Citations

Vascular stents are crucial devices in the treatment of cardiovascular diseases, and their structural design and function critically affect therapeutic efficacy and patient prognosis. Conventional stents can effectively restore vascular patency by providing mechanical support to blood vessels. However, they still face significant challenges including restenosis, thrombosis, and limited adaptability to complex patient-specific lesion characteristics. To address these limitations, drug delivery offers an important strategy to modulate the pathological microenvironment, enhance long-term vascular healing, and reduce systemic side effects. Meanwhile, advances in computational simulations have provided powerful tools for optimizing stent design through structural mechanics, hemodynamics, and drug release modeling. Computational approaches enable the rational design of stent architectures with improved mechanical stability, vascular compatibility, and therapeutic regulation. Consequently, the development of vascular stents is evolving toward the synergistic integration of drug delivery, structural optimization, and intelligent design. This review summarizes the latest advances in functional vascular stents, clinical applications and computational design. This work aims to provide valuable insights for the engineering of efficient, precise, and intelligent vascular stents for cardiovascular therapies.

Abstract Menin, encoded by the MEN1 gene, is a chromatin adaptor critical in AML through its role in the MLL complex. Inhibiting the Menin–MLL interaction promotes differentiation and reduces leukemia burden in MLL-rearranged and NPM1c AMLs, leading to the approval of Menin inhibitors by FDA. However, acquired resistance remains a challenge, highlighting the need to understand long-term effects. To understand the Menin inhibitors' effect in the long-term treatment, we firstly treated the MLL-r and NPM1c AML cell lines for long term and then withdraw the inhibitors to observe the potential recovery of cells. We found the cell growth inhibition and viability decrease were not sustained and proliferation resumed after the withdrawal of 18-30 days treatment of Menin inhibitor both in MLL-r and NPM1c cell lines and NPM1c primary AML cells. In parallel, differentiation cannot be maintained after Menin inhibitor withdrawal. Differentiation marker CD11b expression also gradually lost after 10-day of withdrawal. To determine whether these regrown cells develop resistance, we compared the regrown cells to untreated cells and found that there was no significant difference in IC50 of Menin inhibitors between the regrown and untreated cells, showing the cells regrown due to the reversibility of Menin inhibitors but not resistance. Furthermore, due to the heterogeneous differentiation induced by Menin inhibitors, we compare the effect of differentiation on the cell growth. After 24 days of treatment, CD11bhi and CD11blo cells were sorted after inhibitor removal, we could observe a significant slower cell growth in CD11bhi than CD11blo cells. We also found a CD11bhi group gradually lost the differentiation marker and revert the grow rate as CD11blo. This indicates that these cells underwent dedifferentiation, suggesting that Menin inhibitors alone induce only reversible differentiation. Interestingly, we found the regrown cells silenced HOX/MEIS1 genes permanently showing the HOXA/MEIS1 genes are not playing a role in the long-term treatment of Menin inhibitors. To enhance and stabilize differentiation, we conducted a CRISPR screen targeting chromatin regulators in MOLM13 and OCI-AML3 cells treated with Menin inhibitor or DMSO for 2 weeks. CD11bhi and CD11blo cells were sorted by FACS. Hits included members of the SAGA, LSD1/CoREST, MBD2 NuRD complex, ING5, non-canonical BAF, and MLL/Menin complexes. Knockdown of RCOR1, LSD1, MBD2, MEAF6, KAT6A, and KAT2A enhanced Menin inhibitor–induced differentiation and stabilized it after withdrawal for up to 20 days. We futher screened pharmacological inhibitors of these targets and found that LSD1, KAT6A, and MBD2 inhibitors enhanced differentiation. In particular, combining the experimental MBD2 inhibitor KCC07 with the Menin inhibitor Revumenib accelerated differentiation as early as day 3 (vs. day 7 with Revumenib alone). Long-term co-treatment stabilized differentiation, induced cell death, and suppressed proliferation, indicating chromatin modulation can lock in terminal differentiation, lead to cell death, and potentiate Menin inhibitor effects. RNA-seq of OCI-AML3 cells treated with DMSO, Reumenib, KCC07, or their combination showed that the MBD2/Menin combination inhibition significantly upregulated differentiated monocytes and neutrophils signatures while reducing immature neutrophil signature. GO analysis revealed strong activation of monocyte differentiation and repression of PI3K-AKT signaling. HOXA and MEIS1 expression were only modestly changed, showing the combination mostly enhanced diffrentiation gene programs but not self-renewal maintaining HOX/MEIS1 axis. ATAC-seq revealed globally increased chromatin accessibility in the MBD2/Menin combination inhibition group in comparison with Revumenib only treatment group, with enhanced peaks located predominantly in myeloid differentiation genes, suggesting the MBD2 inhibition also leads to derepression of differentiation related genes repressed by MBD2-NuRD complexes. Our study is the first to demonstrate the reversibility of Menin inhibitor–induced growth inhibition and differentiation. More importantly, we identified differentiation associated chromatin complex targeting (such as MBD2 inhibition) as a low-toxicity strategy that enhances and stabilizes Menin inhibitor–induced differentiation, offering a promising approach to overcome durability limitations in AML therapy.

Abstract Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF ( p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3–34.9) and three (48%, OR = 20.2, 5.9–68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ ( p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality ( p < 0.05). Onset and duration of POF had no impact mortality. Conclusion In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.

Mycoplasma hominis is a commensal in the genital tract of women and has been associated with urogenital and extragenital infections. However, central nervous system infections with this organism in adults are very rare. Here we describe the recovery of M. hominis from a brain abscess associated with a postpartum infection. Seroconversion to the isolated strain was detected by both a metabolic inhibition test and an immunoblotting assay. This case demonstrates the pathogenic potential of M. hominis and the need for rapid recognition of the organism so that appropriate chemotherapeutic intervention can occur.

ABSTRACT A branched-DNA (bDNA) signal amplification method was used to detect the mecA gene directly from blood culture broth growing staphylococci. BACTEC blood culture bottles with positive growth indices and containing staphylococcus-like organisms as shown by Gram stain were tested for the presence of the mecA gene. Comparison of test results was done among 225 patients (one blood culture from each patient). Compared with PCR, the sensitivity and specificity of the bDNA method are 100 and 99%, respectively. The bDNA test is carried out in a 96-well format and requires approximately 6 h to perform. Our preliminary results suggest that direct detection of the mecA gene by bDNA signal amplification is (i) sensitive enough to detect mecA directly from blood culture bottles without the requirement for subculture and (ii) as sensitive and specific as the PCR-based method.

ABSTRACT The identification of methicillin-resistant staphylococcus isolates in the clinical laboratory has typically been performed by using methods that detect phenotypic expression of resistance determinants. However, these methods may be difficult to interpret and some isolates do not express resistance until selective pressure is administered. Assays that detect genetic determinants are not subject to these limitations and have been effective in distinguishing isolates that are capable of expressing the resistance phenotype. In this study, a novel branched-DNA (bDNA) hybridization assay was used to test for the mecA gene in 416 clinical staphylococcal isolates. The results were compared with those obtained by a PCR-based assay and oxacillin disk diffusion. For 155 Staphylococcus aureus and 261 coagulase-negative Staphylococcus isolates, the bDNA assay and PCR results were 100% concordant. Among the S. aureus isolates, 20 were MecA + and 135 were MecA − . For the coagulase-negative staphylococci, 150 were MecA + and 111 were MecA − . The results from the genotypic detection methods were compared with those obtained by oxacillin disk diffusion. No discrepancies were detected among the S. aureus isolates; however, 10 coagulase-negative isolates were MecA + but oxacillin sensitive and 1 isolate was MecA − but oxacillin resistant. Oxacillin resistance was induced in 6 of the 10 MecA + isolates previously classified as oxacillin sensitive. These results suggest that the bDNA method described here is a sensitive and efficient method for detection of methicillin resistance in staphylococci and that genetic detection methods may be useful for detection of potential methicillin resistance in the clinical laboratory.

ABSTRACT A total of 120 pleural fluid specimens from 113 pediatric patients were tested using two rapid antigen detection assays for Streptococcus pyogenes . Results were compared to culture, Gram stain, and PCR results. Each rapid antigen assay detected 9 out of 10 (90%) PCR-positive samples, with 100% specificity. These antigen detection assays are useful to provide microbiological diagnosis of empyema caused by S. pyogenes .