Notes

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Normal/mild CAD or single vessel disease was found on CTA in 174 patients of whom, 0.5% (1/174) had high risk disease on invasive angiography. Among 42 patients with prior CABG who had CTA first, 14.3% (6/42) had pre-TAVR invasive angiography and 2.4% (1/42) had pre-TAVR revascularization.

TAVR CTA CAD evaluation can avoid pre-TAVR invasive angiography in over 70 % of patients while rarely missing high-risk findings. A CTA first strategy to assess CAD should be considered, especially among patients where conservative management of CAD is preferred.
TAVR CTA CAD evaluation can avoid pre-TAVR invasive angiography in over 70 % of patients while rarely missing high-risk findings. A CTA first strategy to assess CAD should be considered, especially among patients where conservative management of CAD is preferred.Vibrio parahaemolyticus is responsible for infection diseases of people who consume the contaminated seafood, but its metabolic regulation profile in response to colistin, the last treatment option for multidrug-resistant Gram-negative bacteria, remains unclear. In this study, the metabolic regulation profile of V. parahaemolyticus ATCC33846 under polymyxin B stimulation has been investigated. V. parahaemolyticus exposed to polymyxin B resulted in 4597 differentially transcribed genes, including 673 significantly up-regulated genes and 569 significantly down-regulated genes. In V. parahaemolyticus under polymyxin B stimulation, the cellular antioxidant systems to prevent bacteria from oxidant stress was activated, the synthesis of some nonessential macromolecules was reduced, and the assembly and modification of lipopolysaccharide and peptidoglycan to resist the attack from other antibiotics were promoted. These findings provide new insights into polymyxin B-related stress response in V. parahaemolyticus which should be useful for developing novel drugs for infection.An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Tanespimycin clinical trial Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.In acne management, oral isotretinoin (IST) is associated with various untoward systemic effects, while its topical formulation has irritation side effects. Delonix (DLX) is a natural galactomannan derived from Delonix regia seed that can fabricate nanoparticles for topical skin delivery. This study aims to develop IST-DLX nanoparticles and assess their prospects for acne treatment. Fluorescent-DLX nanoparticles (made with a lipophilic BODIPY dye) or IST-DLX nanoparticles were prepared and characterized. BODIPY-DLX nanoparticles' skin distribution and IST-DLX nanoparticles' in-vitro targeting were assessed in pig ear skin, inflammatory modulation was assessed in AMJ-2 macrophage cells, while skin penetration and irritation were assessed in Wistar rats. IST-DLX nanoparticles had ≈230 nm, negative zeta potential, and ≈30% encapsulation efficiency. Confocal showed BODIPY in DLX nanoparticles accumulated in hair follicles as compared to BODIPY solution. IST-DLX nanoparticles released ≈37% IST over 48 h and increased IST 3-fold in hair follicles compared to IST solution. IST-DLX nanoparticles suppressed IL-6 expression in cells and reduced photo-irritation in Wistar rats compared to IST solution. In conclusion, IST-DLX nanoparticles may target and deliver adequate IST to skin layers associated with acne, avoid systemic penetration, modulate inflammatory pathogenic acne stage and prevent IST topical photo-irritation.Two-dimensional spatially selective radiofrequency (2DRF) excitation pulses are widely used for reduced field-of-view (FOV) targeted high-resolution diffusion weighted imaging (DWI), especially for anatomically small regions such as the spinal cord and prostate. The reduction in FOV achieved by 2DRF pulses significantly improve the in-plane off-resonance artifacts in single-shot echo planar imaging (ss-EPI). However, long durations of 2DRF pulses create a sensitivity to through-plane off-resonance effects, especially at 3T where the off-resonance field doubles with respect to 1.5T. This work proposes a parameter-based optimization approach to design 2DRF pulses with blips along the slice-select axis, with the goal of maximizing slab sharpness while minimizing off-resonance effects on 1.5T and 3T MRI scanners, separately. Extensive Bloch simulations are performed to evaluate the off-resonance robustness of 2DRF pulses. Three different metrics are proposed to quantify the similarity between the actual and ideal 2D excitation profiles, based on the signals within and outside the targeted reduced-FOV region. In addition, simulations on a digital brain phantom are performed for visual comparison purposes. The results show that maintaining a sharp profile is the primary design requirement at 1.5T, necessitating the usage of relatively high slab sharpness with a time-bandwidth product (TBW) around 8-10. In contrast, off-resonance robustness is the primary design requirement at 3T, requiring the usage of a moderate slap sharpness with TBW around 5-7.
To optimize a sequence combining the delay alternating with nutation for tailored excitation (DANTE) preparative module with the variable-flip-angle rapid acquisition with relaxation enhancement (VF-RARE) sequence (DANTE-VF-RARE) and to investigate its feasibility for vessel wall imaging in Apolipoprotein E-Deficient (ApoE
) mouse at 7 Tesla (T).

Specific T1/T2 values were used for producing a sharper vessel wall in the variable-flip-angle optimization scheme. The DANTE RF pulse flip angle and pulse train length were optimized for maximizing the wall-lumen contrast. ApoE
(fed high fat diet for 20/40/ 60 weeks, n = 9/4/4) and wild-type mice (controls, n = 3) were imaged at 7 T using VF-RARE, DANTE-VF-RARE, time-of-flight (TOF) angiography, and multi-slice T1-weighted 2D RARE coupled with inflow outflow saturation bands (IOSB-RARE). Wall-lumen contrast-to-noise-ratio efficiency (CNR
), lumen area (LA), and wall area (WA) were compared between DANTE-VF-RARE and 2D IOSB-RARE sequences. Additionally, linea carotid arterial wall imaging of ApoE
mouse at 7 T.
DANTE-VF-RARE achieves effective blood signal suppression and is a feasible approach for the 3D carotid arterial wall imaging of ApoE-/- mouse at 7 T.The two gonadal steroid hormones, testosterone and estrogen, regulate spermatogenesis by proliferation, differentiation, and apoptosis of testicular cells. It has been reported that heat stress or increased scrotal temperature impairs spermatogenesis in many mammals. Moreover, testicular heat stress has also been shown to suppress testosterone and estrogen biosynthesis. Furthermore, it is well known that testosterone and estrogen are important for testicular activity. Therefore, we hypothesised that exogenous testosterone and estrogen, alone or in combination, might alleviate the testicular activity in a heat-stressed rat model. To the best of our knowledge, this will be the first report of the exogenous treatment of both testosterone and estrogen in the heat-stressed rat. Our results showed that a combined testosterone and estrogen treatment significantly increased sperm concentration. The histopathological analysis also exhibited a normal histoarchitecture in the combined treatment group along with decreased oxidative stress. The improved spermatogenesis in the combined treatment group was also supported by the increase in PCNA, GCNA, tubule diameter, germinal epithelium height, and Johnsen score in the combined treatment group. Furthermore, the combined treatment also increased the expression of Bcl2, pStat3, and active caspase-3 and decreased expression of Bax. Thus, increased proliferation, apoptotic and anti-apoptotic markers, along with improved histology in the combined treatment group suggest that estrogen and testosterone synergistically act to stimulate spermatogenesis by increasing proliferation and differentiation of germ cells and may also remove the heat-induced damaged germ cells by apoptosis. Overall, the final mechanism of testosterone- and estrogen-mediated improvement of testicular activity could be attributed to amelioration of oxidative stress.The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using γH2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0-1.1 for 1H, 1.7-2.3 for 4He, 2.9-3.4 for 12C and 2.6-3.3 for 16O. Particle radiation did not alter the MSCs' characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as γH2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC.
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