Association between the Lymphocyte-to-C-Reactive Protein Ratio and Survival Outcomes in Cancer Patients with GLIM-Defined Malnutrition: A Multicenter Study.

BACKGROUND AND AIMS: This study assessed the prognostic value of LCR in patients with cancer-associated malnutrition (CAM). Systemic inflammatory markers, particularly the lymphocyte-to-C-reactive protein ratio (LCR), are related to the survival of patients with CAM. The present retrospective analysis based on a prospective multicenter cohort study, which involved 1,437 hospitalized patients with CAM. METHODS: The area under the receiver operating characteristic curve (AUC) of ten inflammatory indicators-LCR, advanced lung cancer inflammation index, neutrophil-to-lymphocyte ratio, prognostic nutritional index, modified Glasgow prognostic score, systemic immune-inflammation index, albumin-to-globulin ratio, LCR score, glucose-to-lymphocyte ratio, and platelet-to-lymphocyte ratio-were constructed. Nutritional status, blood markers, and quality of life (QoL) were evaluated within 48 h of admission. The overall survival (OS) was evaluated from September 1 to December 29, 2021. RESULTS: A total of 1,431 cancer patients diagnosed with malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria. Male patients were 62.8% of all, and the mean age was 60.66 years old. The AUC of LCR was higher than that of other inflammatory markers. The restricted cubic spline (RCS) of the Hazard ratios (HRs) showed an inverse L-shaped relationship with LCR. In addition, patients with low LCR had significantly poorer OS than those with high LCR. The addition of LCR to the model increased the predictive ability of 1-year mortality (AUC increase of 0.036), 3-year mortality (AUC increase of 0.038), and 5-year mortality (AUC increase of 0.031). CONCLUSIONS: Assessing the LCR can help the medical staff identify cancer patients with nutritional deficiency at high risk of oncological outcomes and develop individualized therapeutic strategies.

[Prospective study on the analysis of intestinal microflora changes and prediction on metabolic function in severe burn patients at early stage by 16S ribosomal RNA high-throughput sequencing].

Objective: To analyze the changes of intestinal microflora and to predict the metabolic function of intestinal microflora in severe burn patients at early stage by 16S ribosomal RNA (rRNA) high-throughput sequencing. Methods: In this prospective observational study, 48 patients with severe burns who met the inclusion criteria were admitted to Department of Burns and Plastic Surgery of Affiliated Hospital of Jiangsu University from January 2018 to December 2019 were included in burn group, and 40 healthy volunteers who met the inclusion criteria and underwent physical examination at the Physical Examination Center of Affiliated Hospital of Jiangsu University in the same period were included in healthy group. Fecal samples were collected from patients in burn group in about 1 week after admission and from volunteers in healthy group on the day of physical examination. The 16S rRNA V4 gene sequencing was performed in the feces of patients in burn group and volunteers in healthy group to analyze the relative abundance of various bacteria. The operational classification unit (OTU) was divided by Mothur software to analyze the dominant bacteria. The OTU number, Chao1 index, Ace index, and Shannon index of fecal microflora were analyzed by QIIME1.9.0 software. The principal component analysis for relative abundance of fecal microflora was performed by Canoco Software 5.0. The metabolic function of fecal microflora was predicted by Kyoto Encyclopedia of Genes and Genomes. Data were statistically analyzed with independent sample t test, and Mann-Whitney U test, and Bonferroni correction. Results: The relative abundance of Bacteroides, Enterococcus, Acinetobacter, Macrococcus, and Staphylococcus in feces of patients in burn group was significantly higher than that of volunteers in healthy group (Z=-5.20, -2.37, -5.17, -4.41, -6.03, P<0.05 or P<0.01), and the relative abundance of unclassified-Helicobacillae, Prevotella, Cecobacteria, unclassified-Rumencocci, Pseudobutyrivibrio, Brautia, and unclassified-Digiestive Streptococcaceae (Z=-8.03, -3.21, -7.63, -5.88, -8.05, -8.05, -6.77, P<0.01) and other 12 species of bacteria in the feces of volunteers in healthy group was significantly higher than that of patients in burn group. The diversity of fecal microflora of volunteers in healthy group was better than that of patients in burn group, the main dominant microflora of volunteers in healthy group were Bacteroides, unclassified-Helicobacillae, Prevotella, unclassified- Enterobacteriaceae, Brautia, Parabacteroides, Escherichia coli, etc., and the main dominant microflora of patients in burn group were Bacteroides, Prevotella, unclassified-Enterobacteriaceae, and Parabacteroides. The OTU number, Ace index, Chao1 index, and Shannon index of fecal microflora of patients in burn group were 149±47, 199±45, 190±45, 2.0±0.9, which were significantly lower than 266±57, 323±51, 318±51, 3.8±0.5 of volunteers in healthy group (t=10.325, 11.972, 12.224, 11.662, P<0.01). The relative abundance of fecal microflora of patients in burn group and volunteers in healthy group was clearly divided into two groups by principal component 1, and the contribution rate of principal component 1 was 32.50%, P<0.01. The fecal microflora of volunteers in healthy group were more concentrated on principal component 2, the fecal microflora of patients in burn group were dispersed in principal component 2, and the contribution rate of principal component 2 was 13.44%, P>0.05. The metabolic levels of alanine-aspartate-glutamate, arginine- proline, cysteine-methionine, glycine-serine-threonine, phenylalanine, tryptophan, and tyrosine in amino acid, tricarboxylic acid cycle, glucose and mannose, galactolipin, glycolysis/gluconiogenesis, starch and sucrose in carbohydrate of fecal microflora of patients in burn group were significantly lower than those of volunteers in healthy group (Z=-4.75, -4.54, -4.75, -4.62, -3.71, -3.28, -4.19, -3.82, -4.72, -4.35, -4.75, -4.71, P<0.01). The levels of lipoic acid metabolism and coenzyme Q synthesis of fecal microflora of patients in burn group were significantly higher than those of volunteers in healthy group (Z=-6.07, -4.51, P<0.01). The metabolic level of arachidonic acid of fecal microflora of patients in burn group was similar to that of volunteers in healthy group (P>0.05). Conclusions: There are significant differences in intestinal microflora between severe burn patients at the early stage and healthy people, and the species and diversity of microflora are decreased, and the nutrient metabolism level is decreased in burn patients by 16S rRNA high-throughput sequencing.

Comparative study on the effect of Y content on grain refinement in the simulated coarse-grained heat-affected zone of X70 pipeline steels.

This study aims to investigate the influence of Y content on grain refinement in the simulated coarse-grained heat-affected zone (CGHAZ) of X70 pipeline steels. The results explored that two different grain refinement mechanisms were presented in 0.034 wt.%-Y and 0.075 wt.%-Y steels, respectively. The Y2O2S inclusions and YP precipitates are formed in 0.034 wt.%-Y steel instead of the YP inclusions and more YP precipitates in 0.075 wt.%-Y steel. The grain refinement mechanism in the simulated CGHAZ of 0.034 wt.%-Y steel mainly depends on the formation of acicular ferrite induced by Y2O2S inclusion. Whereas, the grain refinement mechanism in the simulated CGHAZ of 0.075 wt.%-Y steel primarily relies on the austenite boundary pinning effect by higher density of YP precipitates.

[Effects of endotoxin/lipopolysaccharide on early apoptosis of human neutrophil through PIM3].

Objective: To explore the effects of endotoxin/lipopolysaccharide (LPS) on early apoptosis of human neutrophil through PIM3. Methods: Venous blood samples were collected from a healthy adult volunteer to isolate neutrophils. The neutrophils were divided into control group, LPS group, and LPS+ PIM447 group according to the random number table. No treatment was given to the cells in control group. The cells in LPS group underwent LPS stimulation (1 µL, 1 µg/mL). The cells in LPS+ PIM447 group underwent PIM447 (1 µL, final amount-of-substance concentration of 5 µmol/L) intervention 30 min before having the same LPS stimulation as that in LPS group. After conventional culture for 1 h, the early cell apoptosis rate was determined with flow cytometer; the generation level of reactive oxygen species (ROS) was assessed with dihydrogenrhodamine 123 fluorescent probe staining method; and the level of PIM3 was detected by Western blotting. After conventional culture for 2 h, the cell chemotaxis distance was measured by agarose chemotaxis cell model. The sample numbers of each group in the 4 experiments were all 5. Data were processed with one-way analysis of variance and Student-Newman-Keuls test. Results: (1) The early apoptosis rate of cells in LPS group [(0.891±0.012)%] was close to that in control group [(1.351±0.183)%, P>0.05)]. The early apoptosis rate of cells in LPS+ PIM447 group [(82.057±0.121)%] was higher than that in LPS group (P<0.01). (2) The cell chemotaxis distance of cells in LPS group [(984±5) µm] was significantly shorter than that in control group [(2 241±7) µm, P<0.01]. The cell chemotaxis distance of cells in LPS+ PIM447 group [(1 785±11) µm]was significantly longer than that in LPS group (P<0.05). (3) The generation level of ROS in cells of LPS group was significantly higher than that in control group (P<0.05). The generation level of ROS in cells of LPS+ PIM447 group was significantly lower than that in LPS group (P<0.05). (4) The expression level of PIM3 in cells of LPS group (1.297±0.015) was significantly higher than that in control group (0.789±0.021, P<0.05). The expression level of PIM3 in cells of LPS+ PIM447 group (0.731±0.011) was significantly lower than that in LPS group (P<0.05). Conclusions: LPS stimulation can reduce the early apoptosis of human neutrophils. Pre-intervention with PIM447 can significantly increase the early apoptosis of neutrophils after LPS stimulation, recover the chemotaxis, and inhibit the production of ROS. The mechanism may be related to LPS promoting the expression of PIM3.

[The progress of studies on aqueous humor dynamics abnormality induced by trabecular meshwork and Schlemm canal endothelial cell senescence and its relation with glaucoma].

Glaucoma is the second leading cause of blindness in the world next to cataract. Aging is a strong risk factor leading to elevated intraocular pressure (IOP). IOP is associated with aqueous humor circulation. Trabecular meshwork cells and Schlemm canal endothelial cells, which form the conventional outflow pathway, play an important role in maintaining the IOP. Cell senescence induces abnormalities of the aqueous humor dynamics, leading to elevated IOP. Trabecular meshwork cells cause increased intrinsic stiffness, autophagy dysfunction, abnormal expression of microRNA and mitochondrial dysfunction with senescence. The senescence of Schlemm canal endothelial cells decreases cell permeability and mechanotransduction and disrupts the endothelial nitric oxide synthase signaling pathway. The changes will increase aqueous humor outflow resistance and elevate IOP. This review discusses how cell senescence induces aqueous humor dynamics abnormalities and the relation with glaucoma. (Chin J Ophthalmol, 2017, 53: 868-873).

Effect of phospholipid composition on characterization of liposomes containing 9-nitrocamptothecin.

9-Nitrocamptothecin (9-NC), a newly developed camptothecin derivative, had poor solubility in any pharmaceutically acceptable solvents. One way of improving the solubility is to formulate the drug into liposomes. However, 9-NC has low affinity to lipid membranes resulting in a very low drug-to-liposome entrapment. We developed a novel liposome-based 9-NC formulation which was composed of soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), and cholesterol. Compared with conventional liposomes composed of only SPC and cholesterol, 9-NC/lipid molar ratio increased from 1:72 to 1:18 while incorporation efficiency was still maintained about 80%. In addition, after 9-NC was encapsulated into novel liposomes, pharmacokinetic results revealed an increase in area under the plasma concentration-time curve (AUC) and a decrease in distribution volume of 9-NC following intravenous administration to rats. Increased stability in plasma may account for the improved pharmacokinetic behavior of the novel liposomes. Effect of HSPC/SPC molar ratio on characterization of the novel liposomes was also investigated. Except for drug/lipid molar ratio and encapsulation efficiency, HSPC/SPC molar ratio had only a little effect on other properties of novel liposomes. In conclusion, the study suggests that the novel liposomes can act as promising carriers for hydrophobic substances such as 9-NC.

Comparison of K-ras point mutations at codon 12 and p21 expression in pancreatic cancer between Japanese and Chinese patients.

BACKGROUND AND OBJECTIVES: K-ras (Kirsten-ras) point mutation (PM) in codon 12 are suggested to be significantly associated with the tumorigenesis of pancreatic cancer. The incidences of K-ras PMs in human pancreatic cancer are reported to be different between Europeans and Japanese. The present study was designed to compare the incidences and profile of K-ras PMs and ras-p21 expression in primary invasive ductal carcinoma (IDC) of the pancreas between Japanese and Chinese. METHODS: The specimens included 51 Japanese and 34 Chinese patients with the primary IDC of the pancreas. K-ras PMs were tested by allele specific oligonucleotide dot blot hybridization methods and ras-p21 expression was stained by the immunohistochemical method. RESULTS: K-ras PMs were detected in 48 Japanese IDCs (94%) and in 24 Chinese ones (71%). There was a significant difference between the two groups. The GAT mutation was more frequent both in Japanese (61%, 33/54) and in Chinese (60%, 18/30) IDCs. The transitions/transversions ratio in the Japanese group was 2.4 in this study. By contrast, that in the Chinese group was 1.5. The expression of p21 was detected in 24 Japanese IDCs (47%) and in 24 Chinese IDCs (71%). There was a significant difference between the two groups. The expression of p21 and the patterns of K-ras PMs did not show any significant influence on the survival of the patients both in Japanese and Chinese. In the present study, Chinese IDC had a lower frequency of K-ras PMs in codon 12 than Japanese IDC. The pattern of K-ras PMs in Chinese IDC was different from that in Japanese and European IDC, respectively. CONCLUSIONS: Ki-ras PM and p21 expression were frequently seen both in Japanese and Chinese patients with pancreatic cancer. Factors such as lifestyle and environment may have influences on pancreatic carcinogenesis in various populations.

Ki-ras point mutation and p53 expression in human pancreatic cancer: a comparative study among Chinese, Japanese, and Western patients.

The aim of this study was to clarify features of Ki-ras point mutation (PM) and p53 expression in Chinese pancreatic cancer and to compare those with that in other countries. Dot blot hybridization and immunohistochemical methods were performed in 59 Chinese patients. The results showed that Ki-ras PMs at codon 12 and p53 expression were frequent in this group. No relationships were found between Ki-ras PM alone and p53 expression alone, and clinicopathological parameters, including age, gender, clinical stage, and histological grade and classification in Chinese patients. However, their cooperation was significantly associated with a poor prognosis in this group. Comparison showed that there were significant differences in the overall frequency and substitution of Ki-ras PM and in the ratio of transition:transversion in pancreatic cancer among various countries. In addition, the effect of Ki-ras PM and p53 expression on a poor prognosis of pancreatic cancer may be different among various countries. These findings suggested that not only Ki-ras PM and p53 expression are frequent in Chinese pancreatic cancer, but also a gene component to pancreatic cancer may be different between Asian and Western pancreatic cancer. In addition, it seems that cooperation of Ki-ras PM and p53 expression may predict a poor prognosis in Chinese patients with pancreatic cancer.

The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities.

The suppressor of cytokine signaling (SOCS) proteins are a family of cytokine-inducible negative regulators of cytokine signaling. Interferon (IFN)-gamma treatment induces the expression of SOCS1, SOCS2, and SOCS3 mRNAs. To examine the effect of SOCS proteins on IFN-mediated Janus-activated kinase/signal transducers and activators of transcription (STAT) signaling, HeLa- and MCF-7-derived stable cell lines expressing SOCS1, SOCS2, and SOCS3 proteins were established. SOCS1 and SOCS3 but not SOCS2 inhibited the tyrosine phosphorylation and nuclear translocation of STAT1 in response to IFN stimulation. The IFN-mediated antiviral and antiproliferative activities were consistently blocked by the constitutive expression of SOCS1 and SOCS3 but not SOCS2 proteins. The maximum inhibitory activities of SOCS1 and SOCS3 proteins toward the activation of STAT1 were observed at very low levels of SOCS protein expression. In addition, SOCS1 exhibited a much stronger inhibitory activity toward the activation of STAT1 than did SOCS3. These results suggest that SOCS1 and SOCS3 but not SOCS2 are inhibitors of IFN-mediated Janus-activated kinase/STAT signaling pathways.

Comparative study of p53 expression in primary invasive ductal carcinoma of the pancreas between Chinese and Japanese.

Previous studies reported different frequencies of p53 expression between Japanese and Americans or Europeans. The present study was designed to clarify whether there is a significant difference in p53 expression and its clinical implications between Chinese and Japanese patients with primary invasive ductal carcinoma (IDC) of the pancreas. p53 expression was studied in 39 Chinese and 47 Japanese patients, and immunostaining with the SAB method was performed using anti-p53 monoclonal antibody (DO-1) in formalin-fixed and paraffin-embedded specimens. Clinical data were analyzed according to the International Union Against Cancer classification. p53 expression was seen in 71.8% of Chinese and in 48.9% of Japanese patients with IDCs of the pancreas (p < 0.05). The Chinese patients were significantly younger than the Japanese ones (p < 0.05), but there were no significant correlations between p53 immunoreactivity and age, gender, stage, and histopathological grade in separate analyses of the Chinese and Japanese patients. A comparison between them showed that in patients younger than 55 and 65 years old, the incidence of p53 expression was markedly lower in Japanese than in Chinese (p < 0.05). In Japanese patients, those with a p53-positive pancreatic cancer had a significantly lower survival rate than those with a p53-negative tumor, but there was no correlation between p53 expression and the prognosis of Chinese patients. The frequency of p53 expression in IDC of the pancreas is higher in Chinese than in Japanese patients, and the effect of p53 expression on prognosis is different between Chinese and Japanese patients.

p53 protein expression as prognostic factor in human pancreatic cancer.

Mutations in the p53 tumor suppressor gene are considered to play an important role in the carcinogenesis of pancreatic cancer. The present study was designed to assess the clinicopathological significance of the expression of p53 protein in human pancreatic cancer. A total of 64 specimens of pancreatic cancer (44 primary and 20 metastatic lesions) were obtained by surgery in our department between 1982 and 1995, and p53 protein was stained using an immunohistochemical staining method (strepto-avidin-biotin complex method) with 2 kinds of anti-p53 monoclonal antibodies (DO-1 and PAb240). DO-1-p53 was usually stained in the nucleus of cancer cells and was positively expressed in 35 out of 64 specimens (54.7%): 21 out of 44 primary lesions (47.7%), and 14 out of 20 metastatic lesions (70.0%). On the other hand, PAb240-p53 was stained in both the nucleus and cytoplasm in 45 out of 64 specimens (70.3%): 33 out of 44 primary lesions (75.0%) and 12 out of 20 metastatic lesions (60.0%). The survival rate of the patients with DO-1-p53 (+) pancreatic cancer after pancreatectomy was significantly lower than that of patients with DO-1-p53 (-) pancreatic cancer. On the other hand, there were no significant implications of PAb240-p53 protein expression on survival after pancreatectomy. With regard to the clinicopathological characteristics, the rate of DO-1-p53 protein expression was significantly higher in elderly patients (> or = 65 y.o.). As a result, DO-1-p53 protein expression may be a beneficial prognostic factor for patients with pancreatic cancer, and it is a factor independent of the stage and other clinicopathological factors.

Clinicopathological significance of epidermal growth factor and its receptor in human pancreatic cancer.

The expression of epidermal growth factor (EGF) and its receptor (EGF-R) was examined immunohistochemically in 60 primary and 26 metastatic lesions of pancreatic carcinoma. EGF was stained mainly in the cytoplasm of tumor cells, and EGF-R was stained mainly on the surface of cells. The expression rates of EGF and EGF-R were 28% and 43% for primary lesions, and 46% and 46% for metastatic lesions, respectively. The expression of EGF and EGF-R alone did not correlate with any clinicopathological factors such as clinical stage, tumor size, nodal involvement, histology, etc. The median survival period after pancreatectomy was 21.4 months for patients with EGF(+) cancers and 25.1 months for those with EGF (-) ones. On the other hand, the median survival period was 22.7 months for patients with EGF-R (+) cancers and 25.0 months for those with EGF-R (-) cancers. There were no significant differences in survival between groups of patients differing in EGF or EGF-R expression. When the expression of EGF and EGF-R was analysed in combination, the survival curve of patients with EGF(+) and EGF-R(+) cancers was found to be lower than that of the rest of the patients (p = 0.07), and especially the survival curve of patients with EGF(+)EGF-R(+) cancers was significantly lower than that of patients with EGF(+)EGF-R(-) cancers (p = 0.02), and EGF(-)EGF-R(+) cancers (p = 0.06). These results indicate that the expression of EGF or EGF-R alone in pancreatic cancer does not reflect the prognosis of patients; however the coexpression of EGF and EGF-R may be a beneficial prognostic factor for pancreatic cancer.

Clinicopathological significance of Ki-ras point mutation and p21 expression in benign and malignant exocrine tumors of the human pancreas.

CONCLUSION: The present study suggests that Ki-ras point mutations may play an important role in the early stages of tumorigenesis and that a double mutation has a stronger detrimental effect than a single mutation on the survival after pancreatectomy. BACKGROUND: Previous studies have suggested the important role of Ki-ras point mutations in ras gene codon 12 in the tumorigenesis of pancreatic cancer, but their clinicopathological significance is still unclear. The present study was designed to assess the clinicopathological significance of Ki-ras point mutations, and p21 expression in malignant and benign diseases of the pancreas. METHODS: Oligonucleotide dot-blot hybridization for Ki-ras point mutations in codon 12 and immunohistochemical staining for p21 expression were applied. Cases included 44 primary and 15 metastatic lesions of pancreatic cancer, and 17 benign pancreatic diseases. RESULTS: Ki-ras point mutations and p21 expression were detected in 43 and 19 primary lesions, 9 and 6 metastatic lesions, and four and five benign diseases, respectively. The patients with a single mutation had a better survival after pancreatectomy than those with a double mutation. The patients with a p21(+) GAT mutation showed the worst survival after pancreatectomy compared with other categories of patients.

Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1.

Gamma interferon (IFN-gamma) signals to the nucleus through the activation, by tyrosine phosphorylation, of the latent cytoplasmic transcription factor Stat1 (signal transducer and activator of transcription). It has been demonstrated that the activity of Stat1 is dependent on tyrosine phosphorylation which is regulated by Jak tyrosine kinases as well as by the as-yet-unidentified protein tyrosine phosphatase. We report that the N-terminal domain of Stat1, which is highly conserved among all STAT family members, is required for its tyrosine dephosphorylation. A single amino acid substitution (Arg-31 to Ala) in the Stat1 N-terminal domain inhibited Stat1 tyrosine dephosphorylation. The deletion of the Stat1 N-terminal domain resulted in a mutant Stat1 protein which was constitutively phosphorylated on Tyr-701. Upon IFN-gamma stimulation, the tyrosine phosphorylation of this mutant protein was further enhanced but was not down-regulated by protein tyrosine phosphatase in vivo. When expressed in NIH 3T3 cells, this mutant protein greatly enhanced the antiproliferative activity of IFN-gamma. We suggest that the N-terminal domains of STATs are crucial for modulating STAT activities through regulating the tyrosine dephosphorylation of STATs.

Age-associated changes in the estrogen receptor-active proteases of female rabbit liver.

Female rabbit liver cytosol contains a receptor-modifying activity that converts the 250,000 estrogen receptor of liver and uterine cytosol to a 37,000 form. There is an age-dependent increase in this receptor-active protease and in the general protease activity of rabbit liver cytosol, measured with [14C]casein. Sephacryl S-200 chromatography of liver cytosol shows that in the young animal (5 weeks old) the major receptor-modifying activity elutes near the void volume, while in the older animal (13 weeks old) activities having lower molecular weights are present. The general protease activity elution profile is similar to the receptor-active protease profile for the 5-week-old rabbit but not the 13-week-old rabbit. The liver cytosol of the older animal has a high molecular weight protease active toward [14C]casein but not toward the estrogen receptor. The changes in the estrogen receptor forms and the receptor-modifying activity profiles of liver cytosol that occur during development in the rabbit suggest that receptor-modifying activity may initially be associated with the estrogen receptor to form a high molecular weight complex.