Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal carcinoma (IDC), is an aggressive histological subtype that is associated with progression to lethal ...disease. To delineate the molecular and cellular underpinnings of ICC/IDC aggressiveness, this study examines paired ICC/IDC and benign prostate surgical samples by single-cell RNA-sequencing, TCR sequencing, and histology. ICC/IDC cancer cells express genes associated with metastasis and targets with potential for therapeutic intervention. Pathway analyses and ligand/receptor status model cellular interactions among ICC/IDC and the tumor microenvironment (TME) including JAG1/NOTCH. The ICC/IDC TME is hallmarked by increased angiogenesis and immunosuppressive fibroblasts (CTHRC1
ASPN
FAP
ENG
) along with fewer T cells, elevated T cell dysfunction, and increased C1QB
TREM2
APOE
-M2 macrophages. These findings support that cancer cell intrinsic pathways and a complex immunosuppressive TME contribute to the aggressive phenotype of ICC/IDC. These data highlight potential therapeutic opportunities to restore immune signaling in patients with ICC/IDC that may afford better outcomes.
Recently, Anderson et al. (2019) proposed the concept of rankability, which refers to a dataset's inherent ability to produce a meaningful ranking of its items. In the same paper, they proposed a ...rankability measure that is based on an integer program for computing the minimum number of edge changes made to a directed graph in order to obtain a complete dominance graph, i.e., an acyclic tournament graph. In this article, we prove a spectral-degree characterization of complete dominance graphs and apply this characterization to produce a new measure of rankability that is cost-effective and more widely applicable. We support the details of our algorithm with several results regarding the conditioning of the Laplacian spectrum of complete dominance graphs and the Hausdorff distance between their Laplacian spectrum and that of an arbitrary directed graph with weights between zero and one. Finally, we analyze the rankability of datasets from the world of chess and college football.
Intrapleural injection of cholera toxin B conjugated to saporin (CTB-SAP) mimics respiratory motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Seven-day ...CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) primarily through TrkB and PI3K/Akt-dependent mechanisms i.e., Gs-pathway, which can be initiated by adenosine 2A (A2A) receptors in naïve rats, whereas 28-day CTB-SAP rats elicit moderate pLTF though BDNF- and MEK-/ERK-dependent mechanisms i.e., Gq-pathway, which is typically initiated by serotonin (5-HT) receptors in naïve rats. Here, we tested the hypothesis that pLTF following CTB-SAP is
) A2A receptor-dependent at 7 days and
) 5-HT receptor-dependent at 28 days. Adult Sprague-Dawley male rats were anesthetized, paralyzed, ventilated, and exposed to acute intermittent hypoxia (AIH; 3-, 5-min bouts of 10.5% O
) following bilateral, intrapleural injections at 7 days and 28 days of
) CTB-SAP (25 µg) or
) unconjugated CTB and SAP (control). Intrathecal C
delivery included either the
) A2A receptor antagonist (MSX-3; 10 µM; 12 µL) or
) 5-HT receptor antagonist (methysergide; 20 mM; 15 µL). pLTF was abolished with A2A receptor inhibition in 7-day, not 28-day, CTB-SAP rats versus controls (
< 0.05), whereas pLTF was abolished following 5-HT receptor inhibition in 28-day, not 7-day, CTB-SAP rats versus controls (
< 0.05). In addition, 5-HT2A receptor expression was unchanged in CTB-SAP rats versus controls, whereas 5-HT2B receptor expression was decreased in CTB-SAP rats versus controls (
< 0.05). This study furthers our understanding of the contribution of differential receptor activation to pLTF and its implications for breathing following respiratory motor neuron death.
The current study investigates underlying receptor-dependent mechanisms contributing to phrenic long-term facilitation (pLTF) following CTB-SAP-induced respiratory motor neuron death at 7 days and 28 days. We found that A2A receptors are required for enhanced pLTF in 7-day CTB-SAP rats, whereas 5-HT receptors are required for moderate pLTF in 28-day CTB-SAP rats. Targeting these time-dependent mechanisms have implications for breathing maintenance over the course of many neuromuscular diseases.
The purpose of this study was to explore dental hygiene students' and recent graduates' awareness, attitudes, perceived barriers, motivators, and intentions to pursue a career in academia as a dental ...hygiene educator.
Cross-sectional survey research was conducted with a non-probability sample of dental hygiene students and recent graduates (n = 451). The survey included sections for familiarity regarding academic careers for dental hygienists, attitudes toward academic careers, barriers and motivating factors for this career path, and future academic career intentions. Analysis included descriptive, correlations, and regression.
Of 451 surveys started, 296 were at least 80% complete for a completion rate of 66%. The most reported barrier to a career in academia was the cost to obtain the required degree to become an educator (67.6%, n = 200), and for motivating factors was a sense of accomplishment (62.8%, n = 186). Regression analysis of likelihood to pursue a higher education degree showed two main predictors; belief that higher education would advance the dental hygiene profession (β = 0.35, p < 0.001) and willingness to take a pay cut to become an educator (β = 0.24, p < 0.001).
Overall dental hygiene students and recent graduates were familiar with and had a positive view of careers in academia. However, barriers included cost and time for obtaining a higher degree, as well as the pay differential between academia and private practice. The educator shortage in dental hygiene may be alleviated by providing educators with loan forgiveness and offering salaries comparable to clinical practice.
Research priorities are often set by expert clinicians and researchers. We sought to apply an established process in patient-centered research to engage survivors and their caregivers in prioritizing ...research topics in prostate cancer.
A prostate cancer patient survey network, formed in partnership with Us TOO and the National Alliance of State Prostate Cancer Coalitions, engaged in a series of mixed-methods studies to prioritize comparative effectiveness research questions. This was accomplished through an iterative process that included 2 survey rounds and multidisciplinary working groups.
There were 591 and 706 survey respondents in the first and second rounds, respectively, with most having had localized prostate cancer (58.1%). Survey participants represented 45 states in the U.S. Five of the top 11 prioritized research questions related to treatment decision making and/or survivorship care. The following had the highest overall importance ratings: What is the comparative effectiveness of different 1) strategies to improve counseling regarding the side effects of prostate cancer treatment, 2) tools for decision making in localized prostate cancer and 3) sequences of treatments for metastatic prostate cancer?
We present a unique, patient-centered list of prioritized research questions among prostate cancer patients and their caregivers. These research questions may inform funding decisions for organizations that support research, and should be considered as priorities for clinicians, researchers and institutions conducting prostate cancer research. Prostate cancer is a common disease that affects 1 in 9 men over their lifetime. Researchers usually identify questions to study without asking men with prostate cancer. We asked survivors of prostate cancer and their caregivers to help us. They identified research questions and topics that are important to them. Researchers can focus on this list of questions to help men with prostate cancer. Groups who pay for research studies can make these questions their priority.
Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) selectively eliminates respiratory (e.g., phrenic) motor neurons, and mimics motor neuron death and respiratory deficits ...observed in rat models of neuromuscular diseases. Additionally, microglial density increases in the phrenic motor nucleus following CTB-SAP. This CTB-SAP rodent model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons, and the underlying mechanisms that contribute to enhancing or constraining their output at 7 days (d) or 28d post-CTB-SAP injection. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) through the Gs-pathway (inflammation-resistant in naïve rats), while pLTF is elicited though the Gq-pathway (inflammation-sensitive in naïve rats) in control and 28d CTB-SAP rats. In 7d and 28d male CTB-SAP rats and controls, we evaluated the effect of cyclooxygenase-1/2 enzymes on pLTF by delivery of the nonsteroidal anti-inflammatory drug, ketoprofen (IP), and we hypothesized that pLTF would be unaffected by ketoprofen in 7d CTB-SAP rats, but pLTF would be enhanced in 28d CTB-SAP rats. In anesthetized, paralyzed and ventilated rats, pLTF was surprisingly attenuated in 7d CTB-SAP rats and enhanced in 28d CTB-SAP rats (both p < 0.05) following ketoprofen delivery. Additionally in CTB-SAP rats: 1) microglia were more amoeboid in the phrenic motor nucleus; and 2) cervical spinal inflammatory-associated factor expression (TNF-α, BDNF, and IL-10) was increased vs. controls in the absence of ketoprofen (p < 0.05). Following ketoprofen delivery, TNF-α and IL-10 expression was decreased back to control levels, while BDNF expression was differentially affected over the course of motor neuron death in CTB-SAP rats. This study furthers our understanding of factors (e.g., cyclooxygenase-1/2-induced inflammation) that contribute to enhancing or constraining pLTF and its implications for breathing following respiratory motor neuron death.
•Ketoprofen constrains phrenic long-term facilitation in 7d CTB-SAP rats.•Ketoprofen enhances phrenic long-term facilitation in 28d CTB-SAP rats.•Inflammatory-associated marker expression is increased in CTB-SAP rats.•Ketoprofen reverses inflammatory-associated marker expression in CTB-SAP rats.•Microglia have amoeboid morphology in the phrenic motor nucleus in CTB-SAP rats.
Pregnancy-induced noncoding RNA (PINC) and retinoblastoma-associated protein 46 (RbAp46) are upregulated in alveolar cells of the mammary gland during pregnancy and persist in alveolar cells that ...remain in the regressed lobules following involution. The cells that survive involution are thought to function as alveolar progenitor cells that rapidly differentiate into milk-producing cells in subsequent pregnancies, but it is unknown whether PINC and RbAp46 are involved in maintaining this progenitor population. Here, we show that, in the post-pubertal mouse mammary gland, mPINC is enriched in luminal and alveolar progenitors. mPINC levels increase throughout pregnancy and then decline in early lactation, when alveolar cells undergo terminal differentiation. Accordingly, mPINC expression is significantly decreased when HC11 mammary epithelial cells are induced to differentiate and produce milk proteins. This reduction in mPINC levels may be necessary for lactation, as overexpression of mPINC in HC11 cells blocks lactogenic differentiation, while knockdown of mPINC enhances differentiation. Finally, we demonstrate that mPINC interacts with RbAp46, as well as other members of the polycomb repressive complex 2 (PRC2), and identify potential targets of mPINC that are differentially expressed following modulation of mPINC expression levels. Taken together, our data suggest that mPINC inhibits terminal differentiation of alveolar cells during pregnancy to prevent abundant milk production and secretion until parturition. Additionally, a PRC2 complex that includes mPINC and RbAp46 may confer epigenetic modifications that maintain a population of mammary epithelial cells committed to the alveolar fate in the involuted gland.
The tongue plays a crucial role in the swallowing process, and impairment can lead to dysphagia, particularly in motor neuron diseases (MNDs) resulting in hypoglossal-tongue axis degeneration (e.g., ...amyotrophic lateral sclerosis and progressive bulbar palsy). This study utilized our previously established inducible rodent model of dysphagia due to targeted degeneration of the hypoglossal-tongue axis. This model was created by injecting cholera toxin B conjugated to saporin (CTB-SAP) into the genioglossus muscle of the tongue base for retrograde transport to the hypoglossal (XII) nucleus via the hypoglossal nerve, which provides the sole motor control of the tongue. Our goal was to investigate the effect of high-repetition/low-resistance tongue exercise on tongue function, strength, and structure in four groups of male rats: (1) control + sham exercise (
n
= 13); (2) control + exercise (
n
= 10); (3) CTB-SAP + sham exercise (
n
= 13); and (4) CTB-SAP + exercise (
n
= 12). For each group, a custom spout with adjustable lick force requirement for fluid access was placed in the home cage overnight on days 4 and 6 post-tongue injection. For the two sham exercise groups, the lick force requirement was negligible. For the two exercise groups, the lick force requirement was set to ∼40% greater than the maximum voluntary lick force for individual rats. Following exercise exposure, we evaluated the effect on hypoglossal-tongue axis function (
via
videofluoroscopy), strength (
via
force-lickometer), and structure
via
Magnetic Resonance Imaging (MRI) of the brainstem and tongue in a subset of rats. Results showed that sham-exercised CTB-SAP rats had significant deficits in lick rate, swallow timing, and lick force. In exercised CTB-SAP rats, lick rate and lick force were preserved; however, swallow timing deficits persisted. MRI revealed corresponding degenerative changes in the hypoglossal-tongue axis that were mitigated by tongue exercise. These collective findings suggest that high-repetition/low-resistance tongue exercise in our model is a safe and effective treatment to prevent/diminish signs of hypoglossal-tongue axis degeneration. The next step is to leverage our rat model to optimize exercise dosing parameters and investigate corresponding treatment mechanisms of action for future translation to MND clinical trials.
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