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Journal of Medicinal Chemistry Jul 2024In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has... (Review)
Review
In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADP-ribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.
PubMed: 38955347
DOI: 10.1021/acs.jmedchem.4c00113 -
Journal of Physics. Condensed Matter :... Jul 2024We employed the self-consistent Bogoliubov-de Gennes equations to explore the states of chiral Majorana mode in quantum anomalous Hall insulators in proximity to a...
We employed the self-consistent Bogoliubov-de Gennes equations to explore the states of chiral Majorana mode in quantum anomalous Hall insulators in proximity to a superconductor, leading to the development of an extensive topological phase diagram. Our investigation focused on how an additional potential affects the separation of chiral Majorana modes across different phase conditions. We substantiated our findings by examining the zero-energy Local Density of States spectrum and the probability distribution of the chiral Majorana modes. We established the universality of chiral Majorana mode separation by applying an additional potential. This finding serves as a vital resource for future endeavors aimed at controlling and detecting these particles, thereby contributing to the advancement of quantum computing and condensed matter physics.
PubMed: 38955340
DOI: 10.1088/1361-648X/ad5e2c -
Biomedical Materials (Bristol, England) Jul 2024This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal...
Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization, in vitro and in vivo assessment.
This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod.. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32 full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variables X1: concentration of ethanol and X2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334±2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through Transmission Electron Microscopy (TEM) analysis. X-ray diffraction (XRD) analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6h. In vivo, the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the PSI grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis. .
PubMed: 38955335
DOI: 10.1088/1748-605X/ad5e51 -
Physics in Medicine and Biology Jul 2024Sparse-view dual-energy spectral computed tomography (DECT) imaging is a challenging inverse problem. Due to the incompleteness of the collected data, the...
OBJECTIVE
Sparse-view dual-energy spectral computed tomography (DECT) imaging is a challenging inverse problem. Due to the incompleteness of the collected data, the presence of streak artifacts can result in the degradation of reconstructed spectral images. The subsequent material decomposition task in DECT can further lead to the amplification of artifacts and noise.
APPROACH
To address this problem, we propose a novel one-step inverse generation network (OIGN) for sparse-view dual- energy CT imaging, which can achieve simultaneous imaging of spectral images and materials. The entire OIGN consists of five sub-networks that form four modules, including the pre-reconstruction module, the pre-decomposition module, and the following residual filtering module and residual decomposition module. The residual feedback mechanism is introduced to synchronize the optimization of spectral CT images and materials.
MAIN RESULTS
Numerical simulation experiments show that the OIGN has better performance on both reconstruction and material decomposition than other state-of-the-art spectral CT imaging algorithms. OIGN also demonstrates high imaging efficiency by completing two high-quality imaging tasks in just 50 seconds. Additionally, anti-noise testing is conducted to evaluate the robustness of OIGN. Significance. These findings have great potential in high-quality multi-task spectral CT imaging in clinical diagnosis.
PubMed: 38955333
DOI: 10.1088/1361-6560/ad5e59 -
Journal of Physics. Condensed Matter :... Jul 2024Stabilized and metallic light elements hydrides have provided a potential route to achieve the goal of room-temperature superconductors at moderate or ambient pressures....
Stabilized and metallic light elements hydrides have provided a potential route to achieve the goal of room-temperature superconductors at moderate or ambient pressures. Here, we have performed systematic DFT theoretical calculations to examine the effects of different light elements C and N atoms doped in cubic KBHhydrides on the superconductivity at low pressures. As a result of various atoms substituting, we have found that metallic KBMH(M = C, N) hydrides are dynamically stable at 50 GPa, band structures and density of states indicate that sizeablecorrelates with a high B-H density of states at the Fermi level. With the increasing of B atoms in KBMHhydrides, the density of states values at Fermi level have been improved due to the delocalized electrons in B-H bonds, which result in strong electron-phonon coupling (EPC) interaction and increase thefrom 19.04 to 77.07 K for KCHand KBHat 50 GPa. The NHunit in stable KBNHhydrides has weakened the EPC and led to low Tc value of 21.47 K. Our results suggest the light elements hydrides KBHand KBCHcould estimate highvalues at 50 GPa, and the boron hydrides would be potential candidates to design or modulate hydrides superconductors with highat moderate or ambient pressures.
PubMed: 38955332
DOI: 10.1088/1361-648X/ad5e2d -
Physics in Medicine and Biology Jul 2024The trend in the medical field is towards intelligent detection-based medical diagnostic systems. However, these methods are often seen as "black boxes" due to...
The trend in the medical field is towards intelligent detection-based medical diagnostic systems. However, these methods are often seen as "black boxes" due to their lack of interpretability. This situation presents challenges in identifying reasons for misdiagnoses and improving accuracy, which leads to potential risks of misdiagnosis and delayed treatment. Therefore, how to enhance the interpretability of diagnostic models is crucial for improving patient outcomes and reducing treatment delays. So far, only limited researches exist on deep learning-based prediction of spontaneous pneumothorax, a pulmonary disease that affects lung ventilation and venous return. Approach. This study develops an integrated medical image analysis system using explainable deep learning model for image recognition and visualization to achieve an interpretable automatic diagnosis process. Main results. The system achieves an impressive 95.56% accuracy in pneumothorax classification, which emphasizes the significance of the blood vessel penetration defect in clinical judgment. Significance. This would lead to improve model trustworthiness, reduce uncertainty, and accurate diagnosis of various lung diseases, which results in better medical outcomes for patients and better utilization of medical resources. Future research can focus on implementing new deep learning models to detect and diagnose other lung diseases that can enhance the generalizability of this system. .
PubMed: 38955331
DOI: 10.1088/1361-6560/ad5e31 -
Progress in Neurobiology Jun 2024Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use...
Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.
PubMed: 38955325
DOI: 10.1016/j.pneurobio.2024.102652 -
American Journal of Obstetrics and... Jun 2024Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back...
BACKGROUND
Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects.
OBJECTIVE
To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain.
STUDY DESIGN
This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density.
RESULTS
A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12.
CONCLUSION
Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.
PubMed: 38955323
DOI: 10.1016/j.ajog.2024.06.040 -
Acta Tropica Jun 2024Toxoplasmosis, a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii), is prevalent worldwide. The fact should be emphasized that a considerable proportion... (Review)
Review
Toxoplasmosis, a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii), is prevalent worldwide. The fact should be emphasized that a considerable proportion of individuals infected with T. gondii may remain asymptomatic; nevertheless, the condition can have severe implications for pregnant women or immunocompromised individuals. The current treatment of toxoplasmosis primarily relies on medication; however, traditional anti-toxoplasmosis drugs exhibit significant limitations in terms of efficacy, side effects, and drug resistance. The life cycles of T. gondii are characterized by distinct stages and its body morphology goes through dynamic alterations during the growth cycle that are intricately governed by a wide array of post-translational modifications (PTMs). Ubiquitin (Ub) signaling and ubiquitin-like (Ubl) signaling are two crucial post-translational modification pathways within cells, regulating protein function, localization, stability, or interactions by attaching Ub or ubiquitin-like proteins (Ubls) to target proteins. While these signaling mechanisms share some functional similarities, they have distinct regulatory mechanisms and effects. T. gondii possesses both Ub and Ubls and plays a significant role in regulating the parasite's life cycle and maintaining its morphology through PTMs of substrate proteins. Investigating the role and mechanism of protein ubiquitination in T. gondii will provide valuable insights for preventing and treating toxoplasmosis. This review explores the distinctive characteristics of Ub and Ubl signaling in T. gondii, with the aim of inspiring research ideas for the identification of safer and more effective drug targets against toxoplasmosis.
PubMed: 38955322
DOI: 10.1016/j.actatropica.2024.107283 -
Acta Tropica Jun 2024Bats are the second most diverse order of mammals and play a central role in ecosystem dynamics. They are also important reservoirs of potentially zoonotic...
Bats are the second most diverse order of mammals and play a central role in ecosystem dynamics. They are also important reservoirs of potentially zoonotic microorganisms, of which rabies virus is the most lethal among the bat-transmitted zoonotic pathogens. Importantly, recent outbreaks of human rabies have been reported from the Brazilian Amazon. Here we present a survey of bat species and rabies virus (RABV) circulation in a bat assemblage in the Marajó region, northern Brazil. Using data from mist-net captures and bioacoustic sampling, 56 bat species were recorded along the Jacundá River basin over a 10-day expedition in November 2022. For the investigation of RABV, we used the direct fluorescent antibody test (DFAT) and the rapid fluorescent focus inhibition test (RFFIT). In total, 159 bat individuals from 22 species were investigated for RABV. Five adults of the common vampire bat, Desmodus rotundus, showed RABV-specific antibodies in serum samples. Additionally, we report on local residents with injuries caused by D. rotundus bites and the occurrence of colonies of non-hematophagous bats from different species roosting inside human residences. This scenario raises concerns about the risks of new cases of human rabies and other zoonotic diseases associated with bats in the region and highlights the need for epidemiological surveillance and mitigation measures to prevent outbreaks of emerging infectious diseases.
PubMed: 38955321
DOI: 10.1016/j.actatropica.2024.107309