LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling

While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients' survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression

The effect of cubic stiffness nonlinearity on the vortex-induced vibration of a circular cylinder at low Reynolds numbers

The vortex-induced vibration (VIV) of a circular cylinder elastically supported by linear and cubic springs is investigated numerically at low Reynolds numbers. The cylinder has a low mass ratio and zero structural damping. Nine dimensionless cubic stiffness nonlinearity strength values are considered. It is found that within the parameter space examined, the VIV response for the linear and softening springs can be divided into four regimes, namely the initial, upper, lower and desynchronised regimes. When the softening spring nonlinearity gets stronger, there exist a reduction in the peak amplitude and shifts in the initial-upper branch and upper-lower branch transitions to lower Reynolds number ranges. In contrast, as the hardening spring nonlinearity increases, the response envelope moves to a higher Reynolds number range and the profile of the initial and upper branches becomes smoother with the lower branch gradually disappearing. In the hardening spring case, the beating response is observed near the low end of the initial branch up to the high end of the initial branch. The modulations in the vibration amplitude gradually diminish with increasing Reynolds number. The cubic spring results coincide with those of the linear spring when they are presented with the equivalent reduced velocity. Due to the low Reynolds number range considered, the majority of the vortex shedding is in the 2S mode. The wake in the cases with smaller vibration amplitudes exhibits a single-row configuration. Whereas, a double-row vortex street is mainly observed in the upper branch. Disorders in the wake are found to be associated with beating responses which have larger vibration amplitudes

Efficacy and safety of triazavirin therapy for coronavirus disease 2019 : A pilot randomized controlled trial

Acknowledgements: We are deeply grateful to the front-line clinicians who participated in the study while directly fighting the epidemic. This study was supported by the Chinese Academy of Engineering Projects for COVID-19 (2020-KYGG-01-04) and Heilongjiang Province Urgent Project-6 for COVID-19. Data and safety monitoring board members of this trial included Kang Li, Yong Zhang, Songjiang Liu, and Yaohui Shi.Peer reviewedPublisher PD

Polymorphisms in Epigenetic and Meat Quality Related Genes in Fourteen Cattle Breeds and Association with Beef Quality and Carcass Traits

Improvement for carcass traits related to beef quality is the key concern in beef production. Recent reports found that epigenetics mediates the interaction of individuals with environment and nutrition. The present study was designed to analyze the genetic effect of single nucleotide polymorphisms (SNPs) in seven epigenetic-related genes (DNMT1, DNMT3a, DNMT3b, DNMT3L, Ago1, Ago2, and HDAC5) and two meat quality candidate genes (CAPN1 and PRKAG3) on fourteen carcass traits related to beef quality in a Snow Dragon beef population, and also to identify SNPs in a total of fourteen cattle populations. Sixteen SNPs were identified and genotyped in 383 individuals sampled from the 14 cattle breeds, which included 147 samples from the Snow Dragon beef population. Data analysis showed significant association of 8 SNPs within 4 genes related to carcass and/or meat quality traits in the beef populations. SNP1 (13154420A>G) in exon 17 of DNMT1 was significantly associated with rib-eye width and lean meat color score (pG) of DNMT3a was significantly associated with six beef quality traits. Those individuals with the wild-type genotype AA of DNMT3a showed an increase in carcass weight, chilled carcass weight, flank thicknesses, chuck short rib thickness, chuck short rib score and in chuck flap weight in contrast to the GG genotype. Five out of six SNPs in DNMT3b gene were significantly associated with three beef quality traits. SNP15 (45219258C>T) in CAPN1 was significantly associated with chuck short rib thickness and lean meat color score (p<0.05). The significant effect of SNP15 on lean meat color score individually and in combination with each of other 14 SNPs qualify this SNP to be used as potential marker for improving the trait. In addition, the frequencies of most wild-type alleles were higher than those of the mutant alleles in the native and foreign cattle breeds. Seven SNPs were identified in the epigenetic-related genes. The SNP15 in CAPN1 could be used as a powerful genetic marker in selection programs for beef quality improvement in the Snow Dragon Beef population

Комплекс индоцианина зеленого с аргинин-глицин-аспарагиновой кислотой как новый метод интраоперационной визуализации при резекции рака мочевого пузыря

Introduction. Bladder cancer is one of the most common malignancies in humans, causing significant economic and social damage. In the connection, it is proposed to use a highly sensitive bladder cancer detection method, which also detects residual tumours. Additionally, the method can be used to determine the boundaries of the bladder tumour, namely through intraoperative fluorescence molecular imaging. The target agent was synthesised earlier with indocyanine green-arginine-glycine-aspartic acid, which is an integrin avß3-targeted in in vitro and in vivo bladder cancer models.Materials and methods. The toxicity of indocyanine green-arginine-glycine-aspartic acid (Agac-IG) was measured using the MTT-test. Urothelial carcinoma cell lines were introduced in Female BALB/nu and MB49 mice by means of tumour xenografts via injection in the back of the elbow area. Tumour growth was observed on a daily basis and tested by magnetic resonance imaging until it became suitable for in vivo experiments. Then, all the laboratory animals were divided into 2 groups: ig and AGAk-ig (150 μl, 0.2 mg/ml for all mice). Following this, the tumour was surgically removed. The removed tissue was subjected to a fluorescent microscopy on the basis of infrared-spectrum and histologic studies.Results. Operations carried out on subcutaneous and orthotopic mouse models under the control of fluorescent imaging using AGAk-IG demonstrate the effectiveness of using a targeted tumour sample to achieve consistent and accurate RMP-resection. Operations under the control of BIC-spectrometry have demonstrated that the proposed substance can effectively help surgeons to locate tumours, determine their edges and constantly check the presence of tumour residues during surgery.Conclusion. The findings demonstrated the high efficiency of AGAk-IG as a potential molecular fluorescent agent for tumour-specific intraoperative imaging in bladder cancer resection, as well as offering great potential for further clinical studies.Введение. Рак мочевого пузыря является одним из наиболее распространенных злокачественных новообразований, приносящих значительный экономический и социальный ущерб человеку. Для решения данной проблемы предложено использование высокочувствительного метода обнаружения рака мочевого пузыря, выявления остаточной опухоли и определения границ опухоли мочевого пузыря — интраоперационной флюоресцентной молекулярной визуализации. Ранее нами синтезирован таргетный агент — индоцианина зеленого-аргинин-глицин-аспарагиновая кислота, которая является интегрин avß3-целенаправленной в in vitro и in vivo моделях рака мочевого пузыря.Материалы и методы. Токсичность индоцианина зеленого-аргинина-глицин-аспарагиновой кислоты (АГАк-ИЦЗ) была измерена с помощью МТТ-теста. Самки BALB/nu и клеточные линии MB49 уротелиальной карциномы мыши использовали для установки опухолевых ксенотрансплантатов, инъекцией в заднюю локтевую область. Рост опухоли наблюдался ежедневно и проверялся магнитно-резонансной томографией, пока он не становился подходящим для экспериментов in vivo. Далее лабораторные животные были разделены на 2 группы: ИЦЗ и АГАк-ИЦЗ (150 мкл, 0,2 мг/мл для всех мышей). Затем проводилось хирургическое удаление опухоли. Удаленную ткань подвергали флюоресцентной микроскопии на основе ближневолнового инфракрасного спектра и гистологическому исследованию.Результаты. Операции, проведенные на подкожной и ортотопической мышиных моделях под контролем флюоресцентной визуализации с использованием АГАк-ИЦЗ, демонстрируют эффективность использования прицельной опухолевой пробы для достижения аккуратной и точной РМП резекции. Операции под контролем БИК-спектрометрии продемонстрировали, что предлагаемое вещество может эффективно помочь хирургам найти опухоль, определить край опухоли и постоянно проверять наличие остатков опухоли во время операции.Заключение. Таким образом, по результатам исследования продемонстрирована высокая эффективность АГАк-ИЦЗ как потенциального молекулярного флюоресцентного агента для опухолеспецифичной интраоперационной визуализации при резекции рака мочевого пузыря и большой потенциал для проведения дальнейших клинических исследований

Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer

Abstract AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC3 in prostate cancer

Experiments on flow-induced vibration of four flexible cylinders with large aspect ratio in a square configuration

A system consisting of four cylinders positioned in the quadrilateral arrangement represents the prevalent and fundamental constituent within pipe bundles and tube banks in numerous engineering scenarios. This research presents a laboratorial study on flow-induced vibration (FIV) exhibited by four flexible cylinders positioned within a square geometric arrangement. The uniform flows were produced by a carriage on the top of a towing tank. Considering flow velocities and structural parameters, Reynolds number could reach 16000. The spacing between the cylindrical centres was selected as 6.0 D (D denotes the outer diameter of cylinders), and two typical incidence angles 0 degrees and 45 degrees were examined. For each flexible cylinder model, strain gages at seven distinct measuring positions were utilized to collect the oscillation data in cross-flow (CF) and in-line (IL) directions. Principal vibration modes, response frequencies, response amplitudes and motion trajectories were presented to understand the FIV features. For incidence angles 0 degrees, considering the four flexible cylinders as two sets of tandem cylinders arranged in parallel is not appropriate due to the proximate effect. The behaviours of the two upstream cylinders resembles those of the pair of cylinders positioned in a side-by-side configuration, whereas behaviours for the downstream cylinders are influenced by wake interference generated from leading cylinders. IL response frequencies decrease to the values close to the CF response frequencies, resulting in the elliptical-shaped motion trajectories with large IL displacements. For incidence angles 45 degrees, the upstream cylinder displays characteristics akin to those of a solitary cylinder experiencing vortex-induced vibration (VIV). Reactions for the central pair of cylinders result from the amalgamation of VIV and wake-induced flutter. While, reactions observed for down-stream cylinder are characterized by low frequencies, significant IL displacements and more chaotic trajectories

Experimental Study on Streamwise Vortex-Induced Vibration of a Flexible, Slender Cylinder

Laboratory tests on streamwise vortex-induced vibration (VIV) of a flexible, slender cylinder were carried out in a towing tank. A cylinder model, 20 mm in diameter and 3.91 m in length, was towed horizontally to generate a uniform profile of relative velocity in calm water. The aspect ratio (length to diameter) and mass ratio (structural mass to displaced fluid mass) of the cylinder were 195.5 and 1.39, respectively. The Reynolds number was in the range of 1000–3000. The displacement amplitudes and vibration frequencies were investigated in order to examine the dynamic characteristics of the flexible cylinder undergoing streamwise VIV. Experimental results indicated that there were two detached branches in the streamwise response curve, i.e., the first excitation region (1.0 &lt; Vr &lt; 2.6) and the second excitation region (2.6 &lt; Vr &lt; 4.0). This phenomenon is similar to the streamwise VIV of an elastically-mounted rigid cylinder, except that a larger and shifted peak was observed in the second branch in this study. The cylinder’s linear orbits in the first excitation region indicated that the streamwise vibration frequency was equivalent to its transverse counterpart. However, in the second excitation region, the cylinder’s motion showed a figure-of-eight pattern, and the streamwise frequency was twice that in the transverse direction. In addition, two curve-fitted formulae of the maximum displacement amplitudes in the first and second excitation regions, versus the reduced mass-damping parameter, were proposed. This was accomplished by compiling the published streamwise VIV data and those in the present research work

Experiments on flow-induced vibration of four flexible cylinders with large aspect ratio in a square configuration

A system consisting of four cylinders positioned in the quadrilateral arrangement represents the prevalent and fundamental constituent within pipe bundles and tube banks in numerous engineering scenarios. This research presents a laboratorial study on flow-induced vibration (FIV) exhibited by four flexible cylinders positioned within a square geometric arrangement. The uniform flows were produced by a carriage on the top of a towing tank. Considering flow velocities and structural parameters, Reynolds number could reach 16000. The spacing between the cylindrical centres was selected as 6.0 D (D denotes the outer diameter of cylinders), and two typical incidence angles 0 degrees and 45 degrees were examined. For each flexible cylinder model, strain gages at seven distinct measuring positions were utilized to collect the oscillation data in cross-flow (CF) and in-line (IL) directions. Principal vibration modes, response frequencies, response amplitudes and motion trajectories were presented to understand the FIV features. For incidence angles 0 degrees, considering the four flexible cylinders as two sets of tandem cylinders arranged in parallel is not appropriate due to the proximate effect. The behaviours of the two upstream cylinders resembles those of the pair of cylinders positioned in a side-by-side configuration, whereas behaviours for the downstream cylinders are influenced by wake interference generated from leading cylinders. IL response frequencies decrease to the values close to the CF response frequencies, resulting in the elliptical-shaped motion trajectories with large IL displacements. For incidence angles 45 degrees, the upstream cylinder displays characteristics akin to those of a solitary cylinder experiencing vortex-induced vibration (VIV). Reactions for the central pair of cylinders result from the amalgamation of VIV and wake-induced flutter. While, reactions observed for down-stream cylinder are characterized by low frequencies, significant IL displacements and more chaotic trajectories