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Yali Yue,* Feixiang Hu,* Tingdan Hu, Yiqun Sun, Tong Tong, Yajia Gu Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yajia Gu; Tong TongDepartment of Radiology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Shanghai 200032, People’s Republic of ChinaTel +8618121299466; +8617349786369Fax +862164174774Email cjr.guyajia@vip.163.com; t983352@126.comPurpose: The objective of this research was to validate the diagnostic value of three-dimensional texture parameters and clinical characteristics in the differentiation of colorectal signet-ring cell carcinoma (SRCC) and adenocarcinoma (AC).Methods: We retrospectively analyzed data from 102 patients with SRCC or AC confirmed by pathology, including 51 SRCC (from January 2015 to July 2019) and 51 AC patients (from January 2019 to July 2019). CT findings and clinical data, including age, gender, clinical symptoms, serological biomarkers, tumor size, and tumor location, were compared between SRCC and AC. CT texture features were quantified on portal phase images using three-dimensional analysis. A list of texture parameters was generated with MaZda software for the classification of tumors. The texture features, clinical data and CT findings were statistically analyzed for the discrimination ability of SRCC and AC, and the potential predictive parameters that may be used to differentiate the two groups were subsequently tested using the least absolute shrinkage and selection operator (LASSO) and logistic regression analyses. The receiver operating characteristic curve (ROC) provided a range of values for establishing the cutoff value, as well as the sensitivity and specificity of prediction for each significant variable.Results: SRCC occurred more often in men than AC did (80.39% vs 49.02%, P < 0.01). The patients were younger in the SRCC group than in the AC group, without a statistically significant difference (55.84 vs 59.20 years, P = 0.216). There were no significant differences in the clinical symptoms, tumor size, or tumor location between the two groups (P=0.505, P=0.19, P=0.843, respectively). The elevation of serological biomarker CA724 was more common in SRCC than in AC (P< 0.001). Perc.01%3D, Perc.10%3D and s(1,0,0) SumAverg were lower in the SRCC group than in the AC group during the portal phase, with the areas under curve (AUCs) of 0.892–0.929, sensitivity of 76.5–84.3% and specificity of 88.2–96.1%. In the differentiation between SRCC and AC, the 1-NN minimal classification error (MCR) was 29.41%.Conclusion: Three-dimensional texture parameters, including Perc.01%3D, Perc.10%3D and s(1,0,0) SumAverg, exhibited a favorable discriminatory ability to distinguish SRCC from AC.Keywords: computed tomography, colorectal signet-ring cell carcinoma, adenocarcinoma, texture analysis, three-dimensional

Abstract Background In rectal cancers, radical surgery should follow local excisions, in cases of unexpected, unfavorable tumor characteristics. The oncological results of this completion surgery are inconsistent. This retrospective cohort study assessed the clinical and long-term oncological outcomes of patients that underwent completion surgery to clarify whether a local excision compromised the results of radical surgery. Methods Forty-six patients were included, and the reasons for completion surgery, intraoperative complications, residual tumors, local recurrences (LRs), distant metastases, and cancer-specific survival (CSS) were assessed. The results were compared to 583 patients that underwent primary surgery without adjuvant therapy, treated with a curative intention during the same time period. Results The median follow-up was 14.6 years. The reasons for undergoing completion surgery were positive resection margins (24%), high-risk cancer (30%), or both (46%). Intraoperative perforations occurred in 10/46 (22%) cases. Residual tumor in the rectal wall or lymph node involvement occurred in 12/46 (26%) cases. The risk of intraoperative perforation and residual tumor increased with the pT category. Intraoperative perforations did not increase postoperative complications, but they increased the risk of LRs in cases of intramural residual tumors (p = 0.003). LRs occurred in 2.6% of pT1/2 and 29% of pT3 tumors. Both the 5- and 10-year CSS rates were 88.8% (95% CI 80.0–98.6). Moreover, the LRs of patients with pT1/2 cancers were lower in patients with completion surgery than in patients with primary surgery. Conclusions Rectal wall perforations at the local excision site and residual cancer were the main risks for poor oncological outcomes associated with completion surgery. Local excisions followed by early radical surgery did not appear to compromise outcomes compared to patients with primary surgery for pT1/2 rectal cancer. Improvements in clinical staging should allow more appropriate selection of patients that are eligible for a local excision of rectal cancer.

Jifu Hao,* Tiantian Tong,* Kai Jin, Qiannan Zhuang, Te Han, Yanping Bi, Jianzhu Wang, Xiaodan Wang College of Pharmacy, Taishan Medical University, Taian, People’s Republic of China *These authors contributed equally to this work Abstract: A folic acid (FA)-functionalized drug vehicle platform based on Pluronic 127 (P127)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles was orchestrated for an effective delivery of the model drug resveratrol in order to address the problem of poor water solubility and rapid metabolism of resveratrol and improve its targeted accumulation at tumor site. The FA-decorated mixed micelles were prepared using thin-film hydration method and optimized by central composite design approach. The micelles were also characterized in terms of size and morphology, drug entrapment efficiency and in vitro release profile. In addition, the cytotoxicity and cell uptake of the micelles were evaluated in folate receptor-overexpressing MCF-7 cell line. In vivo pharmacokinetic and biodistribution studies were also performed. The average size of the micelles was ~20 nm with a spherical shape and high encapsulation efficiency (99.67%). The results of fluorescence microscopy confirmed the targeting capability of FA-conjugated micelles in MCF-7 cells. FA-modified micelles exhibited superior pharmacokinetics in comparison with that of solution. Further, the low accumulation of resveratrol-loaded FA micelles formulation in the heart and kidney avoided toxicity of these vital organs. It could be concluded that folate-modified P127/TPGS mixed micelles might serve as a potential delivery platform for resveratrol. Keywords: resveratrol, Pluronic 127/TPGS, mixed micelles, folic acid conjugation

Yan Zhang,1 Hui Zhang,2 Wenbin Wu,2 Fuhong Zhang,3,4 Shi Liu,3 Rui Wang,3 Yingchun Sun,1 Ti Tong,1 Xiabin Jing3 1Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China; 2Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, People's Republic of China; 3State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China; 4Department of Otolaryngology, The First Hospital of Lanzhou University, Lanzhou, Gansu, People's Republic of China Abstract: Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA) and paclitaxel (PTX) containing composite micelles (FA-M[PTX]) were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX) on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22) on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain), followed by survival analysis. The results indicated that FA-M(PTX) prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA-M(PTX) group gained significantly prolonged survival time when compared with others given equivalent doses of PTX of 30 mg/kg. The enhanced efficacy of FA-M(PTX) is theoretically ascribed to the target effect of FA; moreover, the extensive pulmonary capillary networks may play a role. In conclusion, FA-M(PTX) displayed great potential as a promising antimetastatic agent, and the FA-conjugated micelles is a preferential targeted delivery system when compared to micelles without FA. Keywords: pulmonary metastasis, folate receptor, paclitaxel, polymer–drug conjugate, targeted drug delivery

Wenbin Wu,1 Yonghui Zheng,2 Rui Wang,2 Weili Huang,3 Lei Liu,2 Xiuli Hu,2 Shi Liu,2 Jun Yue,2 Ti Tong,1 Xiabin Jing21Department of Thoracic Surgery, Second Hospital of Jilin University, Changchun, 2State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 3Department of Gastroenterology, the Affiliated Hospital of Beihua University, Jilin, ChinaBackground: Esophageal cancer is recognized as one of the most refractory pernicious diseases. In addition, it is an aggressive malignancy with a propensity for local progression and distant dissemination. Because of the poor long-term prognosis for patients with esophageal cancer, increasing attention has focused on the integration of targeted agents into current therapeutics. Nevertheless, there have been few studies reported concerning the therapeutic efficacy of paclitaxel-conjugated polymeric micelles in human esophageal cancer in vivo. Therefore, the aim of this research was to investigate the tumor inhibition effect of composite micelles containing folic acid and paclitaxel on the human esophageal EC9706 cancer cell line.Methods and results: Intravenous administration of folate-targeted, paclitaxel-loaded micelles was demonstrated to be more efficient in inhibiting subcutaneous xenograft tumors and extending the survival rate of tumor-bearing nude mice than free paclitaxel and plain paclitaxel micelles at an equivalent paclitaxel dose of 20 mg/kg, which was further backed up by flow cytometry, TUNEL, and expression of apoptosis-related proteins, including Bax, Bcl2, and caspase 3 in this study.Conclusion: The folate-mediated paclitaxel-loaded polymeric micelle is a promising agent for the treatment of human esophageal cancer.Keywords: esophageal cancer, folate, paclitaxel, polymer-drug conjugate, targeted drug delivery

In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics.The VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses.These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors.

Cisplatin resistance is one of the major causes of treatment failure in head and neck squamous cell carcinoma (HNSCC). There is an urgent need to uncover the underlying mechanism for developing effective treatment strategies. A quantitative proteomics assay was used to identify differential proteins in cisplatin-resistant cells. Mitochondrial topoisomerase I (TOP1MT) localization was determined using laser confocal microscopy and nucleocytoplasmic separation assay. Chromatin immunoprecipitation sequencing, dual-luciferase reporter assay, and RNA immunoprecipitation were used to identify the interaction between pseudogenes, miRNAs, and real genes. In vivo experiments verified the interaction between TOP1MT and pseudogenes on cisplatin resistance. TOP1MT was identified as a driving factor of cisplatin resistance in vitro, in vivo, and in HNSCC patients. Moreover, TOP1MT exceptionally translocated to the nucleus in cisplatin-resistant HNSCC cells in a signal peptide–dependent manner. Nuclear TOP1MT (nTOP1MT) transcriptionally regulated the mitochondrial functional pseudogene MTATP6P1, which bound to miR-137 and miR-491-5p as a competing endogenous RNA (ceRNA) and promoted the expression of MTATP6. An increase in MTATP6 enhanced mitochondrial oxidative phosphorylation (OXPHOS), which conferred cisplatin resistance in HNSCC. Our findings revealed that nTOP1MT transcriptionally activated MTAPT6P1 and increased MTATP6 expression via ceRNA, which facilitated OXPHOS and cisplatin resistance. These results provide novel insight for overcoming cisplatin resistance in HNSCC. [ABSTRACT FROM AUTHOR]

Hmong people in the United States of America have started to emerge on the national scene thanks to the recent rise of Hmong politicians winning State representative, senate, and assembly seats. The Hmong-American experience in the United States is a rollercoaster experience. While we have made America our home for the past 45 years, our presence is still largely unknown to the majority of the American people. The struggle of every Hmong person living in a relatively unknown land, unknown culture, and unknown people is very real, it represents that of the whole community struggles to survive. This article focuses on my graduate school experience through the so called multicultural education system. I provide a brief history of the Hmong people, why we are here in the United States, Hmong people's overall educational experience, and my personal experience in maneuvering through the bureaucratic institution of graduate school. My story represents the larger story of the Hmong people experience in the United States. Portions of this story have appeared as a chapter in the book, "Voices of Asian American in higher education: The unheard stories" (Obiakor & Hui-Michael, 2018).

We describe measurements of the pyroelectric coefficient of epitaxial layers of Ba0.6Sr0.4TiO3 (BST) and PbZr0.2Ti0.8O3 (PZT) using a modulated laser as the heat source in the frequency range 1 Hz to 10 MHz. The pyroelectric coefficient is also measured as a function of applied static electric field and for films grown on SrTiO3, DyScO3, and GdScO3 substrates. The heat diffusion equation is solved in cylindrical coordinates for the temperature field in a multilayer sample heated by a Gaussian-shaped laser beam. The secondary contribution to the pyroelectric effect caused by piezoelectric effects and in-plane thermal expansion is revealed by the difference between the pyroelectric coefficients at high and low frequencies. The secondary pyroelectric effect has the same dependence on applied field as the pyroelectric coefficient. The magnitude of the secondary effect changes with heating frequency because of changing mechanical conditions, but the pyroelectric coefficient has no other frequency dependence between 1 Hz and 10 MHz. The secondary effect is approximately 15% and 20% of the total pyroelectric response for PZT and BST films, respectively.

We report laser-based direct measurements of the pyroelectric and electrocaloric effects of PbZr1-xTixO3 epitaxial layers as a function of temperature and electric field. By evaluating the differences between the total pyroelectric and electrocaloric coefficients, we determine the secondary contribution to the electrocaloric effect that is created by a combination of piezoelectric and elastocaloric effects. The secondary contribution to the electrocaloric coefficient has the opposite sign as the primary effect and therefore reduces the overall entropy change of PbZr1-xTixO3 in an electric field. The absolute magnitude of the secondary effect is comparable to the primary effect at elevated temperatures of ≈200°C.

We report pyroelectric current measurements on 150 nm thick PbZr 0.2Ti0.8O3 (PZT) epitaxial films using frequency-domain thermal measurements over the range 0.02 Hz-1.3 MHz. The measured pyroelectric currents are proportional to the rate of temperature change, from ∼10-5 A/m2 to ∼103 A/m2 over the range 10-2 to 106 K/s. The film temperature oscillation is controlled using either a hotplate, microfabricated heater, or modulated laser, and the pyroelectric current is measured from a microelectrode fabricated onto the film. The measured pyroelectric coefficient of the PZT films is nearly constant across the entire frequency range at ≈-200 μC/m2K. © 2012 American Institute of Physics.

We report pyroelectric current measurements on 150 nm thick PbZr 0.2Ti0.8O3 (PZT) epitaxial films using frequency-domain thermal measurements over the range 0.02 Hz-1.3 MHz. The measured pyroelectric currents are proportional to the rate of temperature change, from ∼10-5 A/m2 to ∼103 A/m2 over the range 10-2 to 106 K/s. The film temperature oscillation is controlled using either a hotplate, microfabricated heater, or modulated laser, and the pyroelectric current is measured from a microelectrode fabricated onto the film. The measured pyroelectric coefficient of the PZT films is nearly constant across the entire frequency range at ≈-200 μC/m2K. © 2012 American Institute of Physics.

Abstract Background Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer’s Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer’s Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P

Abstract Recent studies have suggested that Transposable Elements (TEs) residing in introns frequently splice into and alter primary gene-coding transcripts. To re-examine the exonization frequency of TEs into protein-coding gene transcripts, we re-analyzed a Drosophila neuron circadian rhythm RNAseq dataset and a deep long RNA fly midbrain RNAseq dataset using our Transposon Insertion and Depletion Analyzer (TIDAL) program. Our TIDAL results were able to predict several TE insertions from RNAseq data that were consistent with previous published studies. However, we also uncovered many discrepancies in TE-exonization calls, such as reads that mainly support intron retention of the TE and little support for chimeric mRNA spliced to the TE. We then deployed rigorous genomic DNA-PCR (gDNA-PCR) and RT-PCR procedures on TE-mRNA fusion candidates to see how many of bioinformatics predictions could be validated. By testing a w1118 strain from which the deeper long RNAseq data was derived and comparing to an OreR strain, only 9 of 23 TIDAL candidates (

Abstract Background Locally advanced rectal cancer (LARC) poses unique challenges in treatment, with current neoadjuvant chemoradiotherapy (NA-CRT) showing limitations. The CapeOX regimen emerges as a potential less aggressive neoadjuvant chemotherapy (NAC) for LARC. Methods We conducted a retrospective study involving treatment-naïve patients with LARC from March 2014 to March 2021 who received 2–4 cycles of CapeOX NAC followed by radical surgery. Treatment response was evaluated using tumor regression grade (TRG), MRI-based TRG (MRI-TRG), and Neoadjuvant Rectal (NAR) score. Results 94.7% of patients experienced symptom improvement and 96.4% achieved sphincter-preserving surgery. Post-NAC showed significant tumor regression and MRI confirmed a tumor length reduction (P

Objective To investigate the ability of radiological parameter canal bone ratio (CBR) to assess bone mineral density and to differentiate between patients with primary and multiple osteoporotic vertebral compression fracture (OVCF). Methods A retrospective analysis was conducted on OVCF patients treated at our hospital. CBR was measured through full-spine x-rays. Patients were categorized into primary and multiple fracture groups. Receiver operating characteristic curve analysis and area under the curve (AUC) calculation were used to assess the ability of parameters to predict osteoporosis and multiple fractures. Predictors of T values were analyzed by multiple linear regression, and independent risk factors for multiple fractures were determined by multiple logistic regression analysis. Results CBR showed a moderate negative correlation with dual-energy x-ray absorptiometry T values (r = -0.642, p < 0.01). Higher CBR (odds ratio [OR], -6.483; 95% confidence interval [CI], -8.234 to -4.732; p < 0.01) and lower body mass index (OR, 0.054; 95% CI, 0.023–0.086; p < 0.01) were independent risk factors for osteoporosis. Patients with multiple fractures had lower T values (mean ±standard deviation [SD]: -3.76 ±0.73 vs. -2.83 ±0.75, p < 0.01) and higher CBR (mean ±SD: 0.54 ±0.07 vs. 0.46 ±0.06, p < 0.01). CBR had an AUC of 0.819 in predicting multiple fractures with a threshold of 0.53. T values prediction had an AUC of 0.816 with a threshold of -3.45. CBR > 0.53 was an independent risk factor for multiple fractures (OR, 14.66; 95% CI, 4.97–43.22; p < 0.01). Conclusion CBR is negatively correlated with bone mineral density (BMD) and can be a novel opportunistic BMD assessment method. It is a simple and effective measurement index for predicting multiple fractures, with predictive performance not inferior to T values.

In this paper, A mathematical framework of checking accuracy of numerical methods from mathematical software is been developed and investigated. Rössler attractor is used as case study as its analytical solution is non-existence. The algorithms investigated from Mathcad software includes AdamsBDF, Adams, BDF and Runge-Kutta fixed methods. The numerical solutions of each built-in algorithms are compared to well-known Joubert-Greeff method. The estimation of global and local residuals are shown. The graphical results are plotted on an interval of 0 ≤ t ≤ 150. [ABSTRACT FROM AUTHOR]