Urban traffic demand distribution is dynamic in both space and time. A thorough analysis of individuals' travel patterns can effectively reflect the dynamics of a city. This study aims to develop an ...analytical framework to explore the spatiotemporal traffic demand and the characteristics of the community structure shaped by travel, which is analyzed empirically in New York City. It uses spatial statistics and graph-based approaches to quantify travel behaviors and generate previously unobtainable insights. Specifically, people primarily travel for commuting on weekdays and entertainment on weekends. On weekdays, people tend to arrive in the financial and commercial areas in the morning, and the functions of zones arrived in the evening are more diversified. While on weekends, people are more likely to arrive at parks and department stores during the daytime and theaters at night. These hotspots show positive spatial autocorrelation at a significance level of p = 0.001. In addition, the travel flow at different peak times form relatively stable community structures, we find interesting phenomena through the complex network theory: 1) Every community has a very small number of taxi zones (TZs) with a large number of passengers, and the weighted degree of TZs in the community follows power-law distribution; 2) As the importance of TZs increases, their interaction intensity within the community gradually increases, or increases and then decreases. In other words, the formation of a community is determined by the key TZs with numerous traffic demands, but these TZs may have limited connection with the community in which they are located. The proposed analytical framework and results provide practical insights for urban and transportation planning.
Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric ...cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.
Multifunctional nanotheranostic agents have been highly commended due to the application to image-guided cancer therapy. Herein, based on the chemically disordered face centered cubic (fcc) FePt ...nanoparticles (NPs) and graphene oxide (GO), we develop a pH-responsive FePt-based multifunctional theranostic agent for potential in vivo and in vitro dual modal MRI/CT imaging and in situ cancer inhibition. The fcc-FePt will release highly active Fe ions due to the low pH in tumor cells, which would catalyze H
O
decomposition into reactive oxygen species (ROS) within the cells and further induce cancer cell apoptosis. Conjugated with folic acid (FA), the iron platinum-dimercaptosuccinnic acid/PEGylated graphene oxide-folic acid (FePt-DMSA/GO-PEG-FA) composite nanoassemblies (FePt/GO CNs) could effectively target and show significant toxicity to FA receptor-positive tumor cells, but no obvious toxicity to FA receptor-negative normal cells, which was evaluated by WST-1 assay. The FePt-based multifunctional nanoparticles allow real-time monitoring of Fe release by T
-weighted MRI, and the selective contrast enhancement in CT could be estimated in vivo after injection. The results showed that FePt-based NPs displayed excellent biocompatibility and favorable MRI/CT imaging ability in vivo and in vitro. Meanwhile, the decomposition of FePt will dramatically decrease the T
-weighted MRI signal and increase the ROS signal, which enables real-time and in situ visualized monitoring of Fe release in tumor cells. In addition, the self-sacrificial decomposition of fcc-FePt will be propitious to the self-clearance of the as-prepared FePt-based nanocomposite in vivo. Therefore, the FePt/GO CNs could serve as a potential multifunctional theranostic nanoplatform of MRI/CT imaging guided cancer diagnosis and therapy in the clinic.
On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating ...Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O
ratio (PaO
/FiO
) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO
/FiO
ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.
A multifunctional pH-sensitive polymeric nanoparticle system was developed for simultaneous tumor magnetic resonance imaging (MRI) and therapy. The nanoparticles were self-assembled using the ...multi-block polymer poly(lactic acid)-poly(ethylene glycol)-poly(l-lysine)-diethylenetriamine pentaacetic acid (PLA-PEG-PLL-DTPA) and the pH-sensitive material poly(l-histidine)-poly(ethylene glycol)-biotin (PLH-PEG-biotin). The anti-hepatocellular carcinoma (HCC) drug sorafenib was encapsulated inside the nanoparticles. Gd ions were chelated to the DTPA groups which were distributed on the nanoparticle surface. Biotinylated vascular endothelial growth factor receptor (VEGFR) antibodies were linked to the surface biotin groups of nanoparticles through the avidin linker to form the target pH-sensitive theranostic nanoparticles (TPTN). TPTN exhibited spherical or ellipsoidal shapes, uniform particle size distribution (181.4 ± 3.4 nm), positive zeta potential (14.95 ± 0.60 mV), high encapsulation efficiency (95.02 ± 1.47%) and drug loading (2.38 ± 0.04%). The pH-sensitive sorafenib release from TPTN was observed under different pH values (47.81% at pH = 7.4 and 99.32% at pH = 5.0, respectively). In cell cytotoxicity studies, TPTN showed similar antitumor effect against HepG2 cells compared to solubilized sorafenib solution after pre-incubation in acid PBS (pH = 5.0) for 1 h in vitro (P > 0.05). In in vivo anti-tumor studies, TPTN showed significantly higher antitumor effect in H22 tumor (VEGFR overexpressed cell line) bearing mice compared to the solubilized sorafenib solution (oral or i.v. administration) group (P < 0.05). In the MRI test, the T1 relaxivity value of TPTN was 17.300 mM(-1) s(-1) which was 3.6 times higher than Magnevist® (r1 = 4.8 mM(-1) s(-1)). As a positive contrast agent, TPTN exhibited higher resolution and longer imaging time (more than 90 min) in the MRI diagnosis of tumor-bearing mice compared to Magnevist® (more than 60 min). Furthermore, histological examination of TBN (blank TPTN, without sorafenib loaded) showed no visible tissue toxicity compared to normal saline. Thus, TPTN possessed dual-loading drugs and imaging agents, active targeting and pH-triggered drug release properties in one platform with good biocompatibility. All of these results indicated that TPTN was a promising theranostic carrier which could be a platform for the development of novel multifunctional theranostic agents.
The origin recognition complex (ORC), a six-subunit DNA-binding complex, participates in DNA replication in cancer cells. Specifically in prostate cancers, ORC participates the androgen receptor (AR) ...regulated genomic amplification and tumor proliferation throughout the entire cell cycle. Of note, ORC6, the smallest subunit of ORC, has been reported to be dysregulated in some types of cancers (including prostate cancer), however, its prognostic and immunological significances remain yet to be elucidated.
In the current study, we comprehensively investigated the potential prognostic and immunological role of ORC6 in 33 human tumors using multiple databases, such as TCGA, Genotype-Tissue Expression, CCLE, UCSC Xena, cBioPortal, Human Protein Atlas, GeneCards, STRING, MSigDB, TISIDB, and TIMER2 databases.
ORC6 expression was significantly upregulated in 29 types of cancers compared to the corresponding normal adjacent tissues. ORC6 overexpression correlated with higher stage and worse prognostic outcomes in most cancer types analyzed. Additionally, ORC6 was involved in the cell cycle pathway, DNA replication, and mismatch repair pathways in most tumor types. A negative correlation was observed between the tumor endothelial cell infiltration and ORC6 expression in almost all tumors, whereas the immune infiltration of T regulatory cell was noted to be statistically positively correlated with the expression of ORC6 in prostate cancer tissues. Furthermore, in most tumor types, immunosuppression-related genes, especially TGFBR1 and PD-L1 (CD274), exhibited a specific correlation with the expression of ORC6.
This comprehensive pan-cancer analysis revealed that ORC6 expression serves as a prognostic biomarker and that ORC6 is involved in the regulation of various biological pathways, the tumor microenvironment, and the immunosuppression status in several human cancers, suggesting its potential diagnostic, prognostic, and therapeutic value in pan-cancer, especially in prostate adenocarcinoma.
Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the ...providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall Fe3O4 nanoclusters were developed for tumor-targeted dual-mode T1/T2-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall Fe3O4 nanoclusters synthesized by facilely modifying ultrasmall Fe3O4 nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall Fe3O4 nanoclusters shows excellent dual-mode T1 and T2 MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall Fe3O4 nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized Fe3O4 nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.
To develop and externally validate a prognosis nomogram based on contrast-enhanced computed tomography (CECT) combined clinical for preoperative prognosis prediction of patients with pancreatic ...ductal adenocarcinoma (PDAC).
184 patients from Center A with histopathologically confirmed PDAC who underwent CECT were included and allocated to training cohort (n=111) and internal validation cohort (n=28). The radiomic score (Rad - score) for predicting overall survival (OS) was constructed by using the least absolute shrinkage and selection operator (LASSO). Univariate and multivariable Cox regression analysis was used to construct clinic-pathologic features. Finally, a radiomics nomogram incorporating the Rad - score and clinical features was established. External validation was performed using Center B dataset (n = 45). The validation of nomogram was evaluated by calibration curve, Harrell's concordance index (C-index) and decision curve analysis (DCA). The Kaplan-Meier (K-M) method was used for OS analysis.
Univariate and multivariate analysis indicated that Rad - score, preoperative CA 19-9 and postoperative American Joint Committee on Cancer (AJCC) TNM stage were significant prognostic factors. The nomogram based on Rad - score and preoperative CA19-9 was found to exhibit excellent prediction ability: in the training cohort, C-index was superior to that of the preoperative CA19-9 (0.713 vs 0.616,
< 0.001) and AJCC TNM stage (0.713 vs 0.614,
< 0.001); the C-index was also had good performance in the validation cohort compared with CA19-9 (internal validation cohort: 0.694 vs 0.555,
< 0.001; external validation cohort: 0.684 vs 0.607,
< 0.001) and AJCC TNM stage (internal validation cohort: 0.694 vs 0.563,
< 0.001; external validation cohort: 0.684 vs 0.596,
< 0.001). The calibration plot and DCA showed excellent predictive accuracy in the validation cohort.
We established a well-designed nomogram to accurately predict OS of PDAC preoperatively. The nomogram showed a satisfactory prediction effect and was worthy of further evaluation in the future.
Background:
For localized disease, partial nephrectomy of small tumors continues to be the gold-standard treatment. However, temporary clamping is routinely performed during this process to control ...renal blood flow, which can cause renal ischemic/reperfusion injury. We evaluated whether dexmedetomidine postconditioning (DPOC) can reduce renal ischemic/reperfusion injury for patients receiving laparoscopic partial nephrectomy (LPN).
Methods:
This randomized double-blind controlled trial included 77 patients who were scheduled for LPN at our hospital. Patients were randomly allocated to the DPOC or control group. DPOC was performed via intravenous administration of dexmedetomidine at 0.6 μg kg
−1
for 10 min immediately after unclamping the renal artery. In the control group, saline was administered in place of dexmedetomidine under the same protocol. All participants underwent a 6-month follow-up. The primary outcome were the values of
99m
Tc-DTPA-GFR in the affected kidney at one and 6 months post-LPN.
Result:
The GFR values in the DPOC group (35.65 ± 4.89 ml min
−1
.1.73 m
−2
) were significantly higher than those the control group (33.10 ± 5.41 ml min
−1
.1.73 m
−2
;
p
= 0.022) at 1 month after LPN. There was no statistically significant difference in GFR value between the two groups at 6 months after LPN.
Conclusion:
DPOC provides therapeutic benefits to LPN patients, at least on a short-term basis, by alleviating renal ischemic/reperfusion injury.
Clinical Trial Registration
: Chinese Clinical Trial Registry, identifier ChiCTR-TRC-14004766.
To explore the predictive value of computed tomography (CT) imaging features and CT-based texture analysis in assessing inflammatory infiltration in pancreatic ductal adenocarcinoma (PDAC).
A total ...of 43 patients with PDAC confirmed by surgical pathology were included in the study. The clinical, radiological, surgical, and pathological features of the patients were analyzed retrospectively using the chi-square test or Spearman's correlation. Receiver operating characteristic (ROC) curves were utilized to assess the overall predictive ability of the tumor enhancement degree on triphasic contrast-enhanced CT images for the inflammatory infiltration degree in PDAC. Furthermore, all CT data were uploaded to the RadCloud platform for region of interest (ROI) delineation and feature extraction. Then, the Variance Threshold and SelectKBest algorithms were used to find the optimal CT features. Binary logistic regression was employed to analyze the selected features in all three contrast-enhanced CT phases, and regression equations were formulated. ROC analysis was performed to evaluate the predictive effectiveness of each equation.
The analysis revealed a statistically significant correlation between the degree of differentiation and radiological findings such as necrosis and cystic degeneration, vascular invasion, and the presence of ascites (
< 0.05). The enhancement degree of the tumor in both the arterial and venous phases was significantly correlated with the inflammatory infiltration degree (
< 0.05); however, the areas under the ROC curve (AUCs) of arterial and venous enhancement were 0.570 and 0.542, respectively. Regression equations based on the texture features of triphasic contrast-enhanced tumors were formulated, and their AUCs were 0.982, 0.643, and 0.849.
Conventional radiological features are not significantly correlated with the degree of inflammatory infiltration in PDAC. The enhancement degrees in both the arterial phase and venous phase were statistically correlated with the inflammatory infiltration level but had poor predictive value. The texture features of PDAC on contrast-enhanced CT may show a better assessment value, especially in the arterial phase.
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