Citations

AbstractBackgroundThe E‐cadherin, α‐ and β‐Catenin interaction at the cell adherens junction plays a key role in cell adhesion; alteration in the expression and function of these genes are associated with disease progression in several solid tumors including prostate cancer. The membranous β‐Catenin is dynamically linked to the cellular cytoskeleton through interaction with α‐Catenin at amino acid positions threonine 120 (T120) to 151 of β‐Catenin. Nuclear presence of α‐Catenin modulates the sensitivity of cells to DNA damage. The objective of this study is to determine the role of α‐Catenin and protein kinase D1 (PrKD1) in DNA damage response.MethodsProstate cancer cells; LNCaP, LNCaP (Sh‐PrKD1; silenced PrKD1), C4‐2 and C4‐2 PrKD1 were used for various sets of experiments to determine the role of DNA damage in PrKD1 overexpression and silencing cells. These cells were treated with compound‐10 (100 nM) and Etoposide (30 µM), total cell lysates, cytosolic and nuclear fractions were prepared to observe various protein expressions. We performed single cell gel electrophoresis (COMET assay) to determine the etoposide induce DNA damage in C4‐2 and C4‐2 PrKD1 cells. The animal experiments were carried out to determine the tolerability of compound‐10 by mice and generate preliminary data on efficacy of compound‐10 in modulating the α‐Catenin and PrKD1 expressions in inhibiting tumor progression.ResultsPrKD1, a novel serine threonine kinase, phosphorylates β‐Catenin T120. In silico analysis, confirmed that T120 phosphorylation alters β‐ to α‐Catenin binding. Forced expression of PrKD1 in prostate cancer cells increased β‐ and α‐Catenin protein levels associated with reduced etoposide induced DNA damage. Downregulation of α‐Catenin abrogates the PrKD1 mitigation of DNA damage. The in vitro results were corroborated in vivo using mouse prostate cancer patient derived xenograft model by inhibition of PrKD1 kinase activity with compound‐10, a selective PrKD inhibitor, demonstrating decreased total β‐ and α‐Catenin protein levels, and β‐Catenin T120 phosphorylation.ConclusionsAlteration in DNA damage response pathways play major role in prostate cancer progression. The study identifies a novel mechanism of α‐Catenin dependent DNA damage mitigation role for PrKD1 in prostate cancer.

Abstract Background: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo. Methods: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications. Results: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30–1.00, p = 0.048), functional independence (OR = 2.52, 95% CI = 1.02–6.20, p = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03–0.54, p = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups. Conclusion: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the study’s observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population.

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28–30) in 1809 of 2895 patients (62.5%), borderline (score 24–27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06–1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21–2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

AbstractIntroductionLong QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI.Methods and ResultsA retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age‐ and gender‐predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% ‐ 119.1%) and mean % predicted HRR was 80% (range 19.1% ‐ 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS‐associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE).ConclusionsPatients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age‐ and gender‐predicted maximum HR, should be used.

Background: RNA polymerase III (POLR3)-related leukodystrophy is a rare, neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Despite the challenges of caring for a child with POLR3-related leukodystrophy, few studies have examined parents’ disease burden. We sought to investigate quality of life and stress levels amongst parents of children with POLR3-related leukodystrophy. Methods: 43 parents of 32 children completed questionnaires on demographics, stress, quality of life, coping mechanisms, and experience of injustice. Detailed clinical data was collected from all patients. Results: Mothers ( t[27] = –8.66, P < .001) and fathers (t[16] = –4.47, P < .001) had lower quality of life scores compared to the normative population, yet 80% of parents’ stress scores fell within the normal stress range. Parents’ experience of injustice scores were high (>60). Correlations were found between and within parents’ scores. Years since disease onset and certain life circumstances correlated to mothers’ quality of life scores; however, no correlation was found between modifiable factors and fathers’ quality of life scores. Helpful coping mechanisms included those that allowed parents to be involved in their child's life. Conclusions: This is the first study to assess stress and quality of life in this population. These results shed light on the importance of implementing services and social support to improve the well-being of parents.

Traumatic brain injury (TBI), a major cause of death and disability among young people, leads to significant public health and economic challenges. Despite its frequency, treatment options remain largely unsuitable. However, examination of the blood–brain barrier (BBB) can assist with understanding the mechanisms and dynamics of brain dysfunction, which affects TBI sufferers secondarily to the injury. Here, we present a rat model of TBI focused on two standard BBB assessment markers, high- and low-molecular-weight complexes, in order to understand BBB disruption. In addition, we tested a new technique to evaluate BBB disruption on a single brain set, comparing the new technique with neuroimaging. A total of 100 Sprague–Dawley rats were separated into the following five groups: naive rats (n = 20 rats), control rats with administration (n = 20 rats), and TBI rats (n = 60 rats). Rats were assessed at different time points after the injury to measure BBB disruption using low- and high-molecular-weight complexes. Neurological severity score was evaluated at baseline and at 24 h following TBI. During the neurological exam after TBI, the rats were scanned with magnetic resonance imaging and euthanized for assessment of the BBB permeability. We found that the two markers displayed different examples of BBB disruption in the same set of brain tissues over the period of a week. Our innovative protocol for assessing BBB permeability using high- and low-molecular-weight complexes markers in a single brain set showed appropriate results. Additionally, we determined the lower limit of sensitivity, therefore demonstrating the accuracy of this method.

Abstract Purpose To investigate the feasibility of rapid CEST MRI acquisition for evaluating oxidative phosphorylation (OXPHOS) in human skeletal muscle at 3T, utilizing ultrafast Z‐spectroscopy (UFZ) combined with MRI and the Polynomial and Lorentzian line‐shape Fitting (PLOF) technique. Methods UFZ MRI on muscle was evaluated with turbo spin echo (TSE) and 3D EPI readouts. Five healthy subjects performed in‐magnet plantar flexion exercise (PFE) and subsequent changes of amide, PCr, and partial PCr mixed Cr (Cr + ) CEST dynamic signals post‐exercise were enabled by PLOF fitting. PCr/Cr CEST signal was further refined through pH correction by using the ratios between PCr/Cr and amide signals, named PCAR/CAR, respectively. Results UFZ MRI with TSE readout significantly reduces acquisition time, achieving a temporal resolution of <50 s for collecting high‐resolution Z‐spectra. Following PFE, the recovery/decay times (τ) for both PCr and Cr in the gastrocnemius muscle of the calf were notably longer when determined using PCr/Cr CEST compared to those after pH correction with amideCEST, namely = 87.1 ± 15.8 s and = 98.1 ± 20.4 s versus = 32.9 ± 19.7 s and = 43.0 ± 13.0 s, respectively. obtained via 31 P MRS ( = 50.3 ± 6.2 s) closely resemble those obtained from pH‐corrected PCr/Cr CEST signals. Conclusion The outcomes suggest potential of UFZ MRI as a robust tool for non‐invasive assessment of mitochondrial function in skeletal muscles. pH correction is critical for the reliable OXPHOS measurement by CEST.

As a treatment for the widely spread cardiovascular diseases (CVD), bypass vascular grafts have room for improvement in terms of mechanical property match with native arteries. A 3D‐printed nozzle is presented, featuring unique internal structures, to extrude artificial vascular grafts with a flower‐mimicking geometry. The multilayer‐structured graft wall allows the inner and outer layers to interfere sequentially during lateral expansion, replicating the nonlinear elasticity of native vessels. Both experiment and simulation results verify the necessity and benefit of the flower‐mimicking structure in obtaining the self‐toughening behavior. The gelation study of natural polymers and the utilization of sacrificial phase enables the smooth extrusion of the multiphase conduit, where computer‐assisted image analysis is employed to quantify manufacturing fidelity. The cell viability tests demonstrate the cytocompatibility of the gelatin methacryloyl (GelMA)/sodium alginate grafts, suggesting potential for further clinical research with further developments. This study presents a feasible approach for fabricating bypass vascular grafts and inspires future treatments for CVD.

Abstract Purpose To describe neuromuscular monitoring modalities and highlight the importance of neuromuscular monitoring to clinical pharmacy practice. Summary A growing body of literature and clinical practice guidelines have highlighted the importance of neuromuscular monitoring practices to ensure patient safety during surgery and in the intensive care unit. Understanding neuromuscular monitoring modalities can allow pharmacists to enhance participation in institutional discussions and optimization of neuromuscular blocker administration and reversal practices. We have described the various modalities of neuromuscular monitoring and considerations for using different modalities. Conclusion Neuromuscular monitoring should be performed whenever neuromuscular blocking agents are administered. This practice represents an evidence-based approach to minimizing the occurrence of residual neuromuscular blockade and its associated complications.