A Longitudinal MRI-Based Artificial Intelligence System to Predict Pathological Complete Response After Neoadjuvant Therapy in Rectal Cancer: A Multicenter Validation Study.

BACKGROUND: Accurate prediction of response to neoadjuvant chemoradiotherapy is critical for subsequent treatment decisions for patients with locally advanced rectal cancer. OBJECTIVE: To develop and validate a deep learning model based on the comparison of paired MRI before and after neoadjuvant chemoradiotherapy to predict pathological complete response. DESIGN: By capturing the changes from MRI before and after neoadjuvant chemoradiotherapy in 638 patients, we trained a multitask deep learning model for response prediction (DeepRP-RC) that also allowed simultaneous segmentation. Its performance was independently tested in an internal and 3 external validation sets, and its prognostic value was also evaluated. SETTINGS: Multicenter study. PATIENTS: We retrospectively enrolled 1201 patients diagnosed with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy before total mesorectal excision. Patients had been treated at 1 of 4 hospitals in China between January 2013 and December 2020. MAIN OUTCOME MEASURES: The main outcome was the accuracy of predicting pathological complete response, measured as the area under receiver operating curve for the training and validation data sets. RESULTS: DeepRP-RC achieved high performance in predicting pathological complete response after neoadjuvant chemoradiotherapy, with area under the curve values of 0.969 (0.942-0.996), 0.946 (0.915-0.977), 0.943 (0.888-0.998), and 0.919 (0.840-0.997) for the internal and 3 external validation sets, respectively. DeepRP-RC performed similarly well in the subgroups defined by receipt of radiotherapy, tumor location, T/N stages before and after neoadjuvant chemoradiotherapy, and age. Compared with experienced radiologists, the model showed substantially higher performance in pathological complete response prediction. The model was also highly accurate in identifying the patients with poor response. Furthermore, the model was significantly associated with disease-free survival independent of clinicopathological variables. LIMITATIONS: This study was limited by its retrospective design and absence of multiethnic data. CONCLUSIONS: DeepRP-RC could be an accurate preoperative tool for pathological complete response prediction in rectal cancer after neoadjuvant chemoradiotherapy. UN SISTEMA DE IA BASADO EN RESONANCIA MAGNTICA LONGITUDINAL PARA PREDECIR LA RESPUESTA PATOLGICA COMPLETA DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO UN ESTUDIO DE VALIDACIN MULTICNTRICO: ANTECEDENTES:La predicción precisa de la respuesta a la quimiorradioterapia neoadyuvante es fundamental para las decisiones de tratamiento posteriores para los pacientes con cáncer de recto localmente avanzado.OBJETIVO:Desarrollar y validar un modelo de aprendizaje profundo basado en la comparación de resonancias magnéticas pareadas antes y después de la quimiorradioterapia neoadyuvante para predecir la respuesta patológica completa.DISEÑO:Al capturar los cambios de las imágenes de resonancia magnética antes y después de la quimiorradioterapia neoadyuvante en 638 pacientes, entrenamos un modelo de aprendizaje profundo multitarea para la predicción de respuesta (DeepRP-RC) que también permitió la segmentación simultánea. Su rendimiento se probó de forma independiente en un conjunto de validación interna y tres externas, y también se evaluó su valor pronóstico.ESCENARIO:Estudio multicéntrico.PACIENTES:Volvimos a incluir retrospectivamente a 1201 pacientes diagnosticados con cáncer de recto localmente avanzado y sometidos a quimiorradioterapia neoadyuvante antes de la escisión total del mesorrecto. Eran de cuatro hospitales en China en el período entre enero de 2013 y diciembre de 2020.PRINCIPALES MEDIDAS DE RESULTADO:Los principales resultados fueron la precisión de la predicción de la respuesta patológica completa, medida como el área bajo la curva operativa del receptor para los conjuntos de datos de entrenamiento y validación.RESULTADOS:DeepRP-RC logró un alto rendimiento en la predicción de la respuesta patológica completa después de la quimiorradioterapia neoadyuvante, con valores de área bajo la curva de 0,969 (0,942-0,996), 0,946 (0,915-0,977), 0,943 (0,888-0,998), y 0,919 (0,840-0,997) para los conjuntos de validación interna y las tres externas, respectivamente. DeepRP-RC se desempeñó de manera similar en los subgrupos definidos por la recepción de radioterapia, la ubicación del tumor, los estadios T/N antes y después de la quimiorradioterapia neoadyuvante y la edad. En comparación con los radiólogos experimentados, el modelo mostró un rendimiento sustancialmente mayor en la predicción de la respuesta patológica completa. El modelo también fue muy preciso en la identificación de los pacientes con mala respuesta. Además, el modelo se asoció significativamente con la supervivencia libre de enfermedad independientemente de las variables clinicopatológicas.LIMITACIONES:Este estudio estuvo limitado por el diseño retrospectivo y la ausencia de datos multiétnicos.CONCLUSIONES:DeepRP-RC podría servir como una herramienta preoperatoria precisa para la predicción de la respuesta patológica completa en el cáncer de recto después de la quimiorradioterapia neoadyuvante. (Traducción-Dr. Felipe Bellolio ).

Construction of Folate-Conjugated and pH-Responsive Cell Membrane Mimetic Mixed Micelles for Desirable DOX Release and Enhanced Tumor-Cellular Target.

Smart multifunctional polymeric micelles are in urgent demand for future cancer diagnosis and therapy. In this paper, doxorubicin (DOX)-loaded folic acid (FA)-targeting and pH-responsive cell membrane mimetic mixed micelles of P(DMAEMA-co-MaPCL) (PCD) and FA-P(MPC-co-MaPCL) (PMCF) (mass ratio 5/5) were prepared by a dialysis method. The micelle size, morphology, X-ray powder diffraction (XRD), pH responsiveness, in vitro DOX release, cytotoxicity, and cellular uptake were studied in detail. The results indicated that DOX could be efficiently loaded into mixed micelles (PDMCF micelles), and the DOX-loaded mixed micelles (DOX@PDMCF micelles) exhibited a size of 150 nm and pH-responsive DOX release in an extended period. Furthermore, the DOX@PDMCF micelles could efficiently suppress the proliferation of tumor cells, HeLa and MCF-7 cells. Our data suggest that the DOX@PDMCF micelles have the potential to be applied in tumor therapy, especially for treating various folate receptor overexpressed tumors.

Inflow-based vascular-space-occupancy (iVASO) might potentially predict IDH mutation status and tumor grade in diffuse cerebral gliomas.

PURPOSE: The aim of the study is to assess the diagnostic performance of inflow-based vascular-space-occupancy (iVASO) MR imaging for differentiating glioblastomas (grade IV, GBM) and lower-grade diffuse gliomas (grade II and III, LGG) and its potential to predict IDH mutation status. METHODS: One hundred and two patients with diffuse cerebral glioma (56 males; median age, 43.5 years) underwent iVASO and dynamic susceptibility contrast (DSC) MR imaging. The iVASO-derived arteriolar cerebral blood volume (CBVa), relative CBVa (rCBVa), and the DSC-derived relative cerebral blood volume (rCBV) were obtained, and these measurements were compared between the GBM group (n = 43) and the LGG group (n = 59) and between the IDH-mutation group (n = 54) and the IDH-wild group (n = 48). RESULTS: Significant correlation was observed between rCBV and CBVa (P < 0.001) or rCBVa (P < 0.001). Both CBVa (P < 0.001) and rCBVa (P < 0.001) were higher in the GBM group. Both CBVa (P < 0.001) and rCBVa (P < 0.001) were lower in the IDH-mutation group compared to the IDH-wild group. Receiver operating characteristic analyses showed the area under curve (AUC) of 0.95 with CBVa and 0.97 with rCBVa in differentiating GBM from LGG. The AUCs were 0.82 and 0.85 for CBVa and rCBVa in predicting IDH gene status, respectively, which were lower than that of rCBV (AUC = 0.90). Combined rCBV and rCBVa significantly improved the diagnostic performance (AUC = 0.95). CONCLUSIONS: iVASO MR imaging has the potential to predict IDH mutation and grade in glioma.

The Added Value of Inflow-Based Vascular-Space-Occupancy and Diffusion-Weighted Imaging in Preoperative Grading of Gliomas.

OBJECTIVES: The present study aimed to study whether combined inflow-based vascular-space-occupancy (iVASO) MR imaging (MRI) and diffusion-weighted imaging (DWI) improve the diagnostic accuracy in the preoperative grading of gliomas. METHODS: Fifty-one patients with histopathologically confirmed diffuse gliomas underwent preoperative structural MRI, iVASO, and DWI. We performed 2 qualitative consensus reviews: (1) structural MR images alone and (2) structural MR images with iVASO and DWI. Relative arteriolar cerebral blood volume (rCBVa) and minimum apparent diffusion coefficient (mADC) were compared between low-grade and high-grade gliomas. Receiver operating characteristic (ROC) curve analysis was performed to compare the tumor grading efficiency of rCBVa, mADC, and the combination of the two parameters. RESULTS: Two observers diagnosed accurate tumor grade in 40 of 51 (78.4%) patients in the first review and in 46 of 51 (90.2%) in the second review. Both rCBVa and mADC showed significant differences between low-grade and high-grade gliomas. ROC analysis gave a threshold value of 1.52 for rCBVa and 0.85 × 10-3 mm2/s for mADC to provide a sensitivity and specificity of 88.0 and 81.2% and 100.0 and 68.7%, respectively. The area under the ROC curve (AUC) was 0.87 and 0.85 for rCBVa and mADC, respectively. The combination of rCBVa and mADC values increased the AUC to 0.92. CONCLUSION: The combined application of iVASO and DWI may improve the diagnostic accuracy of glioma grading.

Cytokinin is involved in TPS22-mediated selenium tolerance in Arabidopsis thaliana.

Background and Aims: Excess selenium (Se) is toxic to plants, but relatively little is known about the regulatory mechanism of plant Se tolerance. This study explored the role of the TPS22 gene in Se tolerance in Arabidopsis thaliana. Methods: Arabidopsis wild type and XVE mutant seeds were grown on half-strength MS media containing Na2SeO3 for screening of the Se-tolerant mutant tps22. The XVE T-DNA-tagged genomic sequence in tps22 was identified by TAIL-PCR. The TPS22 gene was transformed into the mutant tps22 and wild type plants using the flower infiltration method. Wild type, tps22 mutant and transgenic seedlings were cultivated on vertical plates for phenotype analysis, physiological index measurement and gene expression analysis. Key Results: We identified an Arabidopsis Se-tolerant mutant tps22 from the XVE pool lines, and cloned the gene which encodes the terpenoid synthase (TPS22). TPS22 was downregulated by Se stress, and loss-of-function of TPS22 resulted in decreased Se accumulation and enhanced Se tolerance; by contrast, overexpression of TPS22 showed similar traits to the wild type under Se stress. Further analysis revealed that TPS22 mediated Se tolerance through reduction of Se uptake and activation of metabolism detoxification, which decreased transcription of high-affinity transporters PHT1;1, PHT1;8 and PHT1;9 and significantly increased transcription of selenocysteine methyltransferase (SMT), respectively. Moreover, loss-of-function of TPS22 resulted in reduced cytokinin level and repression of cytokinin signalling components AHK3 and AHK4, and upregulation of ARR3, ARR15 and ARR16. Exogenous cytokinin increased transcription of PHT1;1, PHT2;1 and SMT and decreased Se tolerance of the tps22 mutant. In addition, enhanced Se resistance of the tps22 mutant was associated with glutathione (GSH). Conclusions: Se stress downregulated TPS22, which reduced endogenous cytokinin level, and then affected the key factors of Se uptake and metabolism detoxification. This cascade of events resulted in reduced Se accumulation and enhanced Se tolerance.

Poly(sulfobetaine) versus poly(ethylene glycol) based copolymer modified polyurethane catheters for antifouling.

Polyurethane (PU) catheters are commonly used in clinical treatment. However, the hydrophobic nature of the PU catheter surface leads to adhesion or adsorption to platelets, proteins, bacteria, and other molecules when used in human treatment. To achieve a surface with strong hydrophilicity, high stability and excellent biocompatibility, it is necessary to functionalize the PU catheters. In this paper, a coating with antifouling function was constructed on the surface of PU catheters using plasma technology and an amide coupling reaction. A series of characterization methods, including X-ray photoelectron spectroscopy (XPS), water contact angles (WCA), and atomic force microscopy (AFM), were used to prove the successful modification of the polymer coatings. The coatings showed good stability under conditions such as PBS (pH 7.4, 720 h), 75% ethanol (6 h) and 1 wt% SDS (10 min). Additionally, the coatings exhibit excellent hemocompatibility and antibacterial properties. The PU/PEI/PCSB coating has the best anti-fouling performance among them, which means that using the PCSB copolymer has the potential to modify different clinical catheters into highly effective antifouling coatings.

Phosphorylcholine zwitterionic shell-detachable mixed micelles for enhanced cancerous cellular uptakes and increased DOX release.

To further enhance the cancerous cellular uptakes and increase the drug release of the drug loaded micelles, herein, we fabricated a series of mixed micelles with different mass ratios using two amphiphilic copolymers P(DMAEMA-co-MaPCL) and PCL-SS-PMPC. The mixed micelles showed a prolonged circulation time due to the zwitterionic shells in a physiological environment (pH 7.4). In addition, because of the protonation of tertiary amine groups in PDMAEMA and the breakage of the disulfide bond in PMPC-SS-PCL in a tumor microenvironment, the mixed micelles aggregated, which led to enhanced cancerous cellular penetration and increased DOX release. Moreover, cytotoxicity assay showed that the mixed micelles had good biocompatibility to L929, HeLa and MCF-7 cells, even at a concentration of up to 1 mg mL-1. Furthermore, enhanced antitumour activity and cellular uptake of HeLa and MCF-7 cells were detected after loading with DOX, which was determined by confocal laser scanning microscopy (CLSM) and flow cytometry (FC), especially for the DOX@MIX 3 micelles (20% mass ratio of the P(DMAEMA-co-MaPCL)). Therefore, the mixed strategy provides a simple and efficient ways to promote anticancer drug delivery.

Differential detection of metastatic and inflammatory lymph nodes using inflow-based vascular-space-occupancy (iVASO) MR imaging.

PURPOSE: To investigate the potential value of inflow-based vascular-space-occupancy (iVASO) MR imaging in differentiating metastatic from inflammatory lymph nodes (LNs). METHODS: Ten female New Zealand rabbits with 2.5-3.0 kg body weight were studied. VX2 cells and egg yolk emulsion were inoculated into left and right thighs, respectively, to induce ten metastatic and ten inflammatory popliteal LNs. Conventional MRI and iVASO were performed 2 h prior to, and 10, 20 days after inoculation (D0, D10, D20). The short-axis diameter (S), short- to long-axis diameter ratio (SLR), and arteriolar blood volume (BVa) at each time point and their longitudinal changes of each model were recorded and compared. At D20, all rabbits were sacrificed to perform histological evaluation after the MR scan. RESULTS: The mean values of S, SLR and BVa showed no significant difference between the two groups at D0 (P = 0.987, P = 0.778, P = 0.975). The BVa of the metastatic group was greater than that of the inflammatory at both D10 and D20 (P < 0.05; P < 0.001), whereas the S and SLR of the metastatic group were greater only at D20 (P < 0.001; P = 0.001). Longitudinal analyses showed that the BVa of the metastatic group increased at both D10 and D20 (P = 0.004; P = 0.001), while that of the inflammatory group only increased at D10 (P = 0.024). CONCLUSION: The BVa measured with iVASO has the potential to detect early metastatic LNs.

Synthesis and Characterization of Folate-Modified Cell Membrane Mimetic Copolymer Micelles for Effective Tumor Cell Internalization.

The inefficient targeting and phagocytic clearance of nanodrug delivery systems are two major obstacles in cancer therapy. Here, inspired by the special properties of zwitterionic polymers and folic acid (FA), a partly biodegradable copolymer of FA-modified poly(ε-caprolactone) block poly(2-methacryloxoethyl phosphorylcholine), PCL-b-PMPC-FA, was synthesized via atom transfer radical polymerization (ATRP) and click reaction. Non-FA-modified copolymer PCL-b-PMPC was also synthesized as a control. The hydrodynamic diameter of the PCL-b-PMPC-FA micelles is 158 nm (PDI 0.261), slightly larger than that of the PCL-b-PMPC micelles (139 nm, PDI 0.242). The drug doxorubicin (DOX) could be entrapped in the micelles, and as the pH decreased from 7.4 to 5.0, DOX release (in vitro) was accelerated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that both the PCL-b-PMPC and the PCL-b-PMPC-FA micelles showed low toxicity to L929, HeLa, and MCF-7 cells. In addition, the DOX-loaded micelles, PCL-b-PMPC/DOX and PCL-b-PMPC-FA/DOX micelles, exhibited low toxicity to L929 cells but high toxicity to HeLa and MCF-7 cells, especially the PCL-b-PMPC-FA/DOX micelles. HeLa and MCF-7 cell uptakes of the PCL-b-PMPC-FA/DOX micelles were 4.8 and 4.5 times higher than that of the PCL-b-PMPC/DOX micelles, respectively. Therefore, PCL-b-PMPC-FA micelles have great potential for developing drug delivery systems with extended circulation times and tumor-targeting properties.

The role of cytokinin in selenium stress response in Arabidopsis.

Cytokinins (CKs) regulate many developmental processes and environmental stress responses in plants. In this study, our data provide evidence that CK negatively regulates Arabidopsis selenium (Se) stress response. CK-deficient plant ipt1 3 5 7 exhibited enhanced Se tolerance which was abolished by exogenous benzylaminopurine (BA) application, while CK- receptor -deficient mutants ahk2 and ahk3 were sensitive to Se stress. Further investigation suggested that CK regulated Se tolerance of ipt1 3 5 7 through reduction of Se uptake and activation of metabolism detoxification, which had significantly lower transcriptions of high-affinity transporters PHT1;1, PHT1;8, PHT1;9 and the higher transcription of selenocysteine methyltransferase (SMT) respectively. Moreover, Se tolerance of ipt1 3 5 7 was associated with the enhanced antioxidant levels which had the higher catalase (CAT), ascorbate peroxidase (APX) and glutathione peroxidase (GPX) activities as well as the higher glutathione (GSH) content. On the other hand, loss-of-function mutations in single CK receptor genes could increase Se uptake and reactive oxygen species (ROS) accumulation, which caused Se sensitivity in ahk2 and ahk3 mutants. Taken together, these findings provide new insights to the role of CK in Se stress response in Arabidopsis.

A role for APX1 gene in lead tolerance in Arabidopsis thaliana.

Lead (Pb) is a dangerous and widespread metal pollutant. Numerous studies have been made in understanding heavy metal detoxification and tolerance in plants, however, relatively few are known about the mechanisms involved in Pb stress response. In this study, we provide evidence for a novel role of APX1 gene in Pb tolerance in Arabidopsis. KO-APX1 mutants apx1-3 and apx1-4 showed more resistant than wild type, and the APX1-complementary COM1 restored the growth state of wild type in Pb stress. The two KO-APX1 mutants showed reduced Pb accumulation, which was accompanied by the activation of metal transporters PDR12 and ATM3 genes expression. In addition, glutathione (GSH), phytochelatin (PC) synthesis and related gene GSH1, GSH2, PCS1 and PCS2 expression were also increased in apx1-3 plants subjected to Pb stress. The more improvements in antioxidant enzymes glutathione peroxidase (GPX) and catalase (CAT) activities were found in the mutant apx1-3. Taken together, our results suggest that APX1 gene knockout results in enhanced Pb tolerance mainly through activating the expression of the ATP-bind cassette (ABC)-type transporters and at least partially through GSH -dependent PC synthesis pathway by coordinated control of gene expression.

Shikonin promotes autophagy in BXPC-3 human pancreatic cancer cells through the PI3K/Akt signaling pathway.

The present study aimed to investigate the effect of shikonin on autophagy in BXPC-3 human pancreatic cancer cells and its underlying mechanism. Cell viability was assessed using the Cell Counting Kit-8 assay and the expression of light chain (LC) 3, p62, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-PI3K and p-Akt was analyzed using western blot analysis. Following treatment with 1 µmol/l shikonin for 48 h and 2.5 and 5 µmol/l shikonin for 24 and 48 h, the viability of the BXPC-3 cells was found to be significantly reduced and the protein expression of LC3-II/LC3-I was observed to be increased, while the protein expression of p62, PI3K, Akt, p-PI3K and p-Akt was decreased. These findings suggest that shikonin promotes autophagy in BXPC-3 cells and that the underlying mechanism may be associated with the PI3K/Akt signaling pathway.