Nanocrystal-Loaded Lipid Carriers for Improved Oral Absorption and Anticancer Efficacy of Etoposide: Formulation Development, Transport Mechanism, In Vitro and In Vivo Evaluation.

To improve the oral absorption and anticancer efficacy of the BCS-IV drug etoposide (ETO), oral nanocrystal-loaded lipid carriers (Lipo@NCs) were developed in this study by modifying the BCS-IV drug nanocrystal with the lipid bilayer. The ETO-Lipo@NCs were prepared by the thin film hydration high-pressure homogenization method, and the core of positively charged ETO nanocrystals was prepared by the sonoprecipitation-high pressure homogenization method. The optimized ETO-Lipo@NCs were spherical particles with an average particle size of 220.3 ± 14.2 nm and a zeta potential of -9.95 ± 0.81 mV, respectively. The successful coating of a lipid bilayer on the surface of nanocrystals in ETO-Lipo@NCs was confirmed by several characterization methods. Compared to nanocrystals, the release rate and degree of Lipo@NCs in SIF were significantly decreased, indicating that the lipid bilayer can effectively prevent the rapid dissolution of core nanocrystals. ETO-Lipo@NCs demonstrated a significant improvement in the intestinal permeability and absorption of ETO in a single intestinal perfusion experiment. In the cells, ETO-Lipo@NCs showed enhanced cellular uptake and transepithelial transport compared with ETO nanocrystals. Pharmacokinetic analysis indicated that ETO-Lipo@NCs had a longer plasma half-life than ETO solution, and the oral bioavailability of ETO-Lipo@NCs was 1.96- and 10.92-fold higher than that of ETO nanocrystals and ETO coarse crystals, respectively. Moreover, the ETO-Lipo@NCs orally dosed at 10 mg/kg exhibited an excellent inhibitory effect against tumors in a subcutaneous Lewis lung carcinoma (LLC) xenograft model compared with other preparations. These results indicate that the Lipo@NCs formulation has an oral absorption-promoting effect of the BCS-IV drug ETO, which could warrant further application in the oral delivery of other poorly bioavailable drugs.

Radiomics analysis from magnetic resonance imaging in predicting the grade of nonfunctioning pancreatic neuroendocrine tumors: a multicenter study.

OBJECTIVES: To explore the potential of radiomics features to predict the histologic grade of nonfunctioning pancreatic neuroendocrine tumor (NF-PNET) patients using non-contrast sequence based on MRI. METHODS: Two hundred twenty-eight patients with NF-PNETs undergoing MRI at 5 centers were retrospectively analyzed. Data from center 1 (n = 115) constituted the training cohort, and data from centers 2-5 (n = 113) constituted the testing cohort. Radiomics features were extracted from T2-weighted images and the apparent diffusion coefficient. The least absolute shrinkage and selection operator was applied to select the most important features and to develop radiomics signatures. The area under receiver operating characteristic curve (AUC) was performed to assess models. RESULTS: Tumor boundary, enhancement homogeneity, and vascular invasion were used to construct the radiological model to stratify NF-PNET patients into grade 1 and 2/3 groups, which yielded AUC of 0.884 and 0.684 in the training and testing groups. A radiomics model including 4 features was constructed, with an AUC of 0.941 and 0.871 in the training and testing cohorts. The fusion model combining the radiomics signature and radiological characteristics showed good performance in the training set (AUC = 0.956) and in the testing set (AUC = 0.864), respectively. CONCLUSION: The developed model that integrates radiomics features with radiological characteristics could be used as a non-invasive, dependable, and accurate tool for the preoperative prediction of grade in NF-PNETs. CLINICAL RELEVANCE STATEMENT: Our study revealed that the fusion model based on a non-contrast MR sequence can be used to predict the histologic grade before operation. The radiomics model may be a new and effective biological marker in NF-PNETs. KEY POINTS: The diagnostic performance of the radiomics model and fusion model was better than that of the model based on clinical information and radiological features in predicting grade 1 and 2/3 of nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs). Good performance of the model in the four external testing cohorts indicated that the radiomics model and fusion model for predicting the grades of NF-PNETs were robust and reliable, indicating the two models could be used in the clinical setting and facilitate the surgeons' decision on risk stratification. The radiomics features were selected from non-contrast T2-weighted images (T2WI) and diffusion-weighted imaging (DWI) sequence, which means that the administration of contrast agent was not needed in grading the NF-PNETs.

Carbon Nitride-Based Heterojunction Photoelectrodes with Modulable Charge-Transfer Pathways toward Selective Biosensing.

Photoelectrochemical (PEC) sensing enables the rapid, accurate, and highly sensitive detection of biologically important chemicals. However, achieving high selectivity without external biological elements remains a challenge because the PEC reactions inherently have poor selectivity. Herein, we report a strategy to address this problem by regulating the charge-transfer pathways using polymeric carbon nitride (pCN)-based heterojunction photoelectrodes. Interestingly, because of redox reactions at different semiconductor/electrolyte interfaces with specific charge-transfer pathways, each analyte demonstrated a unique combination of photocurrent-change polarity. Based on this principle, a pCN-based PEC sensor for the highly selective sensing of ascorbic acid in serum against typical interferences, such as dopamine, glutathione, epinephrine, and citric acid was successfully developed. This study sheds light on a general PEC sensing strategy with high selectivity without biorecognition units by engineering charge-transfer pathways in heterojunctions on photoelectrodes.

High-Throughput Screening of Functional Neo-Antigens and Their Specific T-Cell Receptors via the Jurkat Reporter System Combined with Droplet Microfluidics.

T-cell receptor (TCR)-engineered T cells can precisely recognize a broad repertoire of targets derived from both intracellular and surface proteins of tumor cells. TCR-T adoptive cell therapy has shown safety and promising efficacy in solid tumor immunotherapy. However, antigen-specific functional TCR screening is time-consuming and expensive, which limits its application clinically. Here, we developed a novel integrated antigen-TCR screening platform based on droplet microfluidic technology, enabling high-throughput peptide-major histocompatibility complex (pMHC)-to-TCR paired screening with a high sensitivity and low background signal. We introduced DNA barcoding technology to label peptide antigen candidate-loaded antigen-presenting cells and Jurkat reporter cells to check the specificity of pMHC-TCR candidates. Coupled with the next-generation sequencing pipeline, interpretation of the DNA barcodes and the gene expression level of the Jurkat T-cell activation pathway provided a clear peptide-MHC-TCR recognition relationship. Our proof-of-principle study demonstrates that the platform could achieve pMHC-TCR paired high-throughput screening, which is expected to be used in the cross-reactivity and off-target high-throughput paired testing of candidate pMHC-TCRs in clinical applications.

Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System.

Purpose: Gastrointestinal perforation (GIP) is a fatal adverse event (AE). The AE of GIP induced by novel antineoplastic agents has attracted attention recently. We aimed to explore the AE signals of GIP related to novel antineoplastic agents comprehensively based on the FDA Adverse Event Reporting System (FAERS). Methods: The FAERS database containing 71 quarters of records was used for analysis. Reporting odds ratio (ROR), information component (IC), and empirical Bayesian geometric mean (EBGM) were utilized to evaluate the signals of GIP associated with novel antineoplastic drugs. Standardization of drug names was by employing MedEx-UIMA software and Python. Data analysis and visualization were performed using MySQL Workbench and R software. Results: After cleaning and handling the data, 5226 GIP cases were identified that were associated with new antineoplastic medications, where these agents were the main suspected contributors. A total of 37 novel antineoplastic drugs were detected with signals of GIP for ROR and IC. Only 22 drugs showed statistically significant signals for EBGM. We found the GIP signals of 22 novel antineoplastic drugs overlapped for the 3 indicators, including anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, anti-endothelial growth factor receptor, immune checkpoint inhibitors, and so on. Conclusion: The potential risk of GIP associated with several novel antineoplastic agents was identified through data mining, which provided valuable information on the safety risks associated with GIP among these drugs. The potential threat of GIP should be recognized and managed properly when using these novel antineoplastic agents.

A Metabolomics study of metabolites associated with the glomerular filtration rate.

BACKGROUND: Chronic kidney disease (CKD) is a global public health issue. The diagnosis of CKD would be considerably enhanced by discovering novel biomarkers used to determine the glomerular filtration rate (GFR). Small molecule metabolites related to kidney filtration function that might be utilized as biomarkers to measure GFR more accurately could be found via a metabolomics analysis of blood samples taken from individuals with varied glomerular filtration rates. METHODS: An untargeted metabolomics study of 145 plasma samples was performed using ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The 145 samples were divided into four groups based on the patient's measured glomerular filtration rates (mGFRs) determined by the iohexol plasma clearance rate. The data were analyzed using random forest analyses and six other unique statistical analyses. Principal component analysis (PCA) was conducted using R software. RESULTS: A large number of metabolites involved in various metabolic pathways changed significantly between groups with different GFRs. These included metabolites involved in tryptophan or pyrimidine metabolism. The top 30 metabolites that best distinguished between the four groups in a random forest plot analysis included 13 amino acids, 9 nucleotides, and 3 carbohydrates. A panel of metabolites (including hydroxyaparagine, pseudouridine, C-glycosyltryptophan, erythronate, N-acetylalanine, and 7-methylguanidine) for estimating GFR was selected for future testing in targeted analyses by combining the candidate lists with the six other statistical analyses. Both hydroxyasparagine and N,N-dimethyl-proline-proline are unique biomarkers shown to be inversely associated with kidney function that have not been reported previously. In contrast, 1,5-anhydroglucitol (1,5-AG) decreases with impaired renal function. CONCLUSIONS: This global untargeted metabolomics study of plasma samples from patients with different degrees of renal function identified potential metabolite biomarkers related to kidney filtration. These novel potential metabolites provide more insight into the underlying pathophysiologic processes that may contribute to the progression of CKD, lead to improvements in the estimation of GFR and provide potential therapeutic targets to improve kidney function.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Prediction of Therapeutic Effect to Treatment in Patients with Colorectal Liver Metastases Using Functional Magnetic Resonance Imaging and RECIST Criteria: A Pilot Study in Comparison between Bevacizumab-Containing Chemotherapy and Standard Chemotherapy.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) criteria are widely used for evaluating the therapeutic effect of colorectal liver metastases (CRLM) patients, but showed undesirable accuracy. OBJECTIVE: This study aimed to evaluate the value of functional MRI compared with RECIST criteria in predicting the therapeutic effect in CRLM patients receiving neoadjuvant chemotherapy with and without bevacizumab. METHODS: Overall, 137 patients with CRLM who received neoadjuvant chemotherapy followed by hepatic resection between January 2013 and November 2018 were included and were divided into the bevacizumab and non-bevacizumab groups. Apparent diffusion coefficient (ADC) values of pre- and post-treatment diffusion-weighted imaging (DWI) were generated on the whole-volume (ADCmean), periphery (ADCperi), and isocenter (ADCcentral) of the tumor at the maximum slice. Overall survival (OS) and relapse-free survival (RFS) were used as prognostic indicators. RESULTS: Post-treatment ADCmean was significantly associated with OS (p = 0.001) and RFS (p = 0.008) in the bevacizumab group, while RECIST-defined response was found to be only significantly associated with RFS in the non-bevacizumab group (p = 0.042). When categorizing the bevacizumab group by the post-treatment ADCmean cut-off value of 1.15 ×10-3 mm2/s, patients in the ADC response group showed significantly better OS than the non-response group (3-year OS: 91.5% vs. 64.5%, p = 0.001). However, no significant difference was found between RECIST-defined response and non-response in either OS (3-year OS: 60.2% vs. 44.0%, p = 0.104) or RFS (3-year RFS: 26.2% vs. 17.4%, p = 0.129) in the bevacizumab group. CONCLUSIONS: DWI-related parameters such as post-treatment ADCmean could accurately reflect the therapeutic effectiveness and predicting survival in patients treated with bevacizumab, which is superior to the RECIST criteria.

Preoperative serum CA19-9 should be routinely measured in the colorectal patients with preoperative normal serum CEA: a multicenter retrospective cohort study.

OBJECTIVE: Whether preoperative serum carbohydrate antigen 19-9 (CA19-9) is an independent prognostic factor and there are interactions of serum CA19-9 with carcinoembryonic antigen (CEA) on the risk of recurrence in colorectal cancer (CRC) patients are still not clarified. METHODS: Consecutive patients with CRC who underwent curative resection for stage II-III colorectal adenocarcinoma at five hospitals were collected. Based on Cox models, associations of preoperative CA19-9 with recurrence-free survival (RFS) and overall survival (OS) were evaluated in patients with or without elevated CEA, and interactions between CEA and CA19-9 were also calculated. Restricted cubic spline (RCS) curves were used to evaluate the associations between preoperative CA19-9 and CRC outcomes on a continuous scale. RESULTS: A total of 5048 patients (3029 [60.0%] men; median [interquartile range, IQR] age, 61.0 [51.0, 68.0] years; median [IQR] follow-up duration 46.8 [36.5-62.4] months) were included. The risk of recurrence increased with the elevated level of preoperative CA19-9, with the slope steeper in patients with normal CEA than those with elevated CEA. Worse RFS was observed for elevated preoperative CA19-9 (> 37 U/mL) (n = 738) versus normal preoperative CA19-9 (≤ 37 U/mL) (n = 4310) (3-year RFS rate: 59.4% versus 78.0%; unadjusted hazard ratio [HR]: 2.02; 95% confidence interval [CI]:1.79 to 2.28), and significant interaction was found between CA19-9 and CEA (P for interaction = 0.001). Increased risk and interaction with CEA were also observed for OS. In the Cox multivariable analysis, elevated CA19-9 was associated with shorter RFS and OS regardless of preoperative CEA level, even after adjustment for other prognostic factors (HR: 2.08, 95% CI:1.75 to 2.47; HR: 2.25, 95% CI:1.80 to 2.81). Subgroup analyses and sensitivity analyses yielded largely similar results. These associations were maintained in patients with stage II disease (n = 2724). CONCLUSIONS: Preoperative CA19-9 is an independent prognostic factor in CRC patients. Preoperative CA19-9 can be clinically used as a routine biomarker for CRC patients, especially with preoperative normal serum CEA.

Correlation Between the Distance to Mesorectal Fascia and Prognosis of cT3 Rectal Cancer: Results of a Multicenter Study From China.

BACKGROUND: The cT3 substage criteria based on extramural depth of tumor invasion in rectal cancer have several limitations. OBJECTIVE: This study proposed that the distance between the deepest tumor invasion and mesorectal fascia on pretherapy MRI can distinguish the prognosis of patients with cT3 rectal cancer. DESIGN: This is a cohort study. SETTING: This study included a prospective, single-center, observational cohort and a retrospective, multicenter, independent validation cohort. PATIENT: Patients who had cT3 rectal cancer with negative mesorectal fascia undergoing neoadjuvant chemoradiotherapy followed by radical surgery were included in 4 centers in China from January 2013 to September 2014. INTERVENTION: Baseline MRI with the distance between the deepest tumor invasion and mesorectal fascia, extramural depth of tumor invasion, and mesorectum thickness were measured. MAIN OUTCOME MEASURES: The cutoff of the distance between the deepest tumor invasion and mesorectal fascia was determined by time-dependent receiver operating characteristic curves, supported by a 5-year progression rate from the prospective cohort, and was then validated in a retrospective cohort. RESULTS: There were 124 and 274 patients included in the prospective and independent validation cohorts. The distance between the deepest tumor invasion and mesorectal fascia was the only predictor for cancer-specific death (HR, 0.1; 95% CI, 0.0-0.7) and was also a significant predictor for distant recurrence (HR, 0.4; 95% CI, 0.2-0.9). No statistically significant difference was observed in prognosis between patients classified as T3a/b and T3c/d. LIMITATIONS: The sample size is relatively small, and the study focused on cT3 rectal cancers with a negative mesorectal fascia. CONCLUSIONS: A cutoff of 7 mm of the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI can distinguish cT3 rectal cancer from a different prognosis. We recommend using the distance between the deepest tumor invasion and mesorectal fascia on baseline MRI for local and systemic risk assessment and providing a tailored schedule of neoadjuvant treatment. See Video Abstract at http://links.lww.com/DCR/B682.CORRELACIÓN ENTRE LA DISTANCIA DE LA FASCIA MESORRECTAL Y EL PRONÓSTICO DEL CÁNCER DE RECTO cT3: RESULTADOS DE UN ESTUDIO MULTICÉNTRICO DE CHINAANTECEDENTES:Los criterios de subestadificación cT3 basados en la profundidad extramural de invasión tumoral en el cáncer de recto tienen varias limitaciones.OBJETIVO:Este estudio propuso que la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética preterapia puede distinguir el pronóstico de los pacientes con cT3.DISEÑO:Estudio de cohorte.ENTORNO CLINICO:El estudio incluyó una cohorte observacional, prospectiva, unicéntrica, y una cohorte de validación retrospectiva, multicéntrica e independiente.PACIENTE:Se incluyeron pacientes con cáncer de recto cT3 con fascia mesorrectal negativa sometidos a quimio-radioterapia neoadyuvante seguida de cirugía radical en cuatro centros de China desde enero de 2013 hasta septiembre de 2014.INTERVENCIÓN:Imágenes de resonancia magnética de referencia fueron medidas con la distancia entre la invasión tumoral más profunda y la fascia mesorrectal; la profundidad extramural de la invasión tumoral y el grosor del mesorrecto.PRINCIPALES MEDIDAS DE VALORACION:El límite de la distancia entre la invasión tumoral más profunda y la fascia mesorrectal se determinó mediante curvas características operativas del receptor dependientes del tiempo y se apoyó en la tasa de progresión a 5 años de la cohorte prospectiva, y luego se validó en una cohorte retrospectiva.RESULTADOS:Se incluyeron 124 y 274 pacientes en la cohorte de validación prospectiva e independiente, respectivamente. La distancia entre la invasión tumoral más profunda de la fascia mesorrectal fue el único predictor de muerte específica por cáncer (Hazard ratio: 0.1, 95% CI, 0,0-0,7); y también fue un predictor significativo de recurrencia distante Hazard ratio: 0,4, 95% CI, 0,2-0,9). No se observaron diferencias estadísticamente significativas en el pronóstico entre los pacientes clasificados como T3a/b y T3c/d.LIMITACIONES:El tamaño de la muestra es relativamente pequeño y el estudio se centró en los cánceres de recto cT3 con fascia mesorrectal negativa.CONCLUSIONES:Un límite de 7 mm de distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia puede distinguir el cáncer de recto cT3 de diferentes pronósticos. Recomendamos la distancia entre la invasión tumoral más profunda y la fascia mesorrectal en la resonancia magnética de referencia para la evaluación del riesgo local y sistémico, proporcionando un programa personalizado de tratamiento neoadyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B682. (Traducción- Dr. Francisco M. Abarca-Rendon).

Metal-Organic-Framework-Derived Atomically Dispersed Mn-N-C Electrocatalysts Boosting Oxygen Reduction Modulated by Anion Exchange of Permanganate.

Mn-N-C materials have received increasing interest in recent years because of their low Fenton reactivity and ORR activity comparable to those of their Fe-N-C and Co-N-C counterparts. In this contribution, an atomically dispersed Mn-N-C electrocatalyst with a prominent oxygen reduction performance was constructed by employing a cationic Cd-MOF as a precursor that can facilely and accurately introduce MnO4- anions through anion exchange. The best-performing Mn-N-C catalyst displays a 0.96 V (vs RHE) Eonset (onset potential) and a 0.87 V (vs RHE) E1/2 (half-wave potential) in an alkaline solution, which exceed those of the benchmark Pt/C catalyst. In particular, the maximal power density of the self-made zinc-air battery reaches 200 mW·cm-2, surpassing that of most reported Mn-N-C materials.

Perioperative second-line chemotherapy is beneficial for resectable liver metastases that occur during or early after adjuvant chemotherapy for colorectal cancer.

BACKGROUND: The prognosis of patients with liver metastases during or early after adjuvant chemotherapy for colorectal cancer (CRC) is significantly worse. This study aimed to explore the efficacy of perioperative second-line chemotherapy in prolonging survival in those patients. METHODS: Patients who underwent liver resection, with resectable liver metastases that occurred within 12 months after the last cycle of adjuvant chemotherapy for CRC, from January 2006 to December 2019, were included. The long-term outcome of overall survival (OS) and progression-free survival (PFS) between different groups was analyzed. RESULTS: A total of 200 patients were included, of whom 112 underwent direct hepatectomy and 88 received upfront second-line chemotherapy. OS and PFS were significantly better in patients receiving upfront second-line chemotherapy than direct surgery (PFS, P = 0.016; OS, P = 0.013). Further analysis showed that perioperative second-line chemotherapy could provide a greater survival benefit, which was also confirmed by propensity score matching (OS: P = 0.03; PFS: P = 0.04). Multivariate analysis determined that perioperative second-line chemotherapy was an independent factor influencing OS (OR [95% CI]: 0.468 [0.294-0.744], P = 0.001) and PFS (OR [95% CI]: 0.517 [0.353-0.758], P = 0.001). DISCUSSION: Perioperative second-line chemotherapy could improve the survival of patients who underwent hepatectomy, with resectable liver metastases that occurred during or early after adjuvant chemotherapy for CRC.

MRI measurements predict major low anterior resection syndrome in rectal cancer patients.

PURPOSE: Current low anterior resection syndrome (LARS) score is lagging behind and only based on clinical symptoms patient described. Preoperative imaging indicators which can be used to predict LARS is unknown. We proposed preoperative MRI parameters for identifying major LARS. METHODS: Patients receiving curative restorative anterior resection from Sept. 2007 to Sept. 2015 were collected to complete LARS score (median 75.7 months since surgery). MRI measurements associated with LARS were tested, and a multivariate logistic model was conducted for predicting LARS. Receiver operating characteristic curve was used to evaluate the model. RESULTS: Two hundred fifty-five patients undergoing neoadjuvant chemoradiotherapy and 72 patients undergoing direct surgery were enrolled. The incidence of major LARS in NCRT group was significantly higher (53.3% vs.34.7%, P = 0.005). In patients with neoadjuvant chemoradiotherapy, the thickness of ARJ (TARJ), the distance between the tumor's lower edge and anal rectal joint (DTA), and sex were independent factors for predicting major LARS; ORs were 0.382 (95% CI, 0.198-0.740), 0.653 (95% CI, 0.565-0.756), and 0.935 (95% CI, 0.915-0.955). The AUC of the multivariable model was 0.842 (95% CI, 0.794-0.890). In patients with direct surgery, only DTA was the independent factor for predicting major LARS; OR was 0.958 (95% CI, 0.930-0.988). The AUC was 0.777 (95% CI: 0.630-0.925). CONCLUSIONS: Baseline MRI measurements have the potential to predict major LARS in rectal cancer, which will benefit the decision-making and improve patients' life quality.

Deep learning-assisted magnetic resonance imaging prediction of tumor response to chemotherapy in patients with colorectal liver metastases.

Accurate evaluation of tumor response to preoperative chemotherapy is crucial for assigning appropriate patients with colorectal liver metastases (CRLM) to surgery or conservative therapy. However, there is no well-recognized method for predicting pathological response before surgery. Our study constructed and validated a deep learning algorithm using prechemotherapy and postchemotherapy magnetic resonance imaging (MRI) to predict pathological response in CRLM. CRLM patients from center one who had ≤5 lesions and were scheduled to receive preoperative chemotherapy followed by liver resection between January 2013 and November 2016, were included prospectively and chronologically divided into a training cohort (80% of patients) and a testing cohort (20% of patients). Patients from center two were included January 2017 and December 2018 as an external validation cohort. MRI-based models were constructed to discriminate according to pathology tumor regression grade (TRG) between the response (TRG1/2) and nonresponse (TRG3/4/5) groups at the lesion level. From center one, 155 patients (328 lesions) were included; chronologically, 101 (264 lesions) in the training cohort and 54 (64 lesions) in the testing cohort. The model achieved better accuracy (0.875 vs 0.578) and AUC (0.849 vs 0.615) than RECIST for discriminating response; it also distinguished the survival outcomes after hepatectomy better than the RECIST criteria. Evaluations of the external validation cohort (25 patients, 61 lesions) also showed good ability with an AUC of 0.833. In conclusion, the MRI-based deep learning model provided accurate prediction of pathological tumor response to preoperative chemotherapy in patients with CRLM and may inform individualized treatment.

Rosmarinic acid relieves cisplatin-induced ovary toxicity in female mice via suppression of oxidative stress and inflammation.

Rosmarinic acid having potential anti-inflammatory and free radical scavenging activity. We examined the chemotherapeutic effect of rosmarinic against cisplatin (CIS)-induced ovarian toxicity via modulation of oxidative stress and inflammation. Swiss BALB mice used in experimental protocol and mice were divided into different groups. Intraperitoneal injection of CIS (7 mg/kg) was used for ovarian cancer induction. The rats were received rosmarinic acid (2.5, 5, and 10 mg/kg, body weight) treatment for 22 weeks. Body weight, ovary weight food, and water intake were estimated at regular time intervals. Hormonal and antioxidant parameters were estimated in the ovary tissue and serum at the end of the study. Cytokines, inflammatory, and apoptosis parameters were determined at the end of the study. Finally, the ovary tissue histopathology was performed at end of the experimental study. Rosmarinic acid significantly (p < 0.001) improved the body weight and reduced the ovary weight. Rosmarinic acid considerably reduced the hormonal assay parameters, such as antimullerian hormone, estradiol, luteinizing hormone, and follicle-stimulating hormone compared to model control mice. Rosmarinic treatment significantly (p < 0.001) reduced the level of nitric oxide, myeloperoxidase, and boosted the level of antioxidant parameters, such as glutathione, superoxide dismutase, catalase, and glutathione peroxidase in serum and ovary tissue. Rosmarinic acid downregulated the cytokines like interleukin-6, tumor necrosis factor-α, interleukin-1ß; inflammatory parameter includes prostaglandin E2 , cyclooxygenase-2, and inducible nitric oxide synthase at a dose-dependently. Ovary tissue histopathology showed improvement after rosmarinic acid treatment. The result suggests that rosmarinic acid is a protective effect in ameliorating CIS-induced ovary toxicity via alteration of inflammatory and apoptosis parameters.

Effect of Chlamydia trachomatis on adverse pregnancy outcomes: a meta-analysis.

PURPOSE: To analyze the effect of Chlamydia trachomatis (C. trachomatis) on adverse pregnancy outcomes based on the currently available evidence. METHODS: Multiple databases were comprehensively searched from the available date of inception through December 9, 2019. The effect of C. trachomatis on adverse pregnancy outcomes was assessed using pooled odds rations (ORs) and 95% confidence intervals (CIs). Egger's test was used for publication bias. RESULTS: Fifty studies involving 502,141 participants were identified. C. trachomatis infection was found to be associated with preterm birth in antibody detection [OR (95% CI): 1.571 (1.112-2.220), P = 0.010] and high-quality assessment [OR (95% CI): 1.734 (1.295-2.321), P < 0.001], preterm premature rupture of membranes (PPROM) in culture detection [OR (95% CI): 4.339 (1.806-10.424), P = 0.001] and high-quality assessment [OR (95% CI): 2.822 (1.333-5.973), P = 0.007], stillbirth [OR (95% CI): 1.585 (1.219-2.062), P = 0.001], low-birthweight babies [OR (95% CI): 2.205 (1.137-4.274), P = 0.019], and babies small for gestational age [OR (95% CI): 1.193 (1.091-1.305), P < 0.001]. No publication bias was exhibited in miscarriage (P = 0.170), preterm birth (P = 0.303), PPROM (P = 0.341), stillbirth (P = 0.533), and low-birthweight babies (P = 0.535). CONCLUSIONS: C. trachomatis infection during pregnancy is associated with a higher risk of preterm birth, PPROM, stillbirth, low-birthweight babies, and babies small for gestational age.

Heat Transfer and Temperature Characteristics of a Working Digital Camera.

Digital cameras represented by industrial cameras are widely used as image acquisition sensors in the field of image-based mechanics measurement, and their thermal effect inevitably induces thermal-induced errors of the mechanics measurement. To deeply understand the errors, the research for digital camera's thermal effect is necessary. This study systematically investigated the heat transfer processes and temperature characteristics of a working digital camera. Concretely, based on the temperature distribution of a typical working digital camera, the heat transfer of the working digital camera was investigated, and a model describing the temperature variation and distribution was presented and verified experimentally. With this model, the thermal equilibrium time and thermal equilibrium temperature of the camera system were calculated. Then, the influences of thermal parameters of digital camera and environmental temperature on the temperature characteristics of working digital camera were simulated and experimentally investigated. The theory analysis and experimental results demonstrate that the presented model can accurately describe the temperature characteristics and further calculate the thermal equilibrium state of working digital camera, all of which contribute to guiding mechanics measurement and thermal design based on such camera sensors.

The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3.

Cardiomyocyte loss and cardiac fibrosis are the main characteristics of cardiac ischemia and heart failure, and mitochondrial function of cardiomyocytes is impaired in cardiac ischemia and heart failure, so the aim of this study is to identify fate variability of cardiomyocytes and cardiac fibroblasts with mitochondria inhibition and explore the underlying mechanism. The mitochondrial respiratory function was measured by using Oxygraph-2k high-resolution respirometry. The STAT3 expression and activity were evaluated by western blot. Cardiomyocytes and cardiac fibroblasts displayed different morphology. The mitochondrial respiratory function and the expressions of mitochondrial complex I, II, III, IV, and V of cardiac fibroblasts were lower than that of cardiomyocytes. Mitochondrial respiratory complex I inhibitor rotenone and H2O2 (100 µM, 4 h) treatment induced cell death of cardiomyocyte but not cardiac fibroblasts. The function of complex I/II was impaired in cardiomycytes but not cardiac fibroblasts stimulated with H2O2 (100 µM, 4 h) and in ischemic heart of mice. Rotenone and H2O2 (100 µM, 4 h) treatment reduced STAT3 expression and activity in cardiomyocytes but not cardiac fibroblasts. Inhibition of STAT3 impaired mitochondrial respiratory capacity and exacerbated H2O2-induced cell injury in cardiomycytes but not significantly in cardiac fibroblasts. In conclusion, the different susceptibility of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition determines the cell fate under the same pathological stimuli and in which STAT3 plays a critical role.

Assessment of pathological complete response to preoperative chemoradiotherapy by means of multiple mathematical models of diffusion-weighted MRI in locally advanced rectal cancer: A prospective single-center study.

PURPOSE: To assess stretched-exponential, mono-exponential and intravoxel incoherent motion (IVIM) models of diffusion-weighted MRI(DWI) in predicting pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in rectal cancer patients. MATERIALS AND METHODS: This prospective study recruited 98 consecutive patients with locally advanced rectal cancer who underwent 3 Tesla MR examination before, during and after CRT. The apparent diffusion coefficient (ADC), IVIM-derived parameters (D, f, and D*), and stretched-exponential model-derived parameters (DDC and α) were measured. The parameters and their corresponding changes during and after CRT were compared between pCR and non-pCR. Receiver-operating characteristic curve analysis was performed to evaluate the diagnostic performance. Coefficient of variations and intraclass correlation coefficient were calculated to assess reliability and agreement. RESULTS: Nineteen patients achieved pCR while 79 did not. The pCR group had higher ADC and α (ADC2 and α2 ), and their changes (ΔADC2 , and Δα2 ) at the endpoint than non-pCR group. α2 and ADC2 yielded similar AUCs (P = 0.339), Δα2 and ΔADC2 yielded similar AUCs (P = 0.263) ADC and α presented substantial agreement, and α presented the minimum CV (5.0-7.0%). CONCLUSION: ADC and α were useful for assessing pCR after CRT. α might be more useful because it demonstrated better diagnostic performance than IVIM-derived parameters and better reliability than ADC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:175-183.

Vitamin C deficiency exacerbates diabetic glomerular injury through activation of transforming growth factor-ß signaling.

BACKGROUND: The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (VC) in diabetic humans and experimentally diabetic animals. Herein, we access the effects of VC deficiency on the diabetic kidney injury and explore the underlying mechanism. METHODS: l-gulonolactone oxidase conventional knockout (Gulo-/-) mice genetically unable to synthesize VC were subjected to streptozotocin-induced diabetic kidney injury and the role of VC deficiency was evaluated by biochemical and histological approaches. Rat mesangial cells were cultured to investigate the underlying mechanism. RESULTS: Functionally, VC deficiency aggravates the streptozotocin-induced renal insufficiency, exhibiting the increased urine albumin, water intake, and urine volume in Gulo-/- mice. Morphologically, VC deficiency exacerbates the streptozotocin-induced kidney injury, exhibiting the increased glomerular expansion, deposition of Periodic Acid-Schiff- and Masson-positive materials, and expression of α-smooth muscle actin, fibronectin and type 4 collagen in glomeruli of Gulo-/- mice. Mechanistically, VC activates protein kinase B (Akt) to destabilize Ski and thereby induce the expression of Smad7, resulting in suppression of TGF-ß/Smad signaling and extracellular matrix deposition in mesangial cells. CONCLUSIONS: VC is essential for the renal function maintenance in diabetes. GENERAL SIGNIFICANCE: Compensation for the loss of VC could be an effective remedy for diabetic kidney injury.