Evaluation of the tumor-targeting specific imaging and killing effect of a CEA-targeting nanoparticle in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is a prevalent digestive malignancy with significant global mortality and morbidity rates. Improving diagnostic capabilities for CRC and investigating novel therapeutic approaches are pressing clinical imperatives. Additionally, carcinoembryonic antigen (CEA) has emerged as a highly promising candidate for both colorectal tumor imaging and treatment. METHODS: A novel active CEA-targeting nanoparticle, CEA(Ab)-MSNs-ICG-Pt, was designed and synthesized, which served as a tumor-specific fluorescence agent to help in CRC near-infrared (NIR) fluorescence imaging. In cell studies, CEA(Ab)-MSNs-ICG-Pt exhibited specific targeting to RKO cells through specific antibody-antigen binding of CEA, resulting in distribution both within and around these cells. The tumor-targeting-specific imaging capabilities of the nanoparticle were determined through in vivo fluorescence imaging experiments. Furthermore, the efficacy of the nanoparticle in delivering chemotherapeutics and its killing effect were evaluated both in vitro and in vivo. RESULTS: The CEA(Ab)-MSNs-ICG-Pt nanoparticle, designed as a novel targeting agent for carcinoembryonic antigen (CEA), exhibited dual functionality as a targeting fluorescent agent. This CEA-targeting nanoparticle showed exceptional efficacy in eradicating CRC cells in comparison to individual treatment modalities. Furthermore, it exhibits exceptional biosafety and biocompatibility properties. CEA(Ab)-MSNs-ICG-Pt exhibits significant promise due to its ability to selectively target tumors through NIR fluorescence imaging and effectively eradicate CRC cells with minimal adverse effects in both laboratory and in vivo environments. CONCLUSION: The favorable characteristics of CEA(Ab)-MSNs-ICG-Pt offer opportunities for its application in chemotherapeutic interventions, tumor-specific NIR fluorescence imaging, and fluorescence-guided surgical procedures.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

Greenhouse Gas Emissions during Oil Shale Crushing and Its Main Controlling Factors: A Contrast Study of Oil Shale in Yaojie and Fushun Areas, China.

Geological bodies are important sources of greenhouse gas (GHG) emissions. Organic-rich oil shale in sedimentary basins is a good gas source rock, the GHG in which will be released into the atmosphere during crushing to affect climate change. Quantitative calculations of GHG emissions during oil shale crushing were carried out on oil shales from the Yaojie (YJ) and Fushun (FS) mining areas in China. Organic geochemistry, X-ray diffraction, and pore structure analysis experiments, as well as the relationship between storage time and GHG emissions, were analyzed to investigate the main controlling factors of GHG release in different types of oil shales. The results showed that the CH4 and CO2 released from the YJ oil shale were 0.002-0.145 mL/g and 0.011-0.054 mL/g, respectively; the CH4 and CO2 released from the FS oil shale were 0.0001-0.0008 mL/g and 0.002-0.045 mL/g, respectively. Residual CH4 release was closely related to total organic carbon (TOC) and maturity: the CH4 released from the organic-rich and mature YJ oil shale was much higher than that of the FS oil shale, which is relatively organic-lean and immature. The control factors of the released CO2 vary in different regions: CO2 released from the YJ oil shale was somewhat affected by the TOC, while that released from the FS oil shale was mainly controlled by carbonate minerals and their contributing pores. The results of pore structure and organic maceral analyses indicated that both organic and inorganic pores of the YJ oil shale are occupied by asphaltenes, forming a key gas preservation mechanism of residual CH4 and CO2 as solutes dissolved in asphaltenes. In addition, CO2 has a greater absorptive capacity than CH4 and is therefore more difficult to release during the same crushing time. As oil shale is stored for longer periods, residual CH4 will be preferentially released to the atmosphere, while residual CO2 will be released in large quantities during crushing.

Does gastric stump cancer really differ from primary proximal gastric cancer? A multicentre, propensity score matching-used, retrospective cohort study.

BACKGROUND: Although the location of proximal cancer of the remnant stomach is the same as that of primary proximal cancer of the stomach, its clinical characteristics and prognosis are still controversial. AIM: To evaluate the clinicopathological features and prognosis factors of gastric stump cancer (GSC) and primary proximal gastric cancer (PGC). METHODS: From January, 2005 to December, 2016, 178 patients with GSC and 957 cases with PGC who received surgical treatment were enrolled. Patients in both groups underwent 1:1 propensity score matching analysis, and both clinical and pathological data were systematically collected for statistical purposes. Quality of life was evaluated by the C30 and STO22 scale between GSC-malignant (GSC following gastric cancer) and GSC-benign (GSC following benign lesions of the stomach). RESULTS: One hundred and fifty-two pairs were successfully matched after propensity score matching analysis. Of the 15 demographic and pathological variables collected, the analysis further revealed that the number of lymph nodes and positive lymph nodes were different prognostic and clinicopathological factors between PGC and GSC. Univariate and multivariate analyses showed that gender, differentiation degree and tumor-node-metastasis stage were independent risk factors for patients with GSC. Gender, vascular invasion, differentiation degree, depth of infiltration, positive lymph nodes, and tumor-node-metastasis stage were independent risk factors for patients with PGC. The 5-year overall survival and cancer-specific survival of patients with GSC were significantly lower than those in the PGC group, the scores for overall quality of life in the GSC-malignant group were lower than the GSC-benign, and the differences were statistically significant. CONCLUSION: The differences in clinicopathological characteristics between GSC and PGC were clarified, and PGC had a better prognosis than GSC.

Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20(S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents.

A series of heterocyclic ring-fused derivatives of 20(S)-protopanaxadiol (PPD) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these compounds, 33 (SH491, IC50 = 11.8 nM) showed the highest potency with 100% inhibition at 0.1 µM and 44.4% inhibition at an even lower concentration of 0.01 µM, which was much more potent than the lead compound PPD (IC50 = 10.3 µM). Cytotoxicity tests indicated that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation was not due to their cytotoxicity. Interestingly, SH491 also exhibited a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. Mechanistic studies revealed that SH491 inhibits the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, CTSK, MMP-9, and ATPase v0d2. In vivo, SH491 could dramatically decrease the ovariectomy-induced osteoclast activity and relieve osteoporosis obviously. Thus, these PPD derivatives could be served as promising leads for the development of novel antiosteoporosis agents.

Nasogastric tube feeding improves nutritional status and physical state in esophageal cancer patients during chemoradiotherapy: a retrospective study.

OBJECTIVE: To compare the complication rates, nutritional status, and physical state between esophageal cancer (EC) patients managed by nasogastric tube (NGT) feeding versus those managed by oral nutritional supplementation (ONS) during chemoradiotherapy. METHODS: EC patients undergoing chemoradiotherapy managed by nonintravenous nutritional support in our institute were retrospectively recruited and divided into an NGT group and an ONS group based on the nutritional support method. The main outcomes, including complications, nutritional status, and physical state, were compared between groups. RESULTS: The baseline characteristics of EC patients were comparable. There were no significant differences in the incidence of treatment interruption (13.04% vs. 14.71%, P = 0.82), death (2.17% vs. 0.00%, P = 0.84), or esophageal fistula (2.17% vs. 1.47%, P = 1.00) between the NGT group and ONS group. Body weight loss and decrease in albumin level were significantly lower in the NGT group than in the ONS group (both P < 0.05). EC patients in the NGT group had significantly lower Nutritional Risk Screening 2002 (NRS2002) and Patient-Generated Subjective Global Assessment (PG-SGA) scores and significantly higher Karnofsky Performance Status (KPS) scores than patients in the ONS group (all P < 0.05). The rates of grade > 2 esophagitis (10.00% vs. 27.59%, P = 0.03) and grade > 2 bone marrow suppression (10.00% vs. 32.76%, P = 0.01) were significantly lower in the NGT group than in the ONS group. There were no significant differences in the incidence of infection and upper gastrointestinal disorders or therapeutic efficacy between groups (all P > 0.05). CONCLUSIONS: EN through NGT feeding leads to significantly better nutritional status and physical state in EC patients during chemoradiotherapy than EN via ONS. NGT may also prevent myelosuppression and esophagitis..

Multidisciplinary nutritional management improves nutritional and hospitalized outcomes of patients with esophageal cancer undergoing chemoradiotherapy: A randomized control trial.

BACKGROUND: This study aimed to investigate the effects of multidisciplinary whole-course nutrition management on the nutritional status and complications during the course of treatment in patients with esophageal cancer (EC) undergoing chemoradiotherapy. METHODS: A total of 36 EC patients undergoing chemoradiotherapy were divided into a control group (n = 18) and an intervention group (n = 18). Participants in the control group were given routine nutritional support, whereas those in the intervention group were provided whole-course nutrition management from the nutrition support team. Nutrition-related indicators, that is, serum albumin level (ALB), hemoglobin (Hb), and C reactive protein were assessed before, during, and after treatment in both groups. The incidence of complications (e.g., lymphocytopenia, radiation esophagitis, and myelosuppression), clinical outcomes, length of hospital stay, and hospital costs were also recorded. Differences between the 2 groups were tested using the Mann-Whitney U and chi-square tests. RESULTS: The ALB and Hb levels of the patients in the control group decreased significantly [ALB: -2.6 (-5.6, 0), P = .01; Hb: -12.0 (-27.0, -2.0), P = .04] and C reactive protein increased [8.9 (2.9, 14.9), P = .02] compared to those before treatment, while the indicators of participants in the intervention group did not change (P > .05). The incidence of grade ≥ II lymphocytopenia was higher in the control group than that in the intervention group (33.3% vs 61.1%, P = .03). Moreover, compared with the control group, the average length of hospital stay decreased by 12 days [47 (40, 50) vs 35 (23, 40), P = .001], and in-patient expenses decreased by 20,504 CNY in the intervention group (P = .004). CONCLUSION: Multidisciplinary whole-course nutrition management can maintain the nutritional status of patients with EC undergoing chemoradiotherapy. This may lower the incidence of complications, shorten hospital stays, and reduce in-patient expenses.

Tumor Immunophenotyping-Derived Signature Identifies Prognosis and Neoadjuvant Immunotherapeutic Responsiveness in Gastric Cancer.

The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype-related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG-3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in-house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune-activated, and IPSHigh is immune-silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti-PD-1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

The associations between lipid profiles and visceral obesity among gastrointestinal cancer patients: a cross-sectional study.

BACKGROUND: Visceral obesity is associated with cancer incidence and prognosis. Altered lipid profiles are frequently seen in visceral obese patients. The blood test of lipid profiles is more convenient and has no radical side effects than computed tomography (CT), which is presently the most accurate way to measure visceral fat area. This article aims to investigate the associations between lipid profiles and visceral obesity in gastrointestinal cancer patients. METHODS: In total, 399 patients newly diagnosed with gastrointestinal cancer were enrolled in this observational study. Lipid profiles were obtained from blood samples, and visceral fat mass area (VFA) was measured by CT. VFA ≥ 100 cm2 was considered visceral obesity. The area under the receiver operating characteristic curve (AUROC) was utilized to evaluate the prognostic powers of lipid parameters for viscerally obese gastrointestinal cancer patients. RESULTS: Patients who had visceral obesity had higher triglyceride (TG) levels (1.20 ± 0.60 vs. 0.87 ± 0.57 mmo/L, P < 0.001), total cholesterol (TC) levels (3.57 ± 0.84 vs. 3.40 ± 0.82, P = 0.044), and low-density lipoprotein (LDL-C) levels (2.08 ± 0.66 vs. 1.94 ± 0.66, P = 0.047) and lower high-density lipoprotein (HDL-C) levels (0.88 ± 0.24 vs. 1.00 ± 0.26, P < 0.001) than those in the normal group. TG was positively correlated with VFA (r = 0.299, P < 0.001), while HDL-C was inversely correlated with VFA (r = -0.237, P < 0.001). TG and HDL-C had predictive capacity for visceral obesity at cutoff levels of 0.92 mmol/L (AUROC 0.700, 95% CI, 0.653-0.745, P < 0.001) and 0.98 mmol/L (AUROC 0.700, 95% CI, 0.585-0.682, P < 0.001), respectively. TG > 0.92 mmol/L with HDL-C < 0.98 mmol/L was linked with an increased risk of visceral obesity (OR = 4.068, 95% CI, 2.338-7.079, P < 0.001). CONCLUSIONS: Lipid profiles were significantly correlated with VFA. Gastrointestinal cancer patients with TG > 0.92 mmol/L and HDL-C < 0.98 mmol/L were at elevated risk of visceral obesity in the Chinese population. Identifying visceral obesity and taking proper actions in gastrointestinal cancers are helpful for overall tumor prognosis.

Impact of Nutrition Counseling in Head and Neck Cancer Sufferers Undergoing Antineoplastic Therapy: A Randomized Controlled Pilot Study.

Head and neck cancer (HNC) sufferers usually encounter arduous nutritional problems when they are receiving antineoplastic therapy. Consequently, the presence of anxiety and depression is commonly observed in this population. This study aimed to explore the physical and psychological influence of nutritional counseling in patients with HNC. Patients receiving concurrent chemo-radiotherapy were randomly assigned to the nutritional counseling group (n = 32, 52.45%) and the control group (n = 29, 47.54%) according to their treatment patterns. In the nutritional counseling group, registered dietitians provided face-to-face counseling during the antineoplastic treatment course at least every two weeks. Nutrient intake amount, relevant nutritional indexes, quality of life, and the degree of anxiety and depression were compared between the two groups. We observed a decrease in the calorie and protein intake amount in both groups, while the decrease in the control group is even worse. The weight loss is more obvious in the control group. The HADS scores in the intervention group were significantly lower than that in the control group (p < 0.05). The Karnofsky Performance Status (KPS) scores in the intervention group were significantly higher than that in the control group (p < 0.05). The level of serum total protein, serum albumin, transferrin, and the thickness of the triceps skin fold decreased less in the intervention group (p < 0.05). Our findings suggest that nutrition counseling is essential for the maintenance of calorie and protein intake in HNC suffers, which contributes to an improvement in the physical and psychological states. The impacts observed in this pilot study warrant further exploration in a larger prospective trial.

Overexpression of PsnSuSy1, 2 genes enhances secondary cell wall thickening, vegetative growth, and mechanical strength in transgenic tobacco.

KEY MESSAGE: Two homologs PsnSuSy1 and PsnSuSy2 from poplar played largely similar but little distinct roles in modulating sink strength, accelerating vegetative growth and modifying secondary growth of plant. Co-overexpression of them together resulted in small but perceptible additive effects. Sucrose synthase (SuSy) acts as a crucial determinant of sink strength by controlling the conversion of sucrose into UDP-glucose, which is not only the sole precursor for cellulose biosynthesis but also an extracellular signaling molecule for plants growth. Therefore, modification of SuSy activity in plants is of utmost importance. We have isolated two SuSy genes from poplar, PsnSuSy1 and PsnSuSy2, which were preferentially expressed in secondary xylem/phloem. To investigate their functions, T2 tobacco transgenic lines of PsnSuSy1 and PsnSuSy2 were generated and then crossed to generate PsnSuSy1/PsnSuSy2 dual overexpression transgenic lines. SuSy activities in all lines were significantly increased though PsnSuSy1/PsnSuSy2 lines only exhibited slightly higher SuSy activities than either PsnSuSy1 or PsnSuSy2 lines. The significantly increased fructose and glucose, engendered by augmented SuSy activities, caused the alternations of many physiological, biochemical measures and phenotypic traits that include accelerated vegetative growth, thickened secondary cell wall, and increased stem breaking force, accompanied with altered expression levels of related pathway genes. The correlation relationships between SuSy activities and many of these traits were statistically significant. However, differences of almost all traits among three types of transgenic lines were insignificant. These findings clearly demonstrated that PsnSuSy1 and PsnSuSy2 had similar but little distinct functions and insubstantial additive effects on modulating sink strength and affecting allocation of carbon elements among secondary cell wall components.

[Progress on diagnosis and treatment of the terrible triad of elbow joint].

The terrible triad of elbow is a kind of complex elbow fracture dislocation, after reduction, it should get a concentric circles joint reduction and elbow stability, if radial and coronoid process fractures is less piece, the conservative treatment can be performed, but regularly follow up is mandatory. If surgical treatment was chosen, radial head fractures and the lateral collateral ligament complex must be repaired. Single lateral approach can be used and also can be combined with anteromedial approach in surgery. Some problems are still controversial in the treatment of coronoid process fracture with Morry type I and type II, such as fixation or not, whether additional external fixation and repair of the medial collateral ligament injury at the same time.

[Clinical effect of one-stage arthroscopically assisted repair and reconstruction for posterolateral dislocation of knee joint with multiple ligament injuries].

OBJECTIVE: To evaluate clinical outcomes of anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstruction under arthroscopy and repair of the injured posteromedial complex structure of the knee joint in the treatment of posterolateral knee dislocation with multiple ligament injuries. METHODS: From March 2008 to August 2012,22 patients (16 males and 6 females, ranging in age from 20 to 53 years old, with an average of 30.5 years old) with posterolateral dislocation of the knee were treated with primary reconstruction of ACL and PCL, combined with the repair of injuries in the posteromedial complex and soft-tissue. Eight patients had injuries caused by sports,5 patients road accidents and 9 patients falling down. The ACL was reconstructed using the gracilis and semitendinosus tendons. The PCL was reconstructed using LARS artificial ligaments (14 cases), or gracilis and semitendinosus tendons (8 cases). Suture repair was performed in 17 patients with posteromedial ligament injuries,and self-semitendinosus strengthening operations were performed in 5 patients. Continuouspassive montion (CPM) and active exercises were executed after operation at early stage. The IKDC and Lysholm system were used to evaluate therapeutic effects. RESULTS: All the patients were regularly followed up, and the duration ranged from 11 to 56 months (averaged, 39 months). According to the IKDC scale,9 patients got a grade A result, 10 got a grade B result, and 3 got a grade C result. The IKDC subject score was 89.6±3.1 and the Lysholm scores was 90.7±1.8 at the latest follow-up, which were both better than those before operation. CONCLUSION: Reconstructing the ACL and PCL and repairing injured posteromedial complex of the knee followed by an active rehabilitation is an effective method to treat posterolateral knee dislocation.

Characterization and structural analysis of human selenium-dependent glutathione peroxidase 4 mutant expressed in Escherichia coli.

Glutathione peroxidase 4 (GPx4) is a monomeric selenium-dependent glutathione peroxidase highly expressed in mammalian cells, which can reduce phospholipid hydroperoxides. However, it has been difficult to express recombinant mammalian GPx4 in Escherichia coli because of the differences in the selenocysteine (Sec) incorporation machinery between eukaryotes and prokaryotes. In this study, an E. coli BL21(DE3)cys auxotrophic strain was used to express GPx4 mutants. We found that untargeted substitution of Cys-2, Cys-37, Cys-75, Cys-107, and Cys-148 with Sec led to loss of activity, suggesting that mutation of any of these Cys residues in GPx4 could result in a structural change. Additionally, we found that the catalytic activity of GPx4 mutants increased as the number of noncatalytic Sec residues decreased, indicating that the negative effects could be mitigated by replacing these Cys residues with Ser residues. A GPx4 mutant with all Cys residues converted to Ser exhibited a "Ping-Pong" mechanism and structure similar to that of native GPx4, indicating that it could act as a substitute for GPx4, when heterologously expressing the protein in E. coli. This research provides an important foundation for biosynthesis of selenium-dependent GPx4 mutants in E. coli.

Poly(L-glutamic acid)-decorated hybrid colloidal particles from complex particle-templated silica mineralization.

We report the synthesis of polyelectrolyte complex (PEC) particles by mixing the negatively and positively charged polyelectrolytes, poly(L-glutamic acid) (PGA) and poly(2-(N,N-diethylamino) ethylmethacrylate) (PDEAEMA), and the use of negatively charged PEC particles as colloidal templates for silica mineralization under ambient conditions. The structure and property of PEC particles, as well as polypeptide chain conformation, were found to depend on the mixing weight percentage, polymer molecular weight, and solution condition. The negatively charged PEC micelles can be deposited with silica without loss colloid stability, leading to PGA-decorated hybrid particles. These hybrid particles were negatively charged at neutral and basic condition and become positively charged, accompanying the conformational changes of the grafted PGA, upon decreasing pH below isoelectric points due to the protonation/deprotonation of PGA and PDEAEMA. Functional nanoparticles such as gold NPs could be incorporated using polypeptides as the mediating agents. These hybrid particles loaded with drug exhibited noticeable pH-responsive behavior with accelerated release at acidic condition, demonstrating the potential for use as pH-responsive delivery vehicles. This type of polypeptide-decorated hybrid particles represents an interesting class of organic-inorganic hybrids in which the functional properties of polypeptides such as biocompatibility, stimuli responsiveness, and directed growth of metal nanoparticles can be incorporated.