Targeting STAT3 in Cancer with Nucleotide Therapeutics.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an "undruggable" target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors

Goal-Focused Emotion-Regulation Therapy (GET) for young adult survivors of testicular cancer: a pilot randomized controlled trial of a biobehavioral intervention protocol.

BackgroundTesticular cancer diagnosis and treatment, especially given its threat to sexuality and reproductive health, can be distressing in the formative period of young adulthood and the majority of young survivors experience impairing, distressing, and modifiable adverse outcomes that can persist long after medical treatment. These include psychological distress, impairment in pursuit of life goals, persistent physical side effects, elevated risk of secondary malignancies and chronic illness, and biobehavioral burden (e.g., enhanced inflammation, dysregulated diurnal stress hormones). However, few targeted interventions exist to assist young survivors in renegotiating life goals and regulating cancer-related emotions, and none focus on reducing the burden of morbidity via biobehavioral mechanisms. This paper describes the methodology of a randomized controlled biobehavioral trial designed to investigate the feasibility and preliminary impact of a novel intervention, Goal-focused Emotion-Regulation Therapy (GET), aimed at improving distress symptoms, emotion regulation, goal navigation skills, and stress-sensitive biomarkers in young adult testicular cancer patients.MethodsParticipants will be randomized to receive six sessions of GET or Individual Supportive Therapy (ISP) delivered over 8 weeks. In addition to indicators of intervention feasibility, we will measure primary (depressive and anxiety symptoms) and secondary (emotion regulation and goal navigation skills, career confusion) psychological outcomes prior to (T0), immediately after (T1), and 12 weeks after (T2) intervention. Additionally, identified biomarkers will be measured at baseline and at T2.DiscussionGET may have the potential to improve self-regulation across biobehavioral domains, improve overall cancer adjustment, and address the need for targeted supportive care interventions for young adult cancer survivors.Trial registrationClinicaltrials.gov, NCT04150848. Registered on 28 October 2019

Live calcium imaging of Aedes aegypti neuronal tissues reveals differential importance of chemosensory systems for life-history-specific foraging strategies.

BackgroundThe mosquito Aedes aegypti has a wide variety of sensory pathways that have supported its success as a species as well as a highly competent vector of numerous debilitating infectious pathogens. Investigations into mosquito sensory systems and their effects on behavior are valuable resources for the advancement of mosquito control strategies. Numerous studies have elucidated key aspects of mosquito sensory systems, however there remains critical gaps within the field. In particular, compared to that of the adult form, there has been a lack of studies directed towards the immature life stages. Additionally, although numerous studies have pinpointed specific sensory receptors as well as responding motor outputs, there has been a lack of studies able to monitor both concurrently.ResultsTo begin filling aforementioned gaps, here we engineered Ae. aegypti to ubiquitously express a genetically encoded calcium indicator, GCaMP6s. Using this strain, combined with advanced microscopy, we simultaneously measured live stimulus-evoked calcium responses in both neuronal and muscle cells with a wide spatial range and resolution.ConclusionsBy coupling in vivo live calcium imaging with behavioral assays we were able to gain functional insights into how stimulus-evoked neural and muscle activities are represented, modulated, and transformed in mosquito larvae enabling us to elucidate mosquito sensorimotor properties important for life-history-specific foraging strategies

Northern Hemisphere winter snow anomalies: ENSO, NAO and the winter of 2009/10

Winter 2009/10 had anomalously large snowfall in the central parts of the United States and in northwestern Europe. Connections between seasonal snow anomalies and the large scale atmospheric circulation are explored. An El Niño state is associated with positive snowfall anomalies in the southern and central United States and along the eastern seaboard and negative anomalies to the north. A negative NAO causes positive snow anomalies across eastern North America and in northern Europe. It is argued that increased snowfall in the southern U.S. is contributed to by a southward displaced storm track but further north, in the eastern U.S. and northern Europe, positive snow anomalies arise from the cold temperature anomalies of a negative NAO. These relations are used with observed values of NINO3 and the NAO to conclude that the negative NAO and El Niño event were responsible for the northern hemisphere snow anomalies of winter 2009/10

Common DNA methylation dynamics in endometriod adenocarcinoma and glioblastoma suggest universal epigenomic alterations in tumorigenesis

Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated enhancers within EAC samples contain several transcription factor binding site clusters with enriched disease ontology terms highlighting uterine function, while hypermethylated enhancers in GBM are found to overlap active enhancer marks in adult brain. These findings suggest that loss of original cellular identity may be a shared step in tumorigenesis

Factors Affecting Speech Discrimination in Children with Cochlear Implants: Evidence from Early-Implanted Infants

Background To learn words and acquire language, children must be able to discriminate and correctly perceive phonemes. Although there has been much research on the general language outcomes of children with cochlear implants (CIs), little is known about the development of speech perception with regard to specific speech processes, such as speech discrimination. Purpose The purpose of this study was to investigate the development of speech discrimination in infants with CIs and identify factors that might correlate with speech discrimination skills. Research Design Using a Hybrid Visual Habituation procedure, we tested infants with CIs on their ability to discriminate the vowel contrast /i/-/u/. We also gathered demographic and audiological information about each infant. Study Sample Children who had received CIs before 2 yr of age served as participants. We tested the children at two post cochlear implantation intervals: 2–4 weeks post CI stimulation (N = 17) and 6–9 mo post CI stimulation (N = 10). Data Collection and Analysis The infants’ mean looking times during the novel versus old trials of the experiment were measured. A linear regression model was used to evaluate the relationship between the normalized looking time difference and the following variables: chronological age, age at CI stimulation, gender, communication mode, and best unaided pure-tone average. Results We found that the best unaided pure-tone average predicted speech discrimination at the early interval. In contrast to some previous speech perception studies that included children implanted before 3 yr of age, age at CI stimulation did not predict speech discrimination performance. Conclusions The results suggest that residual acoustic hearing before implantation might facilitate speech discrimination during the early period post cochlear implantation; with more hearing experience, communication mode might have a greater influence on the ability to discriminate speech. This and other studies on age at cochlear implantation suggest that earlier implantation might not have as large an effect on speech perception as it does on other language skills

Examining How Middle School Science Teachers Implement a Multimedia-enriched Problem-based Learning Environment

This study examined how a group of ten middle school teachers implemented a technology enriched problem-based learning (PBL) environment. The goal was to understand their motivation, document their implementation techniques, and identify factors that teachers considered important in using technology-based PBL tools in their teaching. The analysis identified four factors that provided the impetus for teachers to consider the adoption of technology-based PBL instruction. These factors are (1) the PBL program addresses the teachers’ curricular needs and implementing it has campus administrative and technical support, (2) the method is aligned with teachers’ pedagogical beliefs, (3) the PBL program offers a new way of teaching and promotes the development of higher-order thinking skills, and (4) the PBL program challenges students in a captivating manner and supports the learning needs of all students. Teachers’ implementation techniques with over 1,000 sixth graders were documented in detail with regard to: 1) the teacher’s roles, 2) the student’s role, and 3) the classroom interactions during the implementation of the PBL program. In addition, a detailed description of contrasting narratives of two pairs of teachers is provided, illustrating the range of implementation techniques that can occur using the same PBL program to allow for individualized instruction to meet different students’ needs. The goal of providing detailed implementation practices is to address the lack of “how to” in PBL implementation in K-12 classrooms as indicated in the literature and offer insights and ideas to those interested in adopting and implementing PBL. Findings are discussed within the theoretical framework and implications are provided