Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma.

Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB::NFIB or MYBL1::NFIB translocations. We have developed the conditions for the generation of both 2D and 3D tumour organoid patient-derived ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies uncover a novel mechanistic effect of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser based on a CuSe nanosheets saturable absorber.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser (EDFL) have been achieved using CuSe nanosheets as novel saturable absorber (SA), where the CuSe nanosheets were prepared by a hydrothermal method. The nonlinear optical properties of CuSe nanosheets were measured using an Z-scan setup, revealing nonlinear absorption coefficients of -3.67 ± 0.22 cm GW-1 at 1560 nm. The prepared CuSe nanosheets were mixed with polyvinyl alcohol (PVA) to obtain a CuSe-PVA SA with a modulation depth of 3.8 ± 0.13%, and it was utilized to realize a Q-switched EDFL, obtaining the narrowest pulse duration of 1.29 µs and the maximum output power of 5.96 mW, which corresponds to a pulse energy of up to 103.7 nJ. In addition, CuSe nanosheets were deposited on a D-shaped fiber (DSF) to fabricate a CuSe-DSF SA with a modulation depth of 5.6 ± 0.17%, and it was utilized to realize a mode-locked EDFL. The mode-locked EDFL demonstrated a low threshold of only 42 mW, a pulse duration of 740 fs, and a maximum output power of 9.7 mW. Meanwhile, it exhibited a high signal-to-noise ratio of 72 dB. To the best of our knowledge, this is the first time of CuSe nanosheets as SA in EDFL. The results demonstrate that CuSe nanosheets are a highly promising nonlinear optical material with great potential for applications in ultrafast photonics.

Continuous-wave operation of a tandem optical parametric oscillator up to 5.19†µm based on periodically poled LiNbO3.

A continuous-wave, tandem optical parametric oscillator (TOPO) based on a MgO-doped periodically poled LiNbO3 (MgO:PPLN) is demonstrated. Because the MgO:PPLN is tandemly pumped by the OPO's signal beam, it outputs simultaneously two groups of signal and idler with a single pump source. The entire range spans from 1398 to 1490 nm, 1914 to 2107 nm, 3720 to 4444 nm, and 4849 to 5190 nm, which is limited by periods of the MgO:PPLN and cavity mirror coatings. The TOPO, whose oscillation threshold of pump power exceeds 7 W, can be easily triggered by marginally increasing the pump power as long as the OPO process occurs. The maximum idler powers are respectively 2.6 W (at 3896 nm) and 34 mW (at 4863 nm), and the corresponding signal powers are both nearly 100 mW.

The Development of a Continuous Constitutive Model for Thin-Shell Components with A Sharp Change in the Property at Welded Joints.

Large-dimension complex integral thin-shell components are widely used in advanced transportation equipment. However, with the dimensional limitations of raw blanks and the manufacturing process, there are inhomogeneous geometric and mechanical properties at welded joints after welding, which have a significant effect on the subsequent forming process. Therefore, in this paper, the microstructure of welded joints with a sharp property change was accurately characterized by the proposed isothermal treatment method using the BR1500HS welded tube as an example. In addition, an accurate constitutive model of welded tubes was established to predict the deformation behavior. Firstly, the heat-treated specimens were subjected to uniaxial tensile tests and the stress-strain curves under different heat treatment conditions were obtained. Then, the continuous change in flow stress in the direction of the base metal zone, the heat-affected zone and the weld zone was described by the relationship between the microhardness, flow stress and center angle of the welded tube. Using such a method, a continuous constitutive model of welded tubes has been established. Finally, the constitutive model was compiled into finite-element software as a user material subroutine (VUHARD). The reliability of the established constitutive model was verified by simulating the free hydro-bulging process of welded tubes. The results indicated that the continuous constitutive model can well describe the deformation response during the free hydro-bulging process, and accurately predicted the equivalent strain distribution and thickness thinning rate. This study provides guidance in accurately predicting the plastic deformation behavior of welded tubes and its application in practice in hydroforming industries.

Study on Stamping-Bulging Process of Thin-Walled Superalloy Diaphragm for S-Shaped Bellows.

A combined stamping-bulging forming process was proposed to achieve high-precision forming of large-diameter, ultra-thin-walled, superalloy welded S-type corrugated diaphragms. The underlying principle is to enhance the diaphragm's forming accuracy by increasing the plastic deformation region and reducing springback. Using the ABAQUS version 6.14 finite element analysis software, finite element models were constructed for the stamping, hydraulic bulging, and combined stamping-bulging forming processes of the welded S-type metal corrugated diaphragms. A comparative analysis was conducted on the forming processes of the welded S-type metal corrugated diaphragms under the three forming methods, focusing on equivalent stress, distribution of wall thickness, and forming accuracy. This analysis determined the optimal forming process and the corresponding process parameters for superalloy welded S-type metal corrugated diaphragms. The results show that under a constant drawing force, as the bulging pressure increases, the plastic deformation of the straight sections of the diaphragm becomes more pronounced, resulting in improved shape accuracy. The combined stamping-bulging forming process guarantees the highest degree of shape accuracy for the diaphragm. The optimal process parameters were identified as a 30 t force and a 5 MPa pressure, with a maximum shape error of 0.02 mm. Concerning a plate thickness of 0.3 mm, the maximum deviation rate was found to be 6.7%, which represents a 30% improvement over traditional stamping processes. The maximum wall thinning rate was found to be 3.3%, a 1% reduction compared to traditional stamping processes, confirming the process's feasibility.

Identification of genes that promote PI3K pathway activation and prostate tumour formation.

We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.

A highly specific and ultrasensitive approach to detect Prymnesium parvum based on RPA-CRISPR-LbaCas12a-LFD system.

BACKGROUND: Harmful algal blooms (HABs), caused by the rapid proliferation or aggregation of microorganisms, are catastrophic for the environment. The Prymnesium parvum is a haptophyte algal species that is found worldwide and is responsible for extensive blooms and death of larval amphibians and bivalves, causing serious negative impacts on the ecological environment. For the prevention and management of environmental pollution, it is crucial to explore and develop early detection strategies for HABs on-site using simple methods. The major challenge related to early detection is the accurate and sensitive detection of algae present in low abundance. RESULTS: Herein, recombinase polymerase amplification (RPA) was combined with clustered regularly interspaced short palindromic repeats and Cas12a protein (CRISPR-LbaCas12a) systems, and the lateral flow dipstick (LFD) was used for the first time for early detection of P. parvum. The internal transcribed spacer (ITS) of P. parvum was selected as the target sequence, and the concentration of single-strand DNA reporters, buffer liquid system, reaction time, and amount of gold particles were optimized. The RPA-CRISPR-LbaCas12a-LFD approach demonstrated highly specificity during experimental testing, with no cross-reaction against different microalgae used as controls. In addition, the lowest detection limit was 10,000 times better than the lowest detection limit of the standalone RPA approach. The feasibility and robustness of this approach were further verified by using the different environmental samples. It also observed that P. parvum are widely distributed in Chinese Sea, but the cell density of P. parvum is relatively low (<0.1 cells/mL). SIGNIFICANCE: The developed approach has an excellent specificity and offers 10,000 times better sensitivity than the standalone RPA approach. These advantages make this approach suitable for early warning detection and prevention of HAB events in environmental water. Also, the outcomes of this study could promote a shift from traditional laboratory-based detection to on-site monitoring, facilitating early warning against HABs.

Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited "on-target" toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2-mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.