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The association between genetic variations and immunotherapy benefit has been widely recognized, while such evidence in gastrointestinal cancer remains limited. We analyzed the genomic profile of 227 immunotherapeutic gastrointestinal cancer patients treated with immunotherapy, from the Memorial Sloan Kettering (MSK) Cancer Center cohort. A gastrointestinal immune prognostic signature (GIPS) was constructed using LASSO Cox regression. Based on this signature, patients were classified into two subgroups with distinctive prognoses (p N = 54) and Peking University Cancer Hospital cohort (N = 92). Multivariate analysis revealed that the GIPS was an independent prognostic biomarker. Notably, the GIPS-high tumor was indicative of a T-cell-inflamed phenotype and immune activation. The findings demonstrated that GIPS was a powerful predictor of immunotherapeutic survival in gastrointestinal cancer and may serve as a potential biomarker guiding immunotherapy treatment decisions.

We studied the characteristics of contrast-enhanced ultrasound (CEUS) in renal pelvic urothelial carcinomas and explored its performance in assessing microvessel density (MVD) of tumor tissues. We retrospectively analyzed the characteristics of 125 cases, which were confirmed pathologically to be renal pelvic urothelial carcinomas using CEUS. We performed CEUS and found that most tumors presented with an enhanced mode of "slow-in (mean = 16.7 ± 2.6 s, range: 12-25 s), hypo-enhancement and fast-out (mean = 69.3 ± 16.2 s, range: 42-113 s)." However, the wash-in pattern, homogeneity and wash-out pattern observed with CEUS was not correlated with pT stage and grade (p0.05). But advanced-pT-stage and high-grade tumors had a higher peak enhancement than early-pT-stage and low-grade tumors (p0.01). Peak enhancement obtained with CEUS can be used to evaluate the pT stage and grade of renal pelvic urothelial carcinomas more effectively. The MVD of those tissues was observed using immunohistochemical staining of cluster of differentiation 34 (CD34). MVD in the advanced-pT-stage and high-grade groups was significantly higher than that in the early-pT-stage and low-grade groups (p0.01). As tumor pT stage and grade improved, CEUS peak enhancement intensity and MVD of tumors also exhibited an upward trend. CEUS peak enhancement intensity has the potential to determine MVD of renal pelvic urothelial carcinomas.

In the current study, two similar substituted imidazo[1,2-α]pyridine ligands with different coordination groups were facilely synthesized, and were further used for construction of two novel Cu(II)...

As a result of thrombosis or intimal hyperplasia, synthetic artificial vascular grafts had a low success rate when they were used to replace small-diameter arteries (inner diameterlt; 6 mm). C-type natriuretic peptides (CNP) have anti-thrombotic effects, and can promote endothelial cell (EC) proliferation and inhibit vascular smooth muscle cell (SMC) over-growth. In this study, poly(ε-caprolactone) (PCL) vascular grafts loaded with CNP (PCL-CNP) were constructed by electrospinning. The PCL-CNP grafts were able to continuously release CNP at least 25 days in vitro. The results of scanning electron microscopy (SEM) and mechanical testing showed that the loading of CNP did not change the microstructure and mechanical properties of the PCL grafts. In vitro blood compatibility analysis displayed that PCL-CNP grafts could inhibit thrombin activity and reduce platelet adhesion and activation. In vitro cell experiments demonstrated that PCL-CNP grafts activated ERK1/2 and Akt signaling in human umbilical vein endothelial cells (HUVECs), as well as increased cyclin D1 expression, enhanced proliferation and migration, and increased vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production. The rabbit arteriovenous (AV)-shunt ex vitro indicated that CNP loading significantly improved the antithrombogenicity of PCL grafts. The assessment of vascular grafts in rat abdominal aorta implantation model displayed that PCL-CNP grafts promoted the regeneration of ECs and contractile SMCs, modulated macrophage polarization toward M2 phenotype, and enhanced extracellular matrix remodeling. These findings confirmed for the first time that loading CNP is an effective approach to improve the hemocompatibility and vascular regeneration of synthetic vascular grafts. STATEMENT OF SIGNIFICANCE: Small-diameter (lt; 6 mm) vascular grafts (SDVGs) have not been made clinically available due to their prevalence of thrombosis, limited endothelial regeneration and intimal hyperplasia. The incorporation of bioactive molecules into SDVGs serves as an effective solution to improve hemocompatibility and endothelialization. In this study, for the first time, we loaded C-type natriuretic peptides (CNP) into PCL grafts by electrospunning and confirmed the effectiveness of loading CNP on improving the hemocompatibility and vascular regeneration of artificial vascular grafts. Regenerative advantages included enhancement of endothelialization, modulation of macrophage polarization toward M2 phenotypes, and improved contractile smooth muscle cell regeneration. Our investigation brings attention to CNP as a valuable bioactive molecule for modifying cardiovascular biomaterial.

OBJECTIVE: To explore the characteristics of immune function of healthy full-term infants at the age of 3 months, and to analyze the relationship of immune function with feeding pattern and sex. METHODS: A total of 84 healthy full-term infants born in four hospitals in Beijing and Hohhot, China were prospectively recruited. Their feeding patterns remained unchanged within 4 months after birth. They were divided into a breast-feeding group and a milk powder feeding group according to their feeding patterns. At the age of 3 months after birth, peripheral venous blood samples of the two groups were collected to evaluate cellular immunity and humoral immunity and perform routine blood test. The laboratory indices were compared between infants with different feeding patterns and sexes. RESULTS: Compared with the milk powder feeding group, the breast-feeding group had significantly lower proportion of T cell second signal receptor CD28, immunoglobulin M, and proportion and absolute count of neutrophils (P

Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effectivepredictive biomarker for gastrointestinal (GI) cancer. Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the MemorialSloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital& Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) genemutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlationsbetween DDR gene mutations and the tumor microenvironment. Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). TheJanjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and ahigher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor,and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that thepresence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs,which could serve as a potential biomarker to guide patient selection for immunotherapy.

To compare gut microbiota of healthy infants that were exclusively breast-fed or formula-fed, we recruited 91 infants, who were assigned into three different groups and fed by breast milk (30 babies), formula A (30 babies) or formula B (31 babies) exclusively for more than 4 months after birth. Faecal bacterial composition was tested. Among different groups, α diversity was lower in breast-fed group than formula-fed groups in 40 days of age, but increased significantly in 6 months of age. The Bifidobacterium represented the most predominant genus and Enterobacteriaceae the second in all groups. In 40 days of age, Bifidobacterium and Bacteroides were significantly higher, while Streptococcus and Enterococcus were significantly lower in breast-fed group than they were in formula A-fed group. Lachnospiraceae was lower in breast-fed than formula B-fed group. Veillonella and Clostridioides were lower in breast-fed than formula-fed groups. In 3 months of age there were less Lachnospiraceae and Clostridioides in breast-fed group than formula-fed groups. There were also significant differences of microbiota between formula A-fed and formula B-fed groups. Those differences may have impacts on their long-term health.

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.

With the expanding use of immune checkpoint inhibitors (ICIs) in gastrointestinal (GI) cancer, the occurrence of acquired resistance (AR) has gradually emerged. However, the progression patterns and survival of patients with AR to ICIs are still unknown.To explore the characteristics and prognosis of AR after ICI therapy in patients with advanced GI cancer.This cohort study screened patients with advanced GI cancer treated with ICIs between January 14, 2016, and December 31, 2020, at Peking University Cancer Hospital. Initial response was defined as complete response, partial response, or stable disease longer than 6 months as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Progression was also based on Response Evaluation Criteria in Solid Tumors version 1.1. Progression or death after the initial response was defined as AR. Oligoprogression of AR was defined as 2 or more disease sites progression. The current status of AR in GI cancer and the patterns of AR and its prognosis were evaluated. The site of AR and subsequent management were also assessed. Data were analyzed from June to August 2021.Patients in the cohort were treated with mono-ICI or combination therapy.Kaplan-Meier analyses and log-rank tests were conducted for overall survival analyses. Univariate and multivariate Cox analyses were conducted to determine the prognostic implications of each variable.Of the 1124 patients who received ICIs, 373 (33.2%) patients (282 men [75.6%]; median [IQR] age, 62 [54-68] years) achieved an initial response, and 173 (46.4%) patients (137 men [79.2%]; median [IQR] age, 61 [54-67] years) developed AR. Almost all patients (167 patients [96.5%]) developed AR within 24.0 months. Progression patterns of AR were most commonly oligoprogression (122 patients [70.5%]) rather than polymetastatic progression (38 patients [22.0%]) and were associated with a good prognosis (38.5 vs 14.0 months; hazard ratio, 0.37; 95% CI, 0.18-0.74; P .001). Lymph nodes (101 patients [58.4%]) appeared to be the most common site of AR. Management after AR was mainly systemic therapy (96 patients [55.5%]).Oligoprogression was the most common pattern of AR progression, and lymph nodes were the most susceptible site for AR. Further study will be needed to determine the most favorable management for AR.

Introduction Multimodal imaging agent has the potential to overcome the shortage and incorporate the advantages of different imaging tools for extremely sensitive diagnosis. To achieve multimodal imaging, combining multiple contrast agents into a special nanostructure has become a main strategy; However, the combination of all of these functions into one nanoplatform usually requires a complicated synthetic procedure that results in heterogeneous nanostructure. Methods In this study, we develop ultrasmall gold nanoclusters with 15 gold atoms (Au15NCs) functionalized with diethylenetriamine-pentaacetic acid dianhydride (DTPAA-Gd) as an optimized multimodal imaging agent to enhance imaging ability. Results The Au15NCs-DTPAA-Gd nanohybrids possess the ultra-small size and are capable of enhancing the contrast in near-infrared fluorescence (NIRF), magnetic resonance (MR) and X-ray computed tomography (CT) imaging. Meanwhile, the integrated DTPAA-Gd component not only endow the nanohybrids to produce higher T1 relaxivity (r1 = 21.4 mM−1 s−1) than Omnipaque (r1 = 3.973 mM−1s−1) but also further enhance X-ray attenuation property of Au15NCs. Importantly, the fluorescence intensity of Au15NCs-DTPAA-Gd did not decrease compared with Au15NCs. Ultimately, in vivo imaging experiments have demonstrated that Au15NCs-DTPAA-Gd nanohybrids can be quickly eliminated from the body through the urinary system and has great potential for anatomical imaging. Conclusion These data manifest Au15NCs-DTPAA-Gd present great potential as a multimodal contrast agent for disease diagnosis, especially for early accurate detection of tumors.

Plant–plant interactions change in response to environmental conditions, and riparian species are commonly influenced by flooding. This study tested whether flooding affects the intraspecific and interspecific competition of two riparian species and whether such effects depend on the topographic positions where plants have established. Seeds of the riparian species Polygonum hydropiper were collected from both low and high positions within the shoreline of the Three Gorges Reservoir. Groups of P. hydropiper seedlings from each position were either grown alone (i.e., without competition), with another group of P. hydropiper seedlings (i.e., intraspecific competition), or with a group of seedlings of the companion species Xanthium sibiricum (i.e., interspecific competition). Each group comprised six replicates. In total, 288 plants of P. hydropiper and 84 plants of X. sibiricum were selected for the experiment. Seedlings were subjected to control and flooding treatments for 60 days. Irrespective of competition type (i.e., intra- or interspecific), both flooding and competition negatively affected the growth and/or photosynthetic capacities of P. hydropiper. Flooding only interacted with competition to explain total biomass. Flooding reduced total biomass in a larger proportion in the absence of competition, and, to a lesser extent, with intraspecific competition, compared to interspecific competition. However, such interaction effects were independent of the positions where the seeds that originated from the plants were collected from. Interspecific competition significantly decreased the chlorophyll content and photosynthetic efficiency of plants, while intraspecific competition did not. In general, plants from lower positions had higher total chlorophyll content than plants from higher positions. These results suggest that flooding may regulate the population dynamics of P. hydropiper by altering its competitive interactions.

Beet necrotic yellow vein virus (BNYVV) is a serious threat to the sugar beet industry worldwide. However, little information is available regarding the genetic diversity and population structure of BNYVV in China. Here, we analyzed multiple sequences from four genomic regions (CP, RNA3, RNA4 and RNA5) of a set of Chinese isolates. Sequence analyses revealed that several isolates were mixed infections of variants with different genotypes and/or different p25 tetrad motifs. In total, 12 distinct p25 tetrads were found in the Chinese BNYVV population, of which four tetrads were newly identified. Phylogenetic analyses based on four genes (CP, RNA3-p25, RNA4-p31 and RNA5-p26) in isolates from around the world revealed the existence of two to four groups, which mostly corresponded to previously reported phylogenetic groups. Two new subgroups and a new group were identified from the Chinese isolates in p25 and p26 trees, respectively. Selection pressure analysis indicated that there was a positive selection pressure on the p25 from the Chinese isolates, but the other three proteins were under a negative selection pressure. There was frequent gene flow between geographically distant populations, which meant that BNYVV populations from different provinces were not geographically differentiated.

Grapevine leafroll-associated virus 3 (GLRaV-3) is the most prevalent causal agent of grapevine leafroll disease (GLD). Of the 75 grapevine samples collected from three regions in China, 46.7% and 94.7% of samples tested positive for GLRaV-3 in reverse transcription-PCR (RT-PCR) and reverse transcription nested PCR (RT-nPCR), respectively. The SSCP analysis for the clones of complete CP gene from 16 GLRaV-3 isolates showed that 15 isolates contained one predominant haplotype and one isolate had no predominant haplotype. The sequences of the CP genes showed 89.9–100% identities at the nucleotide level. Phylogenetic analysis of the CP gene sequences revealed the existence of four well defined variant groups, which corresponded to previously reported phylogenetic groups (1, 2, 3, and 5). Two new sub-groups designated as sub-group 1B and sub-group 3B in groups 1 and 3, respectively, were identified in the Chinese GLRaV-3 population. Recombination analyses illustrated that those two new sub-groups (1B and 3B) were emerged as a result of recombination events between variants in groups 1 and 2, and variants in groups 1 and 3, respectively. These results further indicated that the variants in those new sub-groups are viable and evolutionary successful. Recombinants with highly similar coat protein structure to variants of group 1 were abundantly found in the viral population. In addition, these analyses provided evidence about CP gene as one of the recombination hotspots in GLRaV-3 genome. The population genetic parameters of all available CP sequences suggested that the recombinants might have emerged due to population bottlenecks during transmission. The results provide new insights into the variability and evolution of GLRaV-3.