Relaxation effect of abacavir on rat basilar arteries

Background The use of abacavir has been linked with increased cardiovascular risk in patients with human immunodeficiency virus infection; however, the mechanism involved remains unclear. We hypothesize that abacavir may impair endothelial function. In addition, based on the structural similarity between abacavir and adenosine, we propose that abacavir may affect vascular contractility through endogenous adenosine release or adenosine receptors in blood vessels. Methods The relaxation effect of abacavir on rat basilar arteries was studied using the myograph technique. Cyclic GMP and AMP levels were measured by immunoassay. The effects of abacavir on nucleoside transporters were studied using radiolabeled nucleoside uptake experiments. Ecto-5′ nucleotidase activity was determined by measuring the generation of inorganic phosphate using adenosine monophosphate as the substrate. Results Abacavir induced the relaxation of rat basilar arteries in a concentration-dependent manner. This relaxation was abolished when endothelium was removed. In addition, the relaxation was diminished by the nitric oxide synthase inhibitor, L-NAME, the guanylyl cyclase inhibitor, ODQ, and the protein kinase G inhibitor, KT5820. Abacavir also increased the cGMP level in rat basilar arteries. Abacavir-induced relaxation was also abolished by adenosine A2 receptor blockers. However, abacavir had no effect on ecto-5’ nucleotidase and nucleoside transporters. Short-term and long-term treatment of abacavir did not affect acetylcholine-induced relaxation in rat basilar arteries. Conclusion Abacavir induces acute endothelium-dependent relaxation of rat basilar arteries, probably through the activation of adenosine A2 receptors in endothelial cells, which subsequently leads to the release of nitric oxide, resulting in activation of the cyclic guanosine monophosphate/protein kinase G-dependent pathway in vascular smooth muscle cells. It is speculated that abacavir-induced cardiovascular risk may not be related to endothelial dysfunction as abacavir does not impair relaxation of blood vessels. The most likely explanation of increased cardiovascular risk may be increased platelet aggregation as suggested by other studies

Benefits of 8-wk Mindfulness-based Stress Reduction or Aerobic Training on Seasonal Declines in Physical Activity

Mindfulness-based stress reduction (MBSR) and aerobic exercise training (AET) programs improve health and well-being. Exercise participation has been related to mindfulness and may be altered by MBSR training. Purpose This study aimed to compare 8 wk of MBSR, AET, and no-treatment control during the fall season on objectively measured physical activity in healthy adults. Methods Participants (n = 66) wore an ActiGraph GT3X+ accelerometer for 7 d prerandomization and after 8 wk MBSR or AET interventions, or neither (control). Mean daily minutes (min) of moderate-to-vigorous physical activities (MVPA) were calculated along with weekly time spent in bouts of MVPA ≥10 min (MVPABouts) to assess physical activity sufficient to meet national guidelines. Groups were compared on pairwise changes in outcomes across time. Effect sizes were calculated using Cohen’s d. Results Sufficient data (≥3 weekdays, ≥1 weekend day, and ≥10 h·d−1) were obtained from 49 participants (18 MBSR, 14 AET, and 17 control). Daily MVPA decreased in all groups from prerandomization to postintervention (August to November); control decreased 17.9 ± 25.7 min·d−1, MBSR decreased 5.7 ± 7.5 min·d−1, and AET decreased 7.4 ± 14.3 min·d−1 (mean ± SD), without significant differences among the groups (all P \u3e 0.05). MVPABouts decreased 77.3 ± 106.6 min·wk−1 in control and 15.5 ± 37.0 min·wk−1 in MBSR (between-group difference: P = 0.08; d = 0.86), whereas it increased by 5.7 ± 64.1 min·wk−1 in AET (compared with control: P = 0.029; d = 0.97; compared with MBSR; P = 0.564; d = 0.29). Conclusion Data from participants in a randomized controlled trial showed that although AET increases MVPA bouts compared with no treatment, MBSR training may also mitigate the influence of shorter day length and cooler weather on participation in physical activities. Future research is needed to determine how MBSR affects exercise to inform interventions. Interventions combining MBSR and exercise may be particularly successful at increasing physical activity participation

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.

The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa

Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects.Conclusion: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.Keywords: repeated focused ultrasound, interleukin-4 receptor, blood-brain barrier, brain tumor, target drug deliver

Loss of endothelial hypoxia inducible factor-prolyl hydroxylase 2 induces cardiac hypertrophy and fibrosis

BACKGROUND: Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl-4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. METHODS AND RESULTS: Mice with Egln1Tie2Cre (Tie2-Cre-mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2α attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. CONCLUSIONS: The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF-2α– dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure

Efficient single-molecular white-light emission for iridium-based photoluminescent and electroluminescent white OLEDs

The white organic light-emitting diode has become as a new class of emerging solid-state lighting sources due to its advantage of warm, pure white light emission, flexible lighting, and environmentally friendly indoor lighting. Here, we report three rationally designed cyclometalated [3 + 2+1] iridium(Ⅲ) complexes that emit white emission simultaneously from phosphorescent blue and yellow in the solid-state thin film. The blue GaN-based solid-state white light-emitting diodes with iridium(Ⅲ) complexes as a color converter show a color rendering index of 84.4 and International Commission on Illumination (CIE) coordinates of (0.30, 0.33). In addition, the vacuum-deposited organic light-emitting diode device exhibits a low turn-on voltage of 3.0 V and a maximum luminance (Lmax) of 335 cd m−2 with CIE coordinate of (0.31, 0.33), reaching standard naturally warm white light

Association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with immune checkpoint inhibitors: an updated meta-analysis

BackgroundAlthough numerous studies have reported the association between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs), there remains a lack of a newer and more comprehensive meta-analysis. The main objective of this study is to explore prognostic biomarkers in immunotherapy-related patients, through analyzing the associations between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with ICIs, so as to investigate their prognostic value in cancer patients treated with ICIs.MethodsA comprehensive search was conducted until February 2024 across PubMed, Embase, Web of Science, and the Cochrane Library databases to identify relevant studies evaluating the association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with ICIs. The clinical outcomes were overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR).ResultsThirteen studies were incorporated in this meta-analysis, among which nine evaluated the prognostic value of TLSs. The results showed the high levels of TLSs predicted a significantly prolonged OS (pooled HR = 0.35, 95% CI: 0.24–0.53, p < 0.001) and PFS (pooled HR = 0.47, 95% CI: 0.31–0.72, p < 0.001), while lower ORR (pooled OR = 3.78, 95% CI: 2.26–6.33, p < 0.001) in cancer patients treated with ICIs.ConclusionOur results indicated that high levels of TLSs could predict a favorable prognosis for cancer patients treated with ICIs and have the potential to become a prognostic biomarker of immunotherapy-related patients

Establishing a Target Exposure for Once-Daily Intravenous Busulfan Given with Fludarabine and Thymoglobulin before Allogeneic Transplantation

AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m2 on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM/min and >4993 μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD

Concert recording 2018-02-20a

[Track 1]. Fünf Orchesterlieder nach Ansichtenkartentexten von Peter Altenberg, op. 4. I. Seele, wie bist du schöner... [Track 2]. II. Sahst du nach dem Gewitterregen [Track 3]. III. Über die Grenzen des All [Track 4]. IV. Nichts ist gekommen [Track 5]. V. Hier ist Friede / Alban Berg -- [Track 6]. Flowers of heaven. Three songs on Korean poetry for soprano and cello. I. The home village [Track 7]. II. Wildflowers of the mountain [Track 8]. III. Return to heaven / Robert Mueller -- [Track 9]. Buru for voice and chamber ensemble / Suhki Kang -- [Track 10]. Little sketches for soprano and flute / Ivan Elezovic -- [Track 11]. Labyrinth of love for soprano and small chamber ensemble. II. Eros (Sappho fragment 47) [Track 12]. VI. Liz\u27s lament [Track 13]. VIII. Short talk on the sensation of aeroplane takeoff / Michael Daugherty