KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A non-invasive artificial intelligence model for identifying axillary pathological complete response to neoadjuvant chemotherapy in breast cancer: a secondary analysis to multicenter clinical trial.

BACKGROUND: This study aims to develop a stacking model for accurately predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) using longitudinal MRI in breast cancer. METHODS: We included patients with node-positive breast cancer who received NAC following surgery from January 2012 to June 2022. We collected MRIs before and after NAC, and extracted radiomics features from the tumour, peritumour, and ALN regions. The Mann-Whitney U test, least absolute shrinkage and selection operator, and Boruta algorithm were used to select features. We utilised machine learning techniques to develop three single-modality models and a stacking model for predicting ALN response to NAC. RESULTS: This study consisted of a training cohort (n = 277), three external validation cohorts (n = 313, 164, and 318), and a prospective cohort (n = 81). Among the 1153 patients, 60.62% achieved ypN0. The stacking model achieved excellent AUCs of 0.926, 0.874, and 0.862 in the training, external validation, and prospective cohort, respectively. It also showed lower false-negative rates (FNRs) compared to radiologists, with rates of 14.40%, 20.85%, and 18.18% (radiologists: 40.80%, 50.49%, and 63.64%) in three cohorts. Additionally, there was a significant difference in disease-free survival between high-risk and low-risk groups (p < 0.05). CONCLUSIONS: The stacking model can accurately predict ALN status after NAC in breast cancer, showing a lower false-negative rate than radiologists. TRIAL REGISTRATION NUMBER: The clinical trial numbers were NCT03154749 and NCT04858529.

Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.

Tanshinone IIA attenuates osteoarthritis via inhibiting aberrant angiogenesis in subchondral bone.

Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.

Improving Sexual Function through Penis Enlargement: Comparing Silicone Pearls Implantation and Fat Grafting.

BACKGROUND: Although current penile enlargement techniques can improve appearance, it remains unclear whether these procedures increase sexual function. We aimed to systematically compare the surgical outcomes, with a particular focus on sexual function, in patients and their partners following silicone pearls implantation and fat grafting for penis enlargement. METHODS: A single-site, retrospective study reviewed patients who underwent silicone pearls implantation or fat grafting for penis enlargement. In the operation, silicone pears were connected to form a ring-shaped implant, which was then implanted under the dartos fascia. For patients underwent fat grafting, a total of 40-55 ml of fat was injected for penis enlargement. Preoperative and 6-month postoperative data of patients and their partners were collected. The penis diameter, penis appearance score (PAS) and treatment satisfaction scale (TSS) were evaluated. RESULTS: Both pearls implantation (n = 28) and fat grafting (n = 27) led to an increase in penis diameter. The TSS scores of patients who underwent pearls implantation increased by 11.96%, and the partners' scores increased by 9.17%. Specifically, Confidence, Pleasure from Sexual Activity, and Satisfaction with Orgasm scores of partners showed significant improvements. Partners' Satisfaction with Orgasm increased most. The total TSS scores of patients with fat grafting increased by 16.7%; meanwhile, scores of their partners had not obvious improvement. CONCLUSION: Silicone pearls implantation was found to effectively improve the sexual function of men and the sexual satisfaction of their partners compared to fat grafting. Therefore, pearls implantation is possible to enhanced sexual experiences both for man and their partners. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.

Correction: Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal.

Correction for 'Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal' by Ling-Yang Wang et al., Analyst, 2021, 146, 3988-3999, https://doi.org/10.1039/D1AN00478F.

Neoadjuvant docetaxel plus carboplatin vs epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label phase II trial.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; Pnoninferiority = .004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = .044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups.

Paper-based sample processing for the fast and direct MS analysis of multiple analytes from serum samples.

Amino acids are closely related to human health, and their rapid determination is important for the rapid diagnosis, timely treatment, and assessment of serious diseases. In this work, we propose a novel paper-based sample-processing device combined with isotope-dilution MS for the fast analysis of 11 amino acids from blood samples. By using an isoelectric focusing electrokinetic separation method, without the aid of carrier ampholytes and the addition of inhibitors, this approach uses only the characteristic of the isoelectric point of the target amino acids to achieve separation and purification from other coexisting components in the medium; it can meet the requirements for mass spectrometry detection. Driven by a DC voltage, a stable and sharp pH gradient (pH 3-10.5 over 5 mm) can be established in a glass-fiber paper-based fluidic channel with a MS-friendly electrolyte. Amphoteric species can be well separated from the complex blood matrix and concentrated into a narrow band in the channel within 2 min, which is 20 times faster than a commercial kit method. The method can be applied to both liquid and dry spot samples, and the cleaned sample band can be simply dissolved for direct IDMS detection in ESI MRM mode. This method is a promising strategy for the rapid MS-based detection of amino acids from serum without pre-separation via liquid chromatography.

Salty Biofluidic Sample Clean-Up and Preconcentration with a Paper-Based Ion Concentration Polarization Interface.

Charged species from complex media could be separated and enriched taking advantage of ion concentration polarization (ICP) effect; thus, ICP can be used for sample purification and improvement of detection sensitivity. In this paper, a novel and reliable ICP interface was established on a paper-based analytical device (PAD) by using ion exchange membrane, and electrokinetic stacking of target analytes from salty media was successfully demonstrated. Steady ICP effect was well observed in aqueous solution with up to 400 mM NaCl as shown by a fluorescent probe, which makes it possible to directly process salty physiological samples such as blood and urine with this type of PAD. Application of this method was demonstrated by direct online stacking of total protein from urine samples and image-based colorimetric detection by a smartphone camera. The linear response was in the range of 50-350 mg/L (R2 = 0.99), with recovery rate in the range of 94.8-107.6% and relative standard deviation below 7.1%. The obtained results were consistent with that of the clinical method. As an off-line sample pretreatment method, the feasibility for rapid tandem mass spectrometry detection of amino acids from serum samples was also investigated, and promising results were obtained. This PAD method is of low cost, easy to operate, and reliable. As a disposable PAD, it is useful not only for sensitive point-of-care testing but also for direct purification and concentration of complex and highly conductive physiological samples for fast and accurate detection with advanced analytical instruments.