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Background: Few data are available on metastatic colorectal cancer (mCRC) treated with late-line regorafenib monotherapy or combined with other therapies. This study thus aimed to examine regorafenib combined with immune checkpoint inhibitors (ICIs) compared with regorafenib monotherapy in patients with advanced CRC., Methods: This single-center retrospective cohort study included patients with advanced CRC who experienced recurrence and progression after standard first- and second-line treatments treatment from November 2018 to December 2021. The patients received regorafenib plus ICIs or regorafenib monotherapy. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST). Overall survival (OS) and progression-free survival (PFS) were analyzed via multivariate analysis., Results: The combined group and the monotherapy group included 30 and 43 patients, respectively. The median OS (13.7 vs . 10.1 months; P=0.10) and PFS (4 vs . 3.6 months; P=0.32) were not significantly different between the two groups. In males, the median OS was significantly longer in the combined group compared with the monotherapy group (not reached vs . 8.03 months; P=0.02), but the median PFS showed no significant difference (7.23 vs . 3.90 months; P=0.16). There was no significant difference in OS (P=0.71) or PFS (P=0.89) in females. Eastern Cooperative Oncology Group performance status (ECOG PS) 1 [ vs . 0; hazard ratio (HR) =3.13, 95% confidence interval (CI): 1.61-6.10; P<0.001] was independently associated with PFS. ECOG PS 1 ( vs . 0; HR =3.63, 95% CI: 1.54-8.56; P=0.003) and combined therapy ( vs . monotherapy; HR =0.47, 95% CI: 0.22-0.99; P=0.048) were associated with OS., Conclusions: Regorafenib combined with ICIs led to numerically longer PFS and significantly prolonged OS in patients with mCRC compared to regorafenib monotherapy, especially in male patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-468/coif). J.M.P. reports honoraria and support for attending meetings and travel from MSD, Bristol-Myers Squibb, and Merck. The other authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Ultrawide-bandgap semiconductors, possessing bandgaps distinctly larger than the 3.4 eV of GaN, have emerged as a promising class capable of achieving deep ultraviolet (UV) light detection. Based on first-principles calculations, we propose an unexplored two-dimensional (2D) InTeClO 3 layered system with ultrawide bandgaps ranging from 4.34 eV of bulk to 4.54 eV of monolayer. Our calculations demonstrate that 2D InTeClO 3 monolayer can be exfoliated from its bulk counterpart and maintain good thermal and dynamic stability at room temperature. The ultrawide bandgaps may be modulated by the small in-plane strains and layer thickness in a certain range. Furthermore, the 2D InTeClO 3 monolayer shows promising electron transport behavior and strong optical absorption capacity in the deep UV range. A two-probe InTeClO 3 -based photodetection device has been constructed for evaluating the photocurrent. Remarkably, the effective photocurrent (5.7 A m -2 at photon energy of 4.2 eV) generation under polarized light has been observed in such a photodetector. Our results indicate that 2D InTeClO 3 systems have strong photoresponse capacity in the deep UV region, accompanying the remarkable polarization sensitivity and high extinction ratio. These distinctive characteristics highlight the promising application prospects of InTeClO 3 materials in the field of deep UV optoelectronics.

Objective: To explore the clinical and genetic characteristics of a very early-onset inflammatory bowel disease (VEO-IBD) type 28 child with atypical clinical manifestations., Methods: A VEO-IBD type 28 child with atypical clinical manifestations admitted to the Department of Neonatology, Children's Hospital Affiliated to Shandong University on November 5, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral venous blood samples of the child and his parents were collected for high-throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis., Results: The child, a 50-day-old male, had manifested bronchitis, ulcerative stomatitis, eczema and slightly loose stool. High-throughput sequencing revealed that he has harbored compound heterozygous variants of the IL-10RA gene, namely c.299T>G (p.V100G) and c.301C>T (p.R101W), which were inherited from his father and mother, respectively. Bioinformatic analysis showed that both variants have been recorded in the HGMD database, though the c.299T>G variant has not been included in the gnomAD, 1000 Genomes, ExAC and ESP6500 databases, while the c.301C>T variant has a low population frequency. Both variants were predicted to be deleterious by the online software including SIFT, PolyPhen-2 and Mutation Taster. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PS3+PM2&#95;Supporting+PP3)., Conclusion: The c.299T>G and c.301C>T variants of the IL-10RA gene probably underlay the VEO-IBD type 28 in this child. Above finding has expanded the phenotypic spectrum of VEO-IBD type 28 due to variants of the IL-10RA gene and provided a reference for the clinical diagnosis of this disease.

Background: Septic shock is the most severe complication of sepsis, and is a major cause of childhood mortality, constituting a heavy public health burden., Methods: We analyzed the gene expression profiles of septic shock and control samples from the Gene Expression Omnibus (GEO). Four differentially expressed genes (DEGs) from survivor and control groups, non-survivor and control groups, and survivor and non-survivor groups were selected. We used data about these genes to establish a logistic regression model for predicting the survival of septic shock patients., Results: Leave-one-out cross validation and receiver operating characteristic (ROC) analysis indicated that this model had good accuracy. Differential expression and Gene Set Enrichment Analysis (GSEA) between septic shock patients stratified by prediction score indicated that the systemic lupus erythematosus pathway was activated, while the limonene and pinene degradation pathways were inactivated in the high score group., Conclusions: Our study provides a novel approach for the prediction of the severity of pathology in septic shock patients, which are significant for personalized treatment as well as prognostic assessment., (© 2021. The Author(s).)

Tunneling electroresistance (TER) is the change in tunneling resistance induced by ferroelectric polarization reversal in ferroelectric tunnel junctions (FTJs), and how to achieve a giant TER has always been a central topic in the study of FTJs. In this work, by considering the NaTiO3/BaTiO3/LaTiO3 junction with asymmetric polar interfaces as an example, we propose a novel scheme to realize a giant TER based on the reversible partial metallization of ferroelectric barrier upon the switching of ferroelectric polarization. Density functional theory calculations indicate that high on-state and low off-state conductances are obtained and the TER ratio is as high as 3.20 × 108% due to the reversible partial barrier metallization, which leads to a great difference in the effective tunneling barrier widths. The reversible partial barrier metallization, accompanied by the ferroelectric polarization reversal, is driven by the parallel or anti-parallel alignment of the depolarization electrical field of the ferroelectrical barrier and a strong built-in electrical field cooperatively contributed by the asymmetric polar interfaces and the difference in the work functions of the two leads. The findings suggest a feasible scheme for constructing promising high performance FTJ memory devices by combining both asymmetric polar interfaces and substantially different work functions.

Pediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.

Acute lung injury (ALI) severely impairs gas exchange and results in high mortality. Insulin-like growth factor binding protein 3 (IGFBP-3) plays a crucial role in diverse lung diseases;however, the expression and function of IGFBP-3 in ALI remain unclear. In the present study, mice were injected with lipopolysaccharide to establish ALI, and IGF and IGFBP3 expression was measured using ELISA, western blotting, and immunohistochemical staining. Mice with ALI were then treated with recombinant human IGFBP-3 (rhIGFBP-3), and treatment was evaluated using survival analysis, histological staining analysis, and inflammatory cytokine expression in lung tissues and bronchoalveolar lavage fluid (BALF). The expression of NF-κB and VEGF was also measured using western blotting and ELISA in ALI mice. Our results demonstrated the upregulation of IGF expression in lung tissues and BALF of ALI mice, accompanied by downregulation of IGFBP-3. Administration of rhIGFBP-3 prolonged the survival time and attenuated LPS-induced lung injury. The expression of TNF-α, IL-6, IL-1β, and IFN-γ both in lung tissues and BALF decreased after rhIGFBP-3 treatment, whereas IL-10 expression increased. These results suggest that rhIGFBP-3 inhibits the expression of NF-κB and VEGF in lung tissues. Collectively, our study demonstrates a protective role of rhIGFBP-3 in ALI by regulation of lung inflammation., Competing Interests: None., (IJCEP Copyright © 2020.)

Background: Our objective was to study the phenotype of and molecular genetic mechanisms underlying congenital protein C (PC) deficiency in Chinese neonates. We report the case of a neonate who presented 4 h after birth with purpura fulminans of the skin and thrombosis in the kidney. We also carried out a through literature review to study the genotype and phenotype, relevance, diagnosis, management, and prognosis of neonates with congenital PC deficiency in China., Case Presentation and Literature Review: Following a septic work-up and check of PC and protein S (PS) levels that showed PC deficiency, we investigated the patient's and her parents' genotypes. Our patient was found to have a plasma PC level of 0.8%. Molecular testing revealed a compound heterozygous mutation of the PROC gene: From the father, a c.&#95;262 G > T p. ASP88Tyr mutation in exon 4; from the mother, a C. 400 + 5G mutation in intron 5 that had been previously reported as likely pathogenic. Both parents were found to have heterozygous mutations for PC deficiency. In China, 5 other cases of congenital PC deficiency in the neonatal period were reported in the literature. In those cases, purpura fulminans and thrombosis were the main symptoms, and homozygous or compound heterozygous mutations of the PROC gene were identified., Conclusion: Congenital PC deficiency should be ruled out for neonates presenting with purpura fulminans and thrombosis., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) especially aspirin has been gained increasing attention due to its potential therapy against to lung cancer. Previous investigations have showed different findings in this issue. We studied the safety profile and efficacy of NSAIDs in treating lung cancer., Method: Embase, Pubmed, and Cochrane Library databases were searched from January 2011 to February 2019. We identified the studies meeting a priori inclusion criteria and it also conducted a secondary review. This meta-analysis of 5 prospective studies was launched to evaluate the effect of NSAIDs for patients with lung cancer on the hazard risk (HR). We used the Random-Effect Model to assess pooled HR and between-study heterogeneity. Application of subgroup analysis, meta-regression, as well as sensitivity analysis was to pinpoint the exact sources of the observed heterogeneity., Results: 5 Prospective Cohorts Studies, including 6017 patients with lung cancer were recruited in the final meta-analysis. In general, using of NSAIDs especially aspirin is not associated with mortality of lung cancer: pooled hazard ratio (HR) of 0.88 [95% confidence intervals (CI): 0.73-1.05] with low heterogeneity (Q = 6.95; I = 42.4%, P = .139). Egger (P = .665) and Begg (P = 1.000) test also showed little trial error in this meta-analysis., Conclusion: NSAIDs did not increase the risk of mortality in patients with lung cancer.

Adverse outcome pathways (AOP) have been proposed as a new method to improve the ecological risk assessment of pollutants, but it requires quantitation linkage between exposure, biomarker response and toxicity of pollutants. A toxicokinetic and toxicodynamic (TK-TD) model was used to quantify AOP of the toxicity of Cd and Pb to zebrafish, including the quantitative relationship between Cd and Pb accumulation in gill and oxidative damage level based on ROS or MDA, and LC 50 values at different times. Significant relationships were found between the oxidative damage level characterized by ROS and MDA content and Cd or Pb accumulation in gill (R 2  > 0.60), and the TK model could better simulate the Pb accumulation in the gills (R 2  > 0.60) than Cd. The increasing of Cd or Pb concentrations induced the generation of ROS and the formation of ROS initiated the fluctuation of MDA level in the cells as compared to controls (p < 0.05). For the individual level effect, the Damage Assessment Model (DAM) could successfully explain the change of LC 50-ROS and LC 50-MDA values at different times (R 2  > 0.99). Our findings suggested that the TK-TD model based on ROS and MDA could be used as a quantitative AOP to predict toxicity of metals to zebrafish., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To explore the genetic basis for a neonate with bloody stool and thrombocytopenia., Methods: Clinical data of the neonate was collected. Peripheral venous blood samples were extracted from the neonate and his parents. Next generation sequencing through target capturing was carried out to detect potential mutations of genes associated with thrombocytopenia. Suspected mutation was validated by Sanger sequencing., Results: The 14-day-old male neonate was admitted to hospital for bloody stool for 8 days, decreased platelet count and reduced platelet volume. His liver function and blood coagulation were both normal. Genetic testing revealed a novel deletional mutation in c.1221delG (G407fsX444) of the WAS gene in the patient, which was inherited from his mother., Conclusion: The c.1221delG (G407fsX444) mutation of the WAS gene probably underlies the X-linked thrombocytopenia in the proband. Next generation sequencing can facilitate the diagnose and genetic counseling of such diseases.

The joint toxicity of chemical mixtures has emerged as a popular topic, particularly on the additive and potential synergistic actions of environmental mixtures. We investigated the 24h toxicity of Cu-Zn, Cu-Cd, and Cu-Pb and 96h toxicity of Cd-Pb binary mixtures on the survival of zebrafish larvae. Joint toxicity was predicted and compared using the concentration addition (CA) and independent action (IA) models with different assumptions in the toxic action mode in toxicodynamic processes through single and binary metal mixture tests. Results showed that the CA and IA models presented varying predictive abilities for different metal combinations. For the Cu-Cd and Cd-Pb mixtures, the CA model simulated the observed survival rates better than the IA model. By contrast, the IA model simulated the observed survival rates better than the CA model for the Cu-Zn and Cu-Pb mixtures. These findings revealed that the toxic action mode may depend on the combinations and concentrations of tested metal mixtures. Statistical analysis of the antagonistic or synergistic interactions indicated that synergistic interactions were observed for the Cu-Cd and Cu-Pb mixtures, non-interactions were observed for the Cd-Pb mixtures, and slight antagonistic interactions for the Cu-Zn mixtures. These results illustrated that the CA and IA models are consistent in specifying the interaction patterns of binary metal mixtures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Vav1 play key roles in the progression of human cancer. However, the role of Vav1 in gastric cancer (GC) remains to be elucidated. The present study aimed to investigate the potential relevance of the clinicopathological characteristics and prognostic significance of Vav1 in GC patients., Methods: The protein expression of Vav1 was analyzed by immunohistochemistry in formalin-fixed samples obtained from 105 GC patients., Results: Positive Vav1 expression was correlated with larger tumor size and more lymph node metastasis ( P <0.05) in GC tissues. Serosal invasion (hazard ratio [HR] = 2.764, P = 0.007), lymph node metastasis (HR = 1.298, P = 0.002) and Vav1 expression (HR = 0.436, P = 0.006) were identified as independent factors of the overall survival (OS) of GC patients. For advanced GC patients, lymph node metastasis (HR = 1.310, P = 0.003) and Vav1 expression (HR = 0.443, P = 0.010) were the independent prognostic factors of OS., Conclusion: Vav1 performs important functions in the aggressiveness of GC, and Vav1 may serve as a novel prognostic factor in GC., Competing Interests: None., (IJCEP Copyright © 2018.)

Objective: This study aimed to investigate mRNA and protein expression levels of RABEX-5 and matrix metalloproteinase-9 (MMP-9), their mutual correlation, and biological behavior in gastric cancer (GC) patients., Methods: The expression levels of RABEX-5 and MMP-9 were determined by real-time quantitative PCR and Western blotting in cell lines, GC tissues, and adjacent normal tissues. In addition, RABEX-5 and MMP-9 expression was analyzed by immunohistochemistry in formalin-fixed tissues from 113 GC patients., Results: The mRNA and protein expression levels of RABEX-5 and MMP-9 in GC cell lines and GC tissues were higher than those in normal gastric mucosa cell line and adjacent normal tissues. RABEX-5 expression and MMP-9 expression in GC tissues were significantly and positively correlated. In addition, the size of tumor (p<0.001), Lauren's classification (p=0.009), and N stage (p<0.001) were identified as the relative factors of RABEX-5 expression, whereas the expression of MMP-9 was correlated with N stage (p=0.003). The results of the multivariate analysis revealed that the independent predictive factors of overall survival were T stage (hazard ratio (HR)=2.382; p=0.028), N stage (HR=1.755; p<0.001), RABEX-5 expression (HR=0.452; p=0.004), and MMP-9 expression (HR=0.561; p=0.032)., Conclusions: RABEX-5 and MMP-9 expression levels were elevated in GC tissues and were associated with tumor invasion, metastasis, and prognosis. Therefore, they may be promising prognostic indicators of survival in GC patients.

To investigate miR-378a-3p and miR-378a-5p expression and their relationships with the clinicopathological features of colorectal cancer (CRC). Our results showed that miR-378a-3p and miR-378a-5p expression were dramatically lower in CRC cell lines and tissues than that in adjacent normal colorectal mucosal tissues, respectively. MiR-378a-3p and miR-378a-5p expression were significantly associated with histological differentiation and TNM stage, respectively. CRC patients with low miR-378a-3p and miR-378a-5p expression had a significantly shorter survival time than those patients with high miR-378a-3p and miR-378a-5p expression (p<0.001, p<0.001), respectively. Univariate and multivariable Cox regression analysis showed that tumour size, TNM stage, miR-378a-3p expression and miR-378a-5p expression were independent prognostic factors for CRC patients. Ectopic miR-378a-3p or miR-378a-5p expression inhibited cellular proliferation and colony formation, induced apoptosis and G1-phase cell cycle arrest in CRC cells, but had no effect on migration and invasion of CRC cells. Furthermore, miR-378a-3p over-expression or down-regulation could inhibit or enhance insulin-like growth factor 1 receptor (IGF1R) expression in CRC cells. There was a significantly negative correlation between IGF1R protein expression and miR-378a-3p expression in CRC tissues. MiR-378a-3p over-expression or down-regulation suppressed or enhanced phosphorylated-ERK1/2 protein level, but had no effect on phosphorylated-Akt protein level. In conclusion, miR-378a-3p and miR-378a-5p expression might play an important role as tumour suppressor gene in the initial stage of carcinogenesis of CRC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The phase information of magnetic resonance (MR) phase image can be used in many MR imaging techniques, but phase wrapping of the images often results in inaccurate phase information and phase unwrapping is essential for MR imaging techniques. In this paper we analyze the causes of errors in phase unwrapping with the commonly used Goldstein Brunch-cut algorithm and propose an improved algorithm. During the unwrapping process, masking, filtering, dipole- remover preprocessor, and the Prim algorithm of the minimum spanning tree were introduced to optimize the residues essential for the Goldstein Brunch-cut algorithm. Experimental results showed that the residues, branch-cuts and continuous unwrapped phase surface were efficiently reduced and the quality of MR phase images was obviously improved with the proposed method.

Objective: To establish the method for quantitative determination of sibricose A5 and sibricose A6 in Polygalae Radix by HPLC., Method: The ultrasonic extracting method was applied in sample pre-treatment. The HPLC procedure was performed on the chromatographic column of Agela Promosil C18 (4.6 mm x 250 mm, 5 microm), the mobile phase was acetonitrile-0.1% phosphoric acid water solution (10:90). The detection wavelength was 330 nm and flow velocity was 1 mL x min(-1). The column temperature was 30 degrees C., Result: The method has good linearity in the ranges of 0.0087-0.0694 g x L(-1) (r = 0.9993) for sibricose A5, 0.0090-0.0723 g x L(-1) (r=0.9991) for sibricose A6. The average recoveries of sibricose A5 and sibricose A6 were 101.7%, 97.87%, with the RSD of 1.7%, 1.6%, respectively., Conclusion: The method was simple, quick accurate and reliable. It is appropriate for the quantitative determination of sibricose A5 and sibricose A6 in Polygalae Radix.