential biomarkers for predicting the clinical activity of a novel candidate chemotherapeutic across a patient population. The findings highlight the ability of a 'systems approach' to develop a better understanding of the properties of novel candidate therapeutics and to guide clinical testing and application.See the associated research paper by Kuo et al: http://www.biomedcentral.com/1741-7015/7/77. [ABSTRACT FROM AUTHOR]

The steep rise in the incidence of tick-borne encephalitis (TBE) in the 1990s and its subsequent high level in the Czech Republic are not even over the whole territory. It is manifested markedly in the Czech-Moravian Highland region. In the decades of 1971 through 1992, TBE incidence in the Highland Region did not reach the countrywide average. The rise has been noted only since 1997; in the year 2006 TBE incidence in that administrative region was more than double the countrywide average. Analysis of the situation have not found any socio-economic shifts or land-use changes, or in the numbers of game animals, that could have had an effect on TBE incidence. The rise of infections in localities 500 m above sea level (a.s.l.) and more was markedly steeper than that below that altitudinal limit. At those altitudes there has been found an increase in average monthly temperatures exceeding countrywide averages namely in the period of maximum Ixodes ricinus activity (May-August). Detailed analysis of meteorological conditions and comparison with a long-term study of the influence of modifications of the mountain climate in the Krkonose Mts. on I. ricinus tick distribution and the pathogens transmitted by them, have led to the conclusion that likewise in the Czech-Moravian Highland a marked warming had influenced the local population of the vector I. ricinus, caused an activation of foci of TBE, increased contacts of humans with the vector, consequently giving rise to an apparent increase in the incidence of human cases of TBE. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to pilot test a survey of professionals within the justice system about their knowledge and perceptions of developmental language disorders (DLDs) and to gather initial data supporting their knowledge and perceptions., Method: One hundred thirty-six adults in Texas with law enforcement jobs, primarily police officers, participated in this study. Participants completed a survey consisting of 78 questions about their background, experiences with DLD, and beliefs about communication. Additionally, 42 adults who did not work in law enforcement completed the survey twice to establish the initial measures of survey reliability., Results: This survey demonstrated sufficient test-retest reliability with adults not in law enforcement, and results indicated the emergence of two subscales within the survey. Law enforcement professionals appeared to have limited knowledge of DLD, and many linked language-related behaviors with credibility. A majority did agree with giving accommodations to individuals who struggle with language and reported interest in receiving training to recognize and accommodate DLD., Conclusions: This pilot study demonstrates a need for collaboration between speech-language pathologists and law enforcement professionals and provides data for a survey that could be used across professional groups in the justice system to measure knowledge and perspectives of DLDs. This work represents an initial step in an iterative process of survey development for law enforcement professionals., Supplemental Material: https://doi.org/10.23641/asha.25033718.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified 1-4 , the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interac tions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer ). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)