Clinical outcome and prognostic factors of T4N0M0 colon cancer after R0 resection: A retrospective study.

BACKGROUND: Paradoxically, patients with T4N0M0 (stage II, no lymph node metastasis) colon cancer have a worse prognosis than those with T2N1-2M0 (stage III). However, no previous report has addressed this issue. AIM: To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients. METHODS: Two hundred patients with T4N0M0 colon cancer were treated at Tianjin Medical University General Hospital between January 2017 and December 2021, of which 112 patients were assigned to the training cohort, and the remaining 88 patients were assigned to the validation cohort. Differences between the training and validation groups were analyzed. The training cohort was subjected to multivariate analysis to select prognostic risk factors for T4N0M0 colon cancer, followed by the construction of a nomogram model. RESULTS: The 3-year overall survival (OS) rates were 86.2% and 74.4% for the training and validation cohorts, respectively. Enterostomy (P = 0.000), T stage (P = 0.001), right hemicolon (P = 0.025), irregular review (P = 0.040), and carbohydrate antigen 199 (CA199) (P = 0.011) were independent risk factors of OS in patients with T4N0M0 colon cancer. A nomogram model with good concordance and accuracy was constructed. CONCLUSION: Enterostomy, T stage, right hemicolon, irregular review, and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer. The nomogram model exhibited good agreement and accuracy.

Chemical and Geological Properties of Shale Gas: In Situ Desorption of Lower Cambrian Niutitang Shale in the Micangshan Tectonic Zone of South Shaanxi, China.

Shale gas was recently found in the Lower Cambrian Niutitang Formation (LCNF) of the Micangshan tectonic zone of south Shaanxi (MTZSS), but not in commercial quantities. To determine the laws governing the generation, enrichment, and desorption of shale gases in overmatured shale strata in the LCNF of MTZSS, we carried out in situ desorption experiments on nine shale core samples and got 168 desorbed gas samples at different phases of desorption. Also measured were the chemical and carbon isotopic compositions of these desorbed gas samples and the geochemical parameters of the shale core samples. CH4 was the predominant hydrocarbon shale gas identified in the 82.06-98.48% range, suggesting that the gases were mainly dry. The nonhydrocarbon gases found were CO2 and H2. The CH4 content of the desorbed gas samples dropped continuously during desorption, lowering the dryness index to 98.48 and 92.26% of the first and last desorbed shale gas, respectively. The change in the gas ratio during shale gas desorption proved that the adsorbability of the LCNF to the various gases follows the trend H2 > CO2 > C2H6 > CH4 > He. Further, δ13C2H6 and δ13CH4 become heavier during desorption, showing isotopic fractionation arising from the desorption-diffusion coeffect. As the desorption temperature increases, the value of δ13CH4 increases because 12CH4 is more sensitive to temperature than 13CH4, so it is with the ethane. Similar to the LCNF shale gas in other areas of China, the desorbed shale gases are characteristic of carbon isotope reversal (CIR) (δ13CH4 > δ13C2H6). The cracking of the residual soluble organic matter at the high overmaturity stage mixed with the cracking of kerogen at the early stage of maturation, causing CIR. Furthermore, the desorbed gas content was proportionally and inversely related to the CIR degree and final dryness index of the desorbed gas, respectively. Moreover, the carbon isotope fractionation degree of CH4 and δ13C1 of the last desorbed gas correlated positively with the desorbed gas content and the desorbed time of the gas. In conclusion, the four parameters are effective parameters for identifying shale gas sweet spots.

Identification of differentially expressed miRNAs associated with diamide detoxification pathways in Spodoptera frugiperda.

The fall armyworm (FAW) Spodoptera frugiperda is a severe economic pest of multiple crops globally. Control of this pest is often achieved using insecticides; however, over time, S. frugiperda has developed resistance to new mode of action compounds, including diamides. Previous studies have indicated diamide resistance is a complex developmental process involving multiple detoxification genes. Still, the mechanism underlying the possible involvement of microRNAs in post-transcriptional regulation of resistance has not yet been elucidated. In this study, a global screen of microRNAs (miRNAs) revealed 109 known and 63 novel miRNAs. Nine miRNAs (four known and five novel) were differentially expressed between insecticide-resistant and -susceptible strains. Gene Ontology analysis predicted putative target transcripts of the differentially expressed miRNAs encoding significant genes belonging to detoxification pathways. Additionally, miRNAs are involved in response to diamide exposure, indicating they are probably associated with the detoxification pathway. Thus, this study provides comprehensive evidence for the link between repressed miRNA expression and induced target transcripts that possibly mediate diamide resistance through post-transcriptional regulation. These findings highlight important clues for further research to unravel the roles and mechanisms of miRNAs in conferring diamide resistance.

CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer.

BACKGROUND: There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb). METHODS: We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity. RESULTS: We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs). CONCLUSIONS: We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.

A nomogram to predict the risk of colorectal anastomotic leakage combining inflammatory-nutritional and abdominal aorta calcium index.

Background: Anastomotic leakage is a serious complication after colorectal cancer surgery, which affects the quality of life and the prognosis. This study aims to create a novel nomogram to predict the risk of anastomotic leakage for patients with colorectal cancer based on the preoperative inflammatory-nutritional index and abdominal aorta calcium index. Methods: 292 patients at Tianjin Medical University General Hospital (Tianjin, China) from January 2018 to October 2021 who underwent colorectal cancer surgery with a primary anastomosis were retrospectively reviewed. A nomogram was constructed based on the results of multivariate logistic regression model. The calibration curves and receiver operating characteristic curves were used to verify the efficacy of the nomogram. Results: Univariate and multivariate analyses showed that tumor location (P = 0.002), preoperative albumin (P = 0.006), preoperative lymphocyte (P = 0.035), preoperative neutrophil to lymphocyte ratio (P = 0.024), and superior mesenteric artery calcium volumes score (P = 0.004) were identified as the independent risk factors for postoperative anastomotic leakage in patients with colorectal carcinoma. A nomogram was constructed based on the results of the multivariate analysis, and the C-index of the calibration curves was 0.913 (95%CI: 0.870-0.957) in the training cohort and 0.840 (95%CI: 0.753-0.927) in the validation cohort. Conclusion: The nomogram, combining basic variables, inflammatory-nutritional index and abdominal aorta calcium index, could effectively predict the possibility of postoperative anastomotic leakage for patients with colorectal cancer, which could guide surgeons to carry out the appropriate treatment for the prevention of anastomotic leakage.

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

Construction and Validation of a Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Gastric Cancer.

BACKGROUND: Increasing evidence indicated that the tumor microenvironment (TME) plays a critical role in tumor progression. This study aimed to identify and evaluate mRNA signature involved in lymph node metastasis (LNM) in TME for gastric cancer (GC). METHODS: Gene expression and clinical data were downloaded from The Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was used to evaluate the TME of GC. The heatmap and Venn plots were applied for visualizing and screening out intersect differentially expressed genes (DEGs) involved in LNM in TME. Functional enrichment analysis, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network were also conducted. Furthermore, binary logistic regression analysis were employed to develop a 4-mRNAs signature for the LNM prediction. ROC curves were applied to validate the LNM predictive ability of the riskscore. Nomogram was constructed and calibration curve was plotted to verify the predictive power of nomogram. RESULTS: A total of 88 LNM related DEGs were identified. Functional enrichment analysis and GSEA implied that those genes were associated with some biological processes, such as ion transportation, lipid metabolism and thiolester hydrolase activity. After univariate and multivariate logistic regression analysis, 4 mRNAs (RASSF2, MS4A2, ANKRD33B and ADH1B) were eventually screened out to develop a predictive model. ROC curves manifested the good performance of the 4-mRNAs signature. The proportion of patients with LNM in high-risk group was significantly higher than that in low-risk group. The C-index of nomogram from training and test cohorts were 0.865 and 0.765, and the nomogram was well calibrated. CONCLUSIONS: In general, we identified a 4-mRNAs signature that effectively predicted LNM in GC patients. Moreover, the 4-mRNAs signature and nomogram provide a guidance for the preoperative evaluation and postoperative treatment of GC patients.

DNMT3A-mediated silence in ADAMTS9 expression is restored by RNF180 to inhibit viability and motility in gastric cancer cells.

ADAMTS9 belongs to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family, and its expression is frequently silenced due to promoter hypermethylation in various human cancers. However, the underlying mechanisms remain largely unknown. In this study, we investigated the inhibitory effects of ADAMTS9 on gastric cancer (GC) cells. We initially examined ADAMTS9 protein level in 135 GC and adjacent normal tissue pairs, showing that ADAMTS9 was strikingly decreased in the malignant specimens and patients with low ADAMTS9 expression exhibited more malignant phenotypes and poorer outcome. ADAMTS9 expression was restored in AGS and BGC-823 cells, which then markedly suppressed cellular viability and motility in vitro and in vivo. As ADAMTS9 was enriched in the nuclei of gastric mucosal cells, RNA-sequencing experiment showed that ADAMTS9 significantly altered gene expression profile in BGC-823 cells. Additionally, DNA methyltransferase 3α (DNMT3A) was identified to be responsible for the hypermethylation of ADAMTS9 promoter, and this methyltransferase was ubiquitinated by ring finger protein 180 (RNF180) and then subject to proteasome-mediated degradation. In conclusion, we uncovered RNF180/DNMT3A/ADAMTS9 axis in GC cells and showed how the signaling pathway affected GC cells.

Effects of a high body mass index on the short-term outcomes and prognosis after radical gastrectomy.

PURPOSE: This study aimed to investigate the effects of a high body mass index (BMI) on the outcomes of radical gastrectomy for gastric cancer. METHODS: We conducted a retrospective cohort study of 1729 patients with stage I to III gastric cancer who received open radical gastrectomy from February 2003 to August 2011. The patients were divided into 3 groups according to their BMI: a low BMI group (BMI < 18.5 kg/m2), normal BMI group (18.5 ≤ BMI < 25 kg/m2), and high BMI group (BMI ≥ 25 kg/m2). RESULTS: A total of 871 patients were included in the final analysis, of which the median BMI was 22.7 kg/m2 (range 13.6-44.9 kg/m2). A high BMI increased the risk of postoperative intestinal fistula but not the risk of a reduced number of examined lymph nodes or hospital death. Furthermore, a high BMI did not negatively affect the overall survival (OS) of gastric cancer patients. CONCLUSIONS: A high BMI increased the operative morbidity after radical gastrectomy for gastric cancer. However, a high BMI did not negatively affect the quality of lymphadenectomy or the OS of gastric cancer patients in experienced high-volume centers. A careful approach during operation and meticulous perioperative management are required for gastric cancer patients with a high BMI.

The insulin signaling pathway in Drosophila melanogaster: A nexus revealing an "Achilles' heel" in DDT resistance.

Insecticide resistance is an ongoing challenge in agriculture and disease vector control. Here, we demonstrate a novel strategy to attenuate resistance. We used genomics tools to target fundamental energy-associated pathways and identified a potential "Achilles' heel" for resistance, a resistance-associated protein that, upon inhibition, results in a substantial loss in the resistance phenotype. Specifically, we compared the gene expression profiles and structural variations of the insulin/insulin-like growth factor signaling (IIS) pathway genes in DDT-susceptible (91-C) and -resistant (91-R) Drosophila melanogaster (Drosophila) strains. A total of eight and seven IIS transcripts were up- and down-regulated, respectively, in 91-R compared to 91-C. A total of 114 nonsynonymous mutations were observed between 91-C and 91-R, of which 51.8% were fixed. Among the differentially expressed transcripts, phosphoenolpyruvate carboxykinase (PEPCK), down-regulated in 91-R, encoded the greatest number of amino acid changes, prompting us to perform PEPCK inhibitor-pesticide exposure bioassays. The inhibitor of PEPCK, hydrazine sulfate, resulted in a 161- to 218-fold decrease in the DDT resistance phenotype (91-R) and more than a 4- to 5-fold increase in susceptibility in 91-C. A second target protein, Glycogen synthase kinase 3ß (GSK3ß-PO), had one amino acid difference between 91-C and 91-R, and the corresponding transcript was also down-regulated in 91-R. A GSK3ß-PO inhibitor, lithium chloride, likewise reduced the resistance but to a lesser extent than did hydrazine sulfate for PEPCK. We demonstrate the potential role of IIS genes in DDT resistance and the potential discovery of an "Achilles' heel" against pesticide resistance in this pathway.

Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage.

Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the γ-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the Aß peptide in N2a695 cells but do not inhibit the γ-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits Aß oligomerization and that addition of tafamidis or its amide derivative does not affect TTR's ability to inhibit Aß oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.

RNF180 mediates STAT3 activity by regulating the expression of RhoC via the proteasomal pathway in gastric cancer cells.

Ring finger protein 180 (RNF180) is an important member of the E3 ubiquitin ligase family. As a tumor suppressor gene, RNF180 is significantly associated with the prognosis of patients with gastric cancer (GC) and can inhibit the proliferation, invasion, and migration of GC cells. Signal transducer and activator of transcription 3 (STAT3) are considered one of the most common oncogenes in human cancers with a key role in GC progression. In this study, we explored the molecular signaling pathways by which RNF180 could potentially regulate STAT3 through transcriptomics and proteomics experiments. Here, we found RNF180 overexpression could suppress STAT3 phosphorylation in GC cells. Ubiquitin label-free experiments showed that the ubiquitination level of Ras homolog gene family member C (RhoC) is significantly increased in GC cells transfected with an RNF180 expression vector (RNF180-GFP vector) compared with cells transfected with an empty vector (vehicle vector). We subsequently demonstrated that RNF180 could directly combine with RhoC and promote the ubiquitination and degradation of RhoC protein in GC cells. The phosphorylation level of STAT3 significantly decreased in GC cells after RhoC knockdown using small hairpin RNA (shRNA). Together, these results reveal RNF180 could inhibit GC progression by reducing the phosphorylation of STAT3 via the ubiquitination and degradation of RhoC protein in GC cells. Thus, the protein may be considered a novel therapeutic target for patients with GC.

Dietary antioxidants impact DDT resistance in Drosophila melanogaster.

Insects experience a diversity of subtoxic and/or toxic xenobiotics through exposure to pesticides and, in the case of herbivorous insects, through plant defensive compounds in their diets. Many insects are also concurrently exposed to antioxidants in their diets. The impact of dietary antioxidants on the toxicity of xenobiotics in insects is not well understood, in part due to the challenge of developing appropriate systems in which doses and exposure times (of both the antioxidants and the xenobiotics) can be controlled and outcomes can be easily measured. However, in Drosophila melanogaster, a well-established insect model system, both dietary factors and pesticide exposure can be easily controlled. Additionally, the mode of action and xenobiotic metabolism of dichlorodiphenyltrichloroethane (DDT), a highly persistent neurotoxic organochlorine insecticide that is detected widely in the environment, have been well studied in DDT-susceptible and -resistant strains. Using a glass-vial bioassay system with blue diet as the food source, seven compounds with known antioxidant effects (ascorbic acid, ß-carotene, glutathione, α-lipoic acid, melatonin, minocycline, and serotonin) were orally tested for their impact on DDT toxicity across three strains of D. melanogaster: one highly susceptible to DDT (Canton-S), one mildly susceptible (91-C), and one highly resistant (91-R). Three of the antioxidants (serotonin, ascorbic acid, and ß-carotene) significantly impacted the toxicity of DDT in one or more strains. Fly strain and gender, antioxidant type, and antioxidant dose all affected the relative toxicity of DDT. Our work demonstrates that dietary antioxidants can potentially alter the toxicity of a xenobiotic in an insect population.

Dietary antioxidant vitamin C influences the evolutionary path of insecticide resistance in Drosophila melanogaster.

Herbivorous insects encounter a variety of toxic environmental substances ranging from ingested plant defensive compounds to human-introduced insecticidal agents. Dietary antioxidants are known to reduce the negative physiological impacts of toxins in mammalian systems through amelioration of reactive oxygen-related cellular damage. The analogous impacts to insects caused by multigenerational exposure to pesticides and the effects on adaptive responses within insect populations, however, are currently unknown. To address these research gaps, we used Drosophila as a model system to explore adaptive phenotypic responses to acute dichlorodiphenyltrichloroethane (DDT) exposure in the presence of the dietary antioxidant vitamin C and to examine the structural genomic consequences of this exposure. DDT resistance increased significantly among four replicates exposed to a low concentration of DDT for 10 generations. In contrast, dietary intake of vitamin C significantly reduced DDT resistance after mutigenerational exposure to the same concentration of DDT. As to the genomic consequences, no significant differences were predicted in overall nucleotide substitution rates across the genome between any of the treatments. Despite this, replicates exposed to a low concentration of DDT without vitamin C showed the highest number of synonymous and non-synonymous variants (3196 in total), followed by the DDT plus vitamin C (1174 in total), and vitamin C alone (728 in total) treatments. This study demonstrates the potential role of diet (specifically, antioxidant intake) on adaptive genome responses, and thus on the evolution of pesticide resistance within insect populations.

Should the left gastric artery lymph node be considered as the predictive lymph node for extra-gastric lymph node metastases?

BACKGROUND: To validate the prognostic impacts of the left gastric artery lymph node (No. 7 LN) metastasis and investigate whether the No. 7 LN metastasis should be considered as the predictive LN for extra-gastric LN metastases. METHODS: Between January 2003 and December 2011, a total of 1,586 patients who underwent R0 gastrectomy were retrospected. Patients with LN metastases were divided into three groups: (I) patients with only peri-gastric LN metastases (peri-gastric group); (II) patients with peri-gastric and only No. 7 LN metastases (No. 7 group); and (III) patients with other extra-gastric LN metastases (extra-gastric group). Propensity score matching (PSM) was adopted to accurately evaluate prognoses of all patients after surgery. RESULTS: Of 1,586 patients, 235 (14.82%) were pathologically identified to present with the No. 7 LN metastases. Patients with the No. 7 LN metastases presented the significantly lower survival rate both before and after adjustment by pTNM stage, compared to those without the No. 7 LN metastases. Patients in the No. 7 group were identified to present the significant lower survival rate than those in the peri-gastric group, and to present the similar median overall survival (OS) to those in the extra-gastric group. In addition, patients with extra-gastric LN except No. 7 LN metastases failed to show any superiority of survival outcomes, compared with those with extra-gastric LN metastases including the No. 7 LN metastasis. CONCLUSIONS: The No. 7 LN metastases had the crucial survival implications. Nevertheless, the No. 7 LN failed to be considered as the predictive LN for the extra-gastric LN metastases in gastric cancer (GC).

Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This "protein assembly mutation' remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.

Extranodal soft tissue metastasis as an independent prognostic factor in gastric cancer patients aged under 70 years after curative gastrectomy.

BACKGROUND: Accumulating evidence confirms the potential prognostic value of extranodal soft tissue metastasis (ESTM) in patients with solid cancers. The aim of this study was to elucidate the potential relationship between ESTM and lymph node (LN) metastasis, demonstrate clinicopathological predictive prognostic factors for ESTM and LN metastasis, and identify the prognostic value of ESTM for gastric cancer (GC) patients aged under 70 years. METHODS: A total of 580 GC patients who underwent the curative resection between 2003 and 2011 were included to identify if ESTM is essential to improve the accuracy of prognostic evaluation of the GC patients postoperatively. Overall survival rates were tested by Kaplan-Meier analysis. Univariate and multivariate analyses were applied to clarify the independent prognostic factors. Logistic regression analysis was adopted to clarify the risk factors for evaluating the presence of ESTM and LN metastasis. After cut-point survival analysis, the GC patients were divided into three subgroups based on the number of ESTM and then incorporated into the pTNM stage of gastric carcinoma to identify the possibility and necessity of incorporating ESTM into staging. RESULTS: ESTM was associated with advanced pT, pN and pTNM categories, large tumour size and the presence of signet-ring cell (SRC) variants. Survival analyses revealed that ESTM was associated with the OS and was an independent prognostic predictor in this GC patient cohort. Logistic regression analysis proved that ESTM and pT stage are significantly correlated with LN metastasis. Additionally, the ESTM was incorporated into the eighth edition of the pTNM classification and the prognostic evaluation of pTNME classification were calculated directly, and the results indicated that ESTM can reduce the stage migration. CONCLUSIONS: ESTM is a significant independent predictor of survival in GC patients. To achieve R0 surgery, lymph nodes, soft tissues, fascia and adipose tissue should be resected en bloc at the same time as lymph node dissection. ESTM should be incorporated into pTNM staging according to the number retrieved from postoperative samples.

Prognostic impact of D2-plus lymphadenectomy and optimal extent of lymphadenectomy in advanced gastric antral carcinoma: Propensity score matching analysis.

OBJECTIVE: To investigate the prognostic impact of D2-plus lymphadenectomy including the posterior (No. 8p, No. 12b/p, No. 13, and No. 14v), and para-aortic (No. 16a2, and No. 16b1) lymph nodes (LNs) in subtotal gastrectomy for advanced gastric antral carcinoma. METHODS: A total of 203 patients with advanced gastric cancer (GC) located in the antrum, who underwent R0 gastrectomy with D2 or D2-plus lymphadenectomy between January 2003 and December 2011 were enrolled. Propensity score matching was used to reduce the strength of the confounding factors to accurately evaluate prognoses. The therapeutic value index (TVI) was calculate to evaluate the survival benefit of dissecting each LN station. RESULTS: Of 102 patients with D2-plus lymphadenectomy, 21 (20.59%) were pathologically identified as having LN metastases beyond the extent of D2 lymphadenectomy. After matching, the overall survival (OS) was significantly better in the D2-plus than the D2 group (P=0.030). In the multivariate survival analysis, D2-plus lymphadenectomy (hazard ratio, 0.516; P=0.006) was confirmed to significantly improve the survival rate. In the logistic regression analysis, pN stage [odds ratio (OR), 2.533; 95% confidence interval (95% CI), 1.368-4.691; P=0.003] and extent of LNs metastasis (OR, 5.965; 95% CI, 1.335-26.650; P=0.019) were identified as independent risk factors for LN metastases beyond the extent of D2 lymphadenectomy. The TVI of patient with metastasis to LNs station was 7.1 (No. 8p), 5.7 (No. 12p), 5.1 (No. 13), and 7.1 (both No. 16a2 and No. 16b1), respectively. CONCLUSIONS: D2-plus lymphadenectomy may improve the prognoses of some patients with advanced GC located in the antrum, especially for No. 8p, No. 12b, No. 13, and No. 16.

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

Clinical significance of skip lymph-node metastasis in pN1 gastric-cancer patients after curative surgery.

BACKGROUND: In addition to the stepwise manner of lymph-node metastasis from the primary tumour, the skip lymph-node metastasis (SLNM) was identified as a low-incidence metastasis of gastric cancer (GC). So far, both the mechanism and outcome of SLNM have not been elucidated completely. The purpose of this study was to analyse the clinical significance and the potential mechanism of SLNM in GC patients who had lymph-node metastasis. METHODS: Clinicopathological data and follow-up information of 505 GC patients who had lymph-node metastasis were analysed to demonstrate the significance of SLNM in evaluating the prognostic outcome. According to the pathological results, all GC patients who had lymph-node metastasis were categorized into three groups: patients with the perigastric lymph-node metastasis, patients with the perigastric and extragastric lymph-node metastasis and patients with SLNM.Results: Among the 505 GC patients who had lymph-node metastasis, 24 (4.8%) had pathologically identified SLNM. The location of lymph-node metastasis was not significantly associated with 5-year survival rate and overall survival (OS) (P = 0.194). The stratified survival analysis results showed that the status of SLNM was significantly associated with the OS in patients with pN1 GC (P = 0.001). The median OS was significantly shorter in 19 pN1 GC patients with SLNM than in 100 patients with perigastric lymph-node metastasis (P < 0.001). The case-control matched logistic regression analysis results showed that tumour size (P = 0.002) was the only clinicopathological factor that may predict SLNM in pN1 GC patients undergoing curative surgery. Among the 19 pN1 GC patients with SLNM, 17 (89.5%) had metastatic lymph nodes along the common hepatic artery, around the celiac artery or in the hepatoduodenal ligament. CONCLUSIONS: SLNM may be considered a potentially practicable indicator for prognosis among various subgroups of pN1 GC patients.