METTL3 in cancer-associated fibroblasts-derived exosomes promotes the proliferation and metastasis and suppresses ferroptosis in colorectal cancer by eliciting ACSL3 m6A modification.

BACKGROUND: Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression. METHODS: qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis. RESULTS: CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models. CONCLUSION: CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.

Innovative regression model-based decision support tool for optimizing radiotherapy techniques in thoracic esophageal cancer.

Background: Modern radiotherapy exemplified by intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), has transformed esophageal cancer treatment. Facing challenges in treating thoracic esophageal cancer near vital organs, this study introduces a regression model-based decision support tool for the optimal selection of radiotherapy techniques. Methods: We enrolled 106 patients diagnosed with locally advanced thoracic esophageal cancer in this study and designed individualized IMRT and VMAT radiotherapy plans for each patient. Detailed dosimetric analysis was performed to evaluate the differences in dose distribution between the two radiotherapy techniques across various thoracic regions. Single-factor and multifactorial logistic regression analyses were employed to establish predictive models (P1 and P2) and factors such as TLV/PTV ratio. These models were used to predict the compliance and potential advantages of IMRT and VMAT plans. External validation was performed in a validation group of 30 patients. Results: Using predictive models, we developed a data-driven decision support tool. For upper thoracic cases, VMAT plans were recommended; for middle/lower thoracic cases, the tool guided VMAT/IMRT choices based on TLV/PTV ratio. Models P1 and P2 assessed IMRT and VMAT compliance. In validation, the tool showed high specificity (90.91%) and sensitivity (78.95%), differentiating IMRT and VMAT plans. Balanced performance in compliance assessment demonstrated tool reliability. Conclusion: In summary, our regression model-based decision support tool provides practical guidance for selecting optimal radiotherapy techniques for thoracic esophageal cancer patients. Despite a limited sample size, the tool demonstrates potential clinical benefits, alleviating manual planning burdens and ensuring precise, individualized treatment decisions for patients.

Intravascular large B-cell lymphoma as a covert trigger for hemophagocytic lymphohistiocytosis complicated with capillary leak syndrome: a case report and literature review.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.

PMFFNet: A hybrid network based on feature pyramid for ovarian tumor segmentation.

Ovarian cancer is a highly lethal malignancy in the field of oncology. Generally speaking, the segmentation of ovarian medical images is a necessary prerequisite for the diagnosis and treatment planning. Therefore, accurately segmenting ovarian tumors is of utmost importance. In this work, we propose a hybrid network called PMFFNet to improve the segmentation accuracy of ovarian tumors. The PMFFNet utilizes an encoder-decoder architecture. Specifically, the encoder incorporates the ViTAEv2 model to extract inter-layer multi-scale features from the feature pyramid. To address the limitation of fixed window size that hinders sufficient interaction of information, we introduce Varied-Size Window Attention (VSA) to the ViTAEv2 model to capture rich contextual information. Additionally, recognizing the significance of multi-scale features, we introduce the Multi-scale Feature Fusion Block (MFB) module. The MFB module enhances the network's capacity to learn intricate features by capturing both local and multi-scale information, thereby enabling more precise segmentation of ovarian tumors. Finally, in conjunction with our designed decoder, our model achieves outstanding performance on the MMOTU dataset. The results are highly promising, with the model achieving scores of 97.24%, 91.15%, and 87.25% in mACC, mIoU, and mDice metrics, respectively. When compared to several Unet-based and advanced models, our approach demonstrates the best segmentation performance.

Sweet syndrome induced by FLT3 inhibitors: case report and literature review.

BACKGROUND: Acute febrile neutrophilic dermatosis, also commonly referred to as Sweet syndrome, is often associated with tumors, infections, immune disorders and medications. FLT3 inhibitor-induced Sweet syndrome is a rare complication. METHODS AND RESULTS: We report a patient with relapsed and refractory acute monocytic leukemia harboring high-frequency FLT3-ITD and DNMT3a mutations. The FLT3 inhibitor gilteritinib was administered for reinduction therapy after failure of chemotherapy with a combination of venetoclax, decitabine, aclarubicin, cytarabine and granulocyte colony-stimulating factor. The leukemia patient achieved remission after 1 month of treatment. However, Sweet syndrome induced by gilteritinib, which was confirmed by skin biopsy, developed during induction therapy. Similar cases of Sweet syndrome following FLT3 inhibitor therapy for acute myeloid leukemia were reviewed. CONCLUSION: Attention should be given to this rare complication when FLT3 inhibitors are used for acute myeloid leukemia therapy, and appropriate treatments need to be administered in a timely manner.

Targeting PRAME for acute myeloid leukemia therapy.

Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit disease characteristics, and patients with adverse disease risk characteristics. Over the past 10 years, adaptive T-cell immunotherapy has been recognized as a strategy for treating various malignant tumors. However, it has faced significant challenges in AML, primarily because myeloid blasts do not contain unique surface antigens. The preferentially expressed antigen in melanoma (PRAME), a cancer-testis antigen, is abnormally expressed in AML and does not exist in normal hematopoietic cells. Accumulating evidence has demonstrated that PRAME is a useful target for treating AML. This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up, and its use in antigen-specific immunotherapy for AML.

Myelomonocytic and monocytic acute myeloid leukemia demonstrate comparable poor outcomes with venetoclax-based treatment: a monocentric real-world study.

Venetoclax (VEN), a BCL-2 inhibitor, has transformed treatment strategies for elderly and unfit acute myeloid leukemia (AML) patients by significantly improving response rates and survival. However, the predictive factors for VEN efficacy differ from traditional chemotherapy. The clinical relevance of the FAB (French-American-British) monocytic subtype, including M4 and M5, has been debated as a marker for VEN resistance. This real-world study examined 162 newly diagnosed (ND) and 85 relapsed/refractory (R/R) AML patients who received VEN-based therapy at West China Hospital, Sichuan University, from January 2019 to January 2023. We retrospectively collected clinical and treatment data from electronic medical records. The median age of the cohort was 55.5 years (range: 16.5-83.5). The composite complete remission (cCR) rate in the entire cohort was 60.7%. Specifically, among newly diagnosed (ND) patients, FAB monocytic subtypes exhibited lower cCR compared to non-monocytic subtypes (55.1% vs. 76.3%, P = 0.007). Additionally, there were no significant differences observed between M4 and M5 subtypes, both in the ND group (61.7% vs. 40.9%, p = 0.17) and the R/R group (38.2% vs. 40%, p > 0.9). Furthermore, the median follow-up was 238 (range: 7-1120) days. ND patients with monocytic subtypes had shorter overall survival compared to non-monocytic subtypes (295 days vs. not reached, p = 0.0017). Conversely, R/R patients showed no such difference (204 vs. 266 days, p = 0.72). In summary, our study suggests that the FAB monocytic subtype can predict VEN resistance and shorter survival in ND AML patients. Moreover, there is no significant distinction between M4 and M5 subtypes.

Drug repurposing: insights into the antimicrobial effects of AKBA against MRSA.

Staphylococcus aureus is a major threat in infectious diseases due to its varied infection types and increased resistance. S. aureus could form persister cells under certain condition and could also attach on medical apparatus to form biofilms, which exhibited extremely high resistance to antibiotics. 3-Acetyl-11-keto-beta-boswellic acid (AKBA) is a well-studied anti-tumor and antioxidant drug. This study is aimed to determine the antimicrobial effects of AKBA against S. aureus and its persister cells and biofilms. The in vitro antimicrobial susceptibility of AKBA was assessed by micro-dilution assay, disc diffusion assay and time-killing assay. Drug combination between AKBA and conventional antibiotics was detected by checkerboard assay. And the antibiofilm effects of AKBA against S. aureus were explored by crystal violet staining combined with SYTO/PI probes staining. Next, RBC lysis activity and CCK-8 kit were used to determine the cytotoxicity of AKBA. In addition, murine subcutaneous abscess model was used to assess the antimicrobial effects of AKBA in vivo. Our results revealed that AKBA was found to show effective antimicrobial activity against methicillin-resistant S. aureus (MRSA) with the minimal inhibitory concentration of 4-8 µg/mL with undetectable cytotoxicity. And no resistant mutation was induced by AKBA after 20 days of consecutive passage. Further, we found that AKBA could be synergy with gentamycin or amikacin against S. aureus and its clinical isolates. By crystal violet and SYTO9/PI staining, AKBA exhibited strong biofilm inhibitory and eradication effects at the concentration of 1 ~ 4 µg/mL. In addition, the effective antimicrobial effect was verified in vivo in a mouse model. And no detectable in vivo toxicity was found. These results indicated that AKBA has great potential to development as an alternative treatment for the refractory S. aureus infections.

Identification of Critical Links Based on Electrical Betweenness and Neighborhood Similarity in Cyber-Physical Power Systems.

Identifying critical links is of great importance for ensuring the safety of the cyber-physical power system. Traditional electrical betweenness only considers power flow distribution on the link itself, while ignoring the local influence of neighborhood links and the coupled reaction of information flow on energy flow. An identification method based on electrical betweenness centrality and neighborhood similarity is proposed to consider the internal power flow dynamic influence existing in multi-neighborhood nodes and the topological structure interdependence between power nodes and communication nodes. Firstly, for the power network, the electrical topological overlap is proposed to quantify the vulnerability of the links. This approach comprehensively considers the local contribution of neighborhood nodes, power transmission characteristics, generator capacity, and load. Secondly, in communication networks, effective distance closeness centrality is defined to evaluate the importance of communication links, simultaneously taking into account factors such as the information equipment function and spatial relationships. Next, under the influence of coupled factors, a comprehensive model is constructed based on the dependency relationships between information flow and energy flow to more accurately assess the critical links in the power network. Finally, the simulation results show the effectiveness of the proposed method under dynamic and static attacks.

Efficacy of Diosmin in Reducing Lower-Extremity Swelling and Pain After Total Knee Arthroplasty: A Randomized, Controlled Multicenter Trial.

BACKGROUND: Many patients experience lower-extremity swelling following total knee arthroplasty (TKA), which impedes recovery. Diosmin is a semisynthetic flavonoid that is often utilized to treat swelling and pain caused by chronic venous insufficiency. We aimed to evaluate the efficacy and safety of diosmin in reducing lower-extremity swelling and pain as well as in improving functional outcomes following TKA. METHODS: This study was designed as a randomized, controlled multicenter trial and conducted in 13 university-affiliated tertiary hospitals. A total of 330 patients undergoing TKA were randomized to either receive or not receive diosmin postoperatively. The diosmin group received 0.9 g of diosmin twice per day for 14 consecutive days starting on the day after surgery, whereas the control group received neither diosmin nor a placebo postoperatively. The primary outcome was lower-extremity swelling 1, 2, 3, and 14 days postoperatively. The secondary outcomes were postoperative pain assessed with use of a visual analogue scale, Hospital for Special Surgery score, range of knee motion, levels of the inflammatory biomarkers C-reactive protein and interleukin-6, and complications. RESULTS: At all postoperative time points, diosmin was associated with significantly less swelling of the calf, thigh, and upper pole of the patella as well as with significantly lower pain scores during motion. However, no significant differences in postoperative pain scores at rest, Hospital for Special Surgery scores, range of motion, levels of inflammatory biomarkers, or complication rates were found between the diosmin and control groups. CONCLUSIONS: The use of diosmin after TKA reduced lower-extremity swelling and pain during motion and was not associated with an increased incidence of short-term complications involving the outcomes studied. However, further studies are needed to continue exploring the efficacy and safety of diosmin use in TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.