The BCL-2 inhibitor venetoclax is currently approved for treatment of hematologic diseases and is widely used either as monotherapy or in combination strategies. It has produced promising results in ...the treatment of refractory or relapsed (R/R) and aged malignant hematologic diseases. However, with clinical use, resistance to venetoclax has emerged. We review the mechanism of reduced dependence on BCL-2 mediated by the upregulation of antiapoptotic proteins other than BCL-2, such as MCL-1 and BCL-XL, which is the primary mechanism of venetoclax resistance, and find that this mechanism is achieved through different pathways in different hematologic diseases. Additionally, this paper also summarizes the current investigations of the mechanisms of venetoclax resistance in terms of altered cellular metabolism, changes in the mitochondrial structure, altered or modified BCL-2 binding domains, and some other aspects; this article also reviews relevant strategies to address these resistance mechanisms.
The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). ...We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.
Perivascular fat attenuation index (FAI) was thought to be an indicator of active vessel inflammation surrounding coronary plaques. However, whether this index can be reduced by statin treatment ...remains unknown. We aimed to investigate the serial change of lesion-specific perivascular FAI as quantified by coronary computed tomography (CCTA) after statin treatment.
Consecutive patients with chest pain and intermediate likelihood of coronary artery disease were referred for baseline CCTA. Patients were retrospectively included if they were treated medically and underwent follow-up CCTA at 1-year to 1.5-year interval. Lesion-specific perivascular FAI, as well as other plaque features, were measured at baseline and follow-up.
One hundred and eight patients (mean age 67.7 ± 11.1, 76 males) were included. A significant reduction of the FAI value was found for non-calcified plaques and mixed plaques (−68.0 HU ± 8.5 HU Vs. -71.5 HU ± 8.1 HU, p < .001 and − 70.5 HU ± 8.9 HU Vs. -72.8 HU ± 9.0 HU, p = .014). However, this improvement was not observed for calcified plaques (−70.6 HU ± 9.7 HU Vs. −71.7 HU ± 9.9 HU, p = .258). For non-calcified and mixed plaques, the volumes of non-calcified as well as low attenuation component was significantly reduced whereas total plaque volume and volume of calcified component increased. For calcified plaque, total plaque volume also demonstrated remarkable increase after statin treatment
Lesion-specific perivascular FAI decreased at mid-term follow-up after statin treatment for non-calcified and mixed plaques. Perivascular FAI can be a potential imaging biomarker to monitor the anti-inflammation response to statin treatments.
•FAI decreased after statin treatment for non-calcified and mixed plaques.•LAP volume was reduced for non-calcified and mixed plaques.•FAI was not significantly changed for calcified plaques.
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing ...these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
•WBN composite films were deposited by reactive magnetron sputtering.•The WBN film which exhibited the highest hardness had best wear resistance at room and elevated temperature.•The corrosion ...resistance of the substrate which coated with W2N films or WBN films was superior to the uncoated substrate.•The corrosion resistance of the substrate which coated with W2N films was improved slightly by doping some boron content and the corrosion mechanism was discussed in the view of structure.
WBN composite films with various boron contents ranging from 25.1at.% to 46.5at.% were deposited by a multi-target magnetron sputtering system. The microstructure, mechanical, tribological and corrosion behavior of films were studied using XRD, SEM, FTIR, HRTEM, nano-indentation, Ball-on-disc dry sliding wear tester, Bruker 3D Profiler and compared to W2N. All the films exhibited face-centred cubic (fcc) structure W2N; bcc α-W phases appeared as the B content was 25.1at.% and amorphous BN appeared as the B content was 31.9at.%. The hardness and compressive stress of WBN films first increased and then decreased with increasing the B content. As the B content was 38.1at.%, they reached the maximum values of 36.1GPa and 2.6GPa, respectively. The best wear resistance at room and elevated temperature was found for the film which was shown to exhibit the highest hardness and compressive stress. The corrosion resistance of the substrate which coated with W2N films or WBN films was superior to the uncoated substrate. The corrosion resistance of the substrate which coated with W2N films was improved slightly by doping some boron content.
In light of the escalating global energy crisis, microalgae have emerged as highly promising producers of biofuel and high-value products. Among these microalgae,
has received significant attention ...due to its capacity to generate not only triacylglycerol (TAG) but also eicosapentaenoic acid (EPA) and valuable carotenoids. Recent advancements in genetic tools and the field of synthetic biology have revolutionized
into a powerful biofactory. This comprehensive review provides an initial overview of the current state of cultivation and utilization of the
genus. Subsequently, our review examines the metabolic pathways governing lipids and carotenoids, emphasizing strategies to enhance oil production and optimize carbon flux redirection toward target products. Additionally, we summarize the utilization of advanced genetic manipulation techniques in
. Together, the insights presented in this review highlight the immense potential of
as a valuable model for biofuels and synthetic biology. By effectively integrating genetic tools and metabolic engineering, the realization of this potential becomes increasingly feasible.
Intracavitary and/or interstitial brachytherapy is an integral component of the management of patients with central pelvic-recurrent cervical cancer after primary hysterectomy, and is typically ...delivered using conventional applicators. We investigated the efficacy and safety of three-dimensional (3D)-printed, customizable applicators for those patients.
Twenty-six patients were treated with combination external beam radiotherapy and brachytherapy. Patients with lesions ≤1 and >1 cm before brachytherapy were treated with intracavitary and interstitial brachytherapy, respectively. Dosimetric plans were compared between the vaginal cylinder and 3D-printed applicator for the first 9 patients. Outcomes and treatment-related complications were also investigated.
The median tumor size before brachytherapy was 0.81 cm. Intracavitary, interstitial, and combined interstitial-intracavitary brachytherapy were performed in 22 (85%), 3 (11%), and 1 (4%) of the patients, respectively. The clinical target volume (CTV) coverage goal was achieved with all 3D-printed plans but failed with three single-channel cylinder plans (33.3%). Owing to 3D-printed transvaginal applicator guidance, there was no need to adjust the needle position after implantation. The mean CTV dose for all patients was 71 ± 8.2 Gy; all met the dose constraints to the organs at risk, but 1 (4%) had a rectal D2cc overdose. The 2-year local control, progression-free survival, and overall survival rates were 87.8%, 71.0%, and 91.6%, respectively. Four patients (21%) developed early grade 3–4 hematological toxicities and 1 (4%) developed a late grade 3 adverse event.
High-quality intracavitary and/or interstitial brachytherapy can be achieved using a 3D-printed applicator and yields favorable outcomes with acceptable toxicity.
Transition metal dichalcogenides such as molybdenum disulfide (MoS2) were classified as excellent solid self-lubricant materials in vacuum or dry conditions. However, their poor mechanical and ...oxidation resistance properties limited their applications when used in humid air or at elevated temperature. In this paper, nitrogen was incorporated into the molybdenum disulfide matrix to synthesize the Mo–S–N films using RF magnetron sputtering system to improve above mentioned properties. The results showed the deposited nitrogen-free film was MoSx (x < 2), and due to its substoichiometry with respect to sulfur, both amorphous and crystalline state co-existed in MoSx film. Incorporation nitrogen into MoSx matrix induced the poor crystallinity and the formation of Mo–N, S–N and N–N bonds. All Mo–S–N films exhibit higher hardness and oxidation resistance temperature than that of MoSx mainly due to the Mo–N bonds. By comparison with MoSx film, all Mo–S–N films also had excellent tribological properties in the air at room temperature, 200 and 400 °C.
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•All Mo–S–N films exhibited higher hardness and oxidation resistance temperature than that of MoSx film.•Addition of nitrogen into MoSx matrix could improve room temperature tribological properties in humid air significantly.•Addition of nitrogen broadened the film's effective service temperature range from 200 to 400 °C.
W2N-Cu films with different Cu content ranging from 0 to 6.22at.% were deposited by reactive magnetron sputtering technique. The structure, mechanical and tribological properties were investigated by ...XPS, XRD, HRTEM, nano-indentation CSM, high-temperature ball-on-disc tribo-meter, Bruker 3D Profiler. The results indicated that the incorporation of copper did not affect the cubic structure. W2N-Cu films consist of W2N and Cu crystal phases. An addition of copper induced W2N crystallite size refinement accompanied by increase in hardness with a maximum at 0.9at.% Cu. At room temperature, the friction coefficient of W2N-Cu films decreased gradually and the wear rate increased with increasing Cu content. At high temperatures, the friction coefficient of W2N-Cu films decreased with increasing Cu content but the wear rate increased. Overall, the results reveal that the friction properties of W2N-Cu films, in the temperature range of 25–600°C, can be improved by addition of a copper element, but the wear resistance failed to improve under same conditions.
•W2N-Cu composite films consist a mixture of W2N and Cu crystal phases.•The addition of copper into W2N led to the decrease of hardness.•The W2N-Cu film has a low friction coefficient in the temperature range of 25–600°C.
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