Mcelroydonovan6202

The confounding effects of next-generation sequencing (NGS) noise on detection of low frequency circulating tumor DNA (ctDNA) without a priori knowledge of solid tumor mutations has limited the applications of circulating cell-free DNA (ccfDNA) in clinical oncology. Here, we use a 118 gene panel and leverage ccfDNA technical replicates to eliminate NGS-associated errors while also enhancing detection of ctDNA from pancreatic ductal adenocarcinomas (PDACs). Pre-operative ccfDNA and tumor DNA were acquired from 14 patients with PDAC (78.6% stage II-III). Post-operative ccfDNA was also collected from 11 of the patients within 100 days of surgery. ctDNA detection was restricted to variants corresponding to pathogenic mutations in PDAC present in both replicates. PDAC-associated pathogenic mutations were detected in pre-operative ccfDNA in four genes (KRAS, TP53, SMAD4, ALK) from five patients. Of the nine ctDNA variants detected (variant allele frequency 0.08%-1.59%), five had a corresponding mutation in tumor DNA. Pre-operative detection of ctDNA was associated with shorter survival (312 vs. 826 days; χ2=5.4, P = 0.021). Guiding ctDNA detection in pre-operative ccfDNA based on mutations present in tumor DNA yielded a similar survival analysis. Detection of ctDNA in the post-operative ccfDNA with or without tumor-informed guidance was not associated with outcomes. Therefore, the detection of PDAC-derived ctDNA during a broad and untargeted survey of ccfDNA with NGS may be a valuable, non-invasive, prognostic biomarker to integrate into the clinical assessment and management of patients prior to surgery.Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. Memantine order We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.Understanding how the extracellular matrix affects cancer development constitutes an emerging research field. Fibronectin and collagen are two intriguing matrix components found in cancer. Large concentrations of fibronectin or collagen type I have been implicated in poor prognosis in patients. In a mouse model, we had shown that genetically decreasing circulating fibronectin resulted in smaller tumors. We therefore aimed to manipulate fibronectin pharmacologically and determine how cancer development is affected. Deletion of fibronectin in human breast cancer cells (MDA-MB-231) using shRNA (knockdown Kd) improved survival and diminished tumor burden in a model of metastatic lesions and in a model of local growth. Based on these findings, it seemed reasonable to attempt to prevent fibronectin accumulation using a bacterial derived peptide called pUR4. Treatment with this peptide for 10 days in the breast cancer local growth model or for 5 days in a melanoma skin cancer model (B16) was associated with a significant suppression of cancer growth. Treatment aimed at inhibiting collagen type I accumulation without interfering with fibronectin could not affect any changes in vivo. In the absence of fibronectin, diminished cancer progression was due to inhibition of proliferation, even though changes in blood vessels were also detected. Decreased proliferation could be attributed to decreased ERK phosphorylation and diminished YAP expression. In summary, manipulating fibronectin diminishes cancer progression, mostly by suppressing cell proliferation. This suggests that matrix modulation could be used as an adjuvant to conventional therapy as long as a decrease in fibronectin is obtained.Familiar and unfamiliar voice perception are often understood as being distinct from each other. For identity perception, theoretical work has proposed that listeners use acoustic information in different ways to perceive identity from familiar and unfamiliar voices Unfamiliar voices are thought to be processed based on close comparisons of acoustic properties, while familiar voices are processed based on diagnostic acoustic features that activate a stored person-specific representation of that voice. To date no empirical study has directly examined whether and how familiar and unfamiliar listeners differ in their use of acoustic information for identity perception. Here, we tested this theoretical claim by linking listeners' judgements in voice identity tasks to complex acoustic representation - spectral similarity of the heard voice recordings. Participants (N = 177) who were either familiar or unfamiliar with a set of voices completed an identity discrimination task (Experiment 1) or an identity sorting task (Experiment 2). In both experiments, identity judgements for familiar and unfamiliar voices were guided by spectral similarity Pairs of recordings with greater acoustic similarity were more likely to be perceived as belonging to the same voice identity. However, while there were no differences in how familiar and unfamiliar listeners used acoustic information for identity discrimination, differences were apparent for identity sorting. Our study therefore challenges proposals that view familiar and unfamiliar voice perception as being at all times distinct. Instead, our data suggest a critical role of the listening situation in which familiar and unfamiliar voices are evaluated, thus characterising voice identity perception as a highly dynamic process in which listeners opportunistically make use of any kind of information they can access.Collagens extracted from different tissues and fish species display different physicochemical properties, thus novel sources require characterization. Gulf corvina (Cynoscion othonopterus) is processed industrially for food. Of the by-products, the swim bladder is used for fish maw, but other tissues are treated as waste. In the present study, pepsin-soluble collagen from Gulf corvina skin and swim bladder was extracted and characterized. Skin produced a higher collagen yield (82 ± 1.53 %) than swim bladder (69 ± 1.60 %). Both collagens exhibited electrophoresis bands corresponding to ([α1(I)]2α2(I)) and β chains, all characteristic of type I collagen. Spectra analysis showed the collagens to maintain their triple-helix structure. The skin collagen had a lower denaturation temperature (29.8 °C) than the swim bladder collagen (32.5 °C), due to its relatively low imino acid content (168 vs. 190 /1000 residues, respectively). Both collagens were highly soluble in acidic pH ranges; Zeta potential values were 5.5 for the skin collagen and 6.2 for the swim bladder collagen. Gulf corvina skin and swim bladder are excellent sources of type I collagen with similar physicochemical properties.With the rise of new tools, from controlled genetic manipulations and optogenetics to improved microscopy, it is now possible to make clear, quantitative and reproducible measurements of biological processes. The humble fruit fly Drosophila melanogaster, with its ease of genetic manipulation combined with excellent imaging accessibility, has become a major model system for performing quantitative in vivo measurements. Such measurements are driving a new wave of interest from physicists and engineers, who are developing a range of testable dynamic models of active systems to understand fundamental biological processes. The reproducibility of the early Drosophila embryo has been crucial for understanding how biological systems are robust to unavoidable noise during development. Insights from quantitative in vivo experiments in the Drosophila embryo are having an impact on our understanding of critical biological processes, such as how cells make decisions and how complex tissue shape emerges. Here, to highlight the power of using Drosophila embryogenesis for quantitative biology, I focus on three main areas (1) formation and robustness of morphogen gradients; (2) how gene regulatory networks ensure precise boundary formation; and (3) how mechanical interactions drive packing and tissue folding. I further discuss how such data has driven advances in modelling.

Explore the spectrum of clinical manifestations of pentosan polysulfate (PPS) maculopathy observed across a range of practice settings.

Multi-institutional retrospective study.

Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019 through December 4, 2020.

Members of The Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics.

Pentosan polysulfate exposure characteristics and fundus imaging features.

There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2 to 18.9), with a median cumulative exposure of 1.5 kg (0.9 - 2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption tandardized ophthalmic screening of patients treated with PPS.

A clear link between insomnia concerns and suicidal ideation has been shown in a variety of populations. These investigations failed to use a theoretical lens in understanding this relationship. Research within the veteran population has demonstrated that feelings of thwarted belongingness (TB), but not perceived burdensomeness (PB), mediate the insomnia and suicidal ideation relationship. Using two high risk samples, the present investigation replicated and extended this line of inquiry to include interpersonal hopelessness about TB, a key component of the Interpersonal Psychological Theory of Suicide.

Using medical record review and survey data, study 1 replicated the finding that TB is a stronger explanatory factor of the insomnia to suicidal ideation/suicide risk relationship in a sample of N=200 treatment-seeking active-duty personnel. Study 2 found that insomnia symptoms had an indirect effect on suicidal ideation through TB and PB but not interpersonal hopelessness in a sample of N=151 college students with a history of suicidal thoughts and/or behaviors.