Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy.

Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.

ß-Ionone represses renal cell carcinoma progression through activating LKB1/AMPK-triggered autophagy.

ß-Ionone, the end ring analog of ß-carotenoids, has been proven to have an antitumor effect in a variety of cancers. In this study, we investigated the impact of ß-ionone on renal cell carcinoma (RCC) cell lines (786-O and ACHN) using colony formation assays, flow cytometry analysis, and western blot analysis. We found that ß-ionone effectively inhibited the proliferation of RCC cells in vitro, which was also confirmed in a xenograft model. Moreover, we found that ß-ionone could induce autophagy, as indicated by LC3 puncta in 786-O and ACHN cell lines and the expression of LC3 in ß-ionone-treated RCC cells. To further explore the underlying mechanism, we assessed liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway activity, and the results showed that ß-ionone inhibited the proliferation of RCC cells by inducing autophagy via the LKB1/AMPK signaling pathway. In summary, our findings provide a new therapeutic strategy of ß-ionone-induced autophagy in RCC.

Differential Alterations in Topology Property of Resting State Networks Associated With Mental Health and Childhood Trauma.

Context: Childhood trauma can lead to greater vulnerability to psychopathology and can affect person's mental health throughout his or her life cycle. Research on the associations between childhood trauma and developmental outcomes is critical to creating effective interventions. Objective: The study intended to identify brain networks that are susceptible to childhood trauma by comparing differences in the networks of individuals with and without trauma, to investigate how changes in networks can mediate the effects childhood adversity on mental health. Design: The research team performed a prospective cross-sectional survey. Setting: The study took place at the Second Hospital of Hebei Medical University in Shijiazhuang, China. Participants: Participants were 80 individuals aged 18-30 years, with and without childhood trauma. Outcome Measures: Participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). The research team: (1) assessed participants' depressive symptoms using the Beck Depression Inventory (BDI); anxiety levels using the State-Trait Anxiety Inventory (STAI); personality traits using the Three-Dimensional Personality Questionnaire (TPQ), and childhood traumatic experiences using the Childhood Trauma Questionnaire (CTQ); (2) analyzed the data using independent component analysis (ICA) and graph theory based on resting-state functional networks to assess the functional connectivity (FC) and global efficiency of participants' brains; (3) performed a correlation analysis between changes in the topological properties of participants' brains and neglect and abuse, (4) explored the mediating effects between childhood trauma and mental health, and (5) explored gender as a moderator of the relationship between neglect and changes in the global efficiency of within-network connectivity. Results: Childhood trauma was associated with altered global efficiency of the salience network (SAN) and the default mode network (DMN). Compared with the healthy control group, the childhood trauma group's global efficiency of the SAN for the left (P = .022) and right (P = .013) bilateral anterior insula were significantly higher and the global efficiency of the DMN for the right lateral precuneus was significantly lower (P = .022). Compared with males, neglect was significantly more likely to affect the global efficiency of the SAN for females (R2 = 0.473, t = -2.33, F(3,76) = 24.66, B = -0.005, and P = .022). The childhood trauma group's mean score for novelty seeking on the TPQ was significantly higher than that of the healthy control group (P = .029), showing that the global efficiency of the SAN and DMN had a significant role as a mediator between neglect and novelty seeking. Conclusions: These findings indicate that childhood trauma can alter resting-state functional networks in healthy youth. This abnormality in brain circuitry is especially relevant to the DMN and SAN networks.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

Ion-Specific Effects on Vesicle-to-Micelle Transitions of an Amino Acid Surfactant Probed by Chemical Trapping.

Ion-specific effects widely exist in biological and chemical systems and cannot be explained by classical theories. The complexity of ion-specific effects in protein systems at the molecular level necessitates the use of mimetic models involving smaller molecules, such as amino acids, oligopeptides, and other organic molecules bearing amide bonds. Therefore, it is of theoretical value to determine the effect of additional salts on the aggregation transitions of acyl amino acid surfactants. Herein, the effects of specific tetraalkylammonium ions (TAA+) on sodium lauroyl glycinate (SLG) aggregation were studied by dynamic light scattering (DLS) and transmission electron microscopy. Although previous studies have shown that the kosmotropic TAA+ ions tend to induce micellar growth or micelle-to-vesicle transitions of some anionic surfactants, TAA+ addition in the present study induced partial vesicle-to-micelle transitions in SLG solutions. The chemical trapping (CT) method was employed to estimate changes in the interfacial molarities of water, amide bonds, and carboxylate groups during such transitions. The vesicle-to-micelle transitions were accompanied by a marked rise in interfacial water molarity and a decline in interfacial amide bonds molarity, suggesting that the hydrated TAA+ entered the interfacial region and disrupted hydrogen bonding, thus preventing the SLG monomers from packing tightly. Molecular dynamic simulation was also performed to demonstrate the salt-induced cleavage of amide-amide bonds between SLG headgroups. Furthermore, both CT and DLS results show that the ability of tetraalkylammonium cations to induce such transitions increased with increasing size and hydrophobicity of the cation, which follows the Hofmeister series. The current study offers critical molecular-level evidence for understanding the specific effects of tetraalkylammonium ions on the aggregation transitions of an acyl amino acid surfactant.

Feasibility study of hallux valgus measurement with a deep convolutional neural network based on landmark detection.

OBJECTIVE: To develop a deep learning algorithm based on automatic detection of landmarks that can be used to automatically calculate forefoot imaging parameters from radiographs and test its performance. MATERIALS AND METHODS: A total of 1023 weight-bearing dorsoplantar (DP) radiographs were included. A total of 776 radiographs were used for training and verification of the model, and 247 radiographs were used for testing the performance of the model. The radiologists manually marked 18 landmarks on each image. By training our model to automatically label these landmarks, 4 imaging parameters commonly used for the diagnosis of hallux valgus could be measured, including the first-second intermetatarsal angle (IMA), hallux valgus angle (HVA), hallux interphalangeal angle (HIA), and distal metatarsal articular angle (DMAA). The reference standard was determined by the radiologists' measurements. The percentage of correct key points (PCK), intragroup correlation coefficient (ICC), Pearson correlation coefficient (r), root mean square error (RMSE), and mean absolute error (MAE) between the predicted value of the model and the reference standard were calculated. The Bland-Altman plot shows the mean difference and 95% LoA. RESULTS: The PCK was 84-99% at the 3-mm threshold. The correlation between the observed and predicted values of the four angles was high (ICC: 0.89-0.96, r: 0.81-0.97, RMSE: 3.76-6.77, MAE: 3.22-5.52). However, there was a systematic error between the model predicted value and the reference standard (the mean difference ranged from - 3.00 to - 5.08°, and the standard deviation ranged from 2.25 to 4.47°). CONCLUSION: Our model can accurately identify landmarks, but there is a certain amount of error in the angle measurement, which needs further improvement.

Validation of the 8th Edition Nodal Staging and Proposal of New Nodal Categories for Future Editions of the TNM Classification of Non-Small Cell Lung Cancer.

BACKGROUND: The International Association for the Study of Lung Cancer (IASLC) N classifications, which depend on the location and involvement of the lymph nodes, provide accurate prognoses. This study validated the efficiency of classifications using a single-institution dataset and proposed a modified system based on 5-level N1 node dissection. METHODS: From January 2005 to December 2014, 1851 patients with completely resected non-small cell lung cancer were reviewed. According to the IASLC recommendations, N1 is further subdivided into N1a (single) and N1b (multiple), N2 is divided into N2a1 (single station without N1), N2a2 (single station with N1), and N2b (multiple station). Additionally, we evaluated dividing N0 into N0a (with level 13/14 examination) and N0b (without level 13/14 examination), and N1 into N1a* (only level 13/14 positive) and N1b* (level 10-12 positive). Overall survival was also compared. RESULTS: Multivariate analysis showed that the N classifications recommended by the IASLC and those proposed and evaluated by this study could both significantly predict the prognoses of patients (p < 0.001, respectively). There was no significant difference in survival between N1b and N1a (hazard ratio [HR] 1.049, p = 0.83) and N2a1 and N1b (HR 1.314, p = 0.261); however, there were significant differences between N0a and N0b (HR 1.778, p < 0.001) and N1a* and N1b* (HR 2.014, p = 0.019). The survival curve of N1a* overlapped N0b (HR 0.997, p = 0.991), and N2a1 overlapped N1b* (HR 0.842, p = 0.444). CONCLUSION: More detailed nodal information is required to facilitate future revisions of N staging.

Photoredox-catalyzed redox-neutral difluoroalkylation to construct perfluoroketones with difluoroenoxysilanes.

A mild and facile approach to construct various perfluoroketones via photo-catalyzed difluoroalkylation of difluoroenoxysilanes is developed. The reaction includes a strategy of combination of two fluorine-containing functional groups, which confers the reaction with characteristics like high efficiency, mild conditions, and broad scope. A variety of fluoroalkyl halides including perfluoroalkyl iodides, bromo difluoro esters and amides can be employed as radical precursors. Control experiments indicate that a single-electron transfer pathway may be involved in the reaction.

Inflammatory factor-based prognostic risk stratification for patients with metastatic castration-resistant prostate cancer treated with docetaxel.

To develop a simple inflammatory factor-based prognostic risk stratification system for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel as the initial treatment, we reviewed the data of 399 consecutive patients who received first-line docetaxel chemotherapy between January 2013 and June 2019 retrospectively. The optimal cut-off values for the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in terms of survival were calculated by ROC curves. Patients were stratified into favourable (lower NLR and lower PLR), intermediate (higher NLR and lower PLR, or lower NLR and higher PLR) and poor (higher NLR and higher PLR) groups. Kaplan-Meier curves were drawn to evaluate overall survival (OS) and progression-free survival (PFS). The ROC curve analysis determined the cut-offs for the NLR and PLR to be 2.355 and 104.275 respectively. Multivariate Cox regression analysis showed that being in the poor patient group (NLR ≥2.355 and PLR ≥104.275) was an independent prognostic risk factor and Kaplan-Meier curves analysis revealed that respondents with NLR <2.355 and PLR <104.275 had significantly longer OS and PFS. So it can be concluded that concurrently high NLR and PLR values are predictors for poor chemotherapy outcomes after androgen deprivation therapy failure in patients with mCRPC.

Simultaneous determination of interfacial molarities of an alcohol, bromide ion, and water during an alcohol induced microstructural transition: the difference between medium and long chain alcohols.

The transitions between surfactant aggregate structures are triggered by changes in chemical or physical stimulations, including addition of additives. Effects of added alcohols on aggregate morphologies correlate strongly with alcohol chain length. The local molarities of alcohol, water, and counterions in the interfacial regions play an important role in controlling the aggregate morphologies. However, direct experimental estimates of changes of interfacial alcohol molarities during alcohol induced micelle-to-vesicle transitions have never been reported. Ellipsoidal-wormlike micelle-vesicle transitions in CTAB/KBr aqueous solutions in the presence of long-chain octanol were characterized by using combined rheological, dynamic light scattering (DLS), transmission electron microscopy (TEM) and turbidity measurements. However, the transitions are absent with added butanol. The chemical trapping method (CT) was employed to understand the differences between medium- and long-chain alcohols in determining aggregate morphology. The CT method was used to estimate interfacial water, alcohol, and counterion molarities with increasing stoichiometric alcohol concentrations. With 55 mM alcohol added, the interfacial octanol molarity is 0.9 M, which is three times higher than that for butanol. With added octanol, the ellipsoidal-wormlike micelle-vesicle transition is accompanied by a concurrent sharp increase of interfacial water molarities and a decrease of interfacial counterion molarity, which is not observed with added butanol. The CT data was also employed to estimate the changes of Israelachvili's packing parameter with increasing added alcohol concentration. Our result provides critical molecular level information for understanding the morphological transitions of CTAB/additives.

Thermal ablation versus hepatic resection for the treatment of liver metastases from gastrointestinal stromal tumors: a retrospective study.

Objective: The study aimed to compare effectiveness and safety of thermal ablation and hepatic resection in patients with liver metastases of gastrointestinal stromal tumors (GISTs).Method: A total of 55 patients (27 in the ablation group and 28 in the surgery group) with liver metastases were included. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier's survival estimate curves. Univariate and multivariate regression analyses were carried out to identify potential prognostic factors.Results: The median OS was 102.0 months in the ablation group and 117.0 months in the surgery group (p = .875). The 1-, 3- and 5-year OS rates were 100%, 88.9% and 74.1% in the ablation group and 92.8%, 82.1% and 78.6% in the surgery group, respectively. The 1-, 3- and 5-year PFS rates were 48.1%, 25.9% and 18.5% in the ablation group and 67.8%, 64.3% and 64.3% in the surgery group, respectively. Multivariate analysis showed that preoperative tyrosine kinase inhibitor (TKI) treatment (progressive disease, PD) (HR, 13.985; 95% CI, 1.791-109.187; p = .012) was the only significant independent prognostic factor for OS. Tumor number (HR, 1.318; 95% CI, 1.021-1.702; p = .034) was identified as an independent predictor for PFS in multivariate analysis. There were fewer postoperative complications (18.5% vs. 78.6%, p = .001) and shorter lengths of hospital stay (8.0 vs. 16.5 days, p = .001) in the ablation group.Conclusion: Compared with resection, thermal ablation offered comparable OS for liver metastases of GISTs. Furthermore, thermal ablation had the advantages of fewer complications and shorter lengths of hospital stay.

Impact of Early Oral Feeding on Anastomotic Leakage Rate After Esophagectomy: A Systematic Review and Meta-analysis.

BACKGROUND: Esophageal cancer occupies a vital position in fatal cancer-related disease, with esophagectomy procedures helping to improve patient survival. The timing when oral intake should be resumed after esophagectomy and whether early oral feeding (EOF) or delayed oral feeding (DOF) should be the optimal regimen are controversial. METHODS: Databases (PubMed, Embase, Cochrane library) were searched. All records were screened by two authors through full-text reading. Data on the anastomotic leakage rate were extracted and synthesized in meta-analyses. Postoperative pneumonia rate and length of hospital stay were also assessed. RESULTS: Seven studies from 49 records were included after full-text reading; 1595 patients were totally included in the analysis. No significant difference was observed between the EOF and DOF groups (odds ratio [OR] 1.68; 95% confidence interval [CI] 0.70-4.03; p = 0.2495; I2 = 70%). Higher anastomotic leakage rate was observed in EOF compared with DOF (OR 2.89; 95% CI 1.56-5.34; p = 0.0007; I2 = 10%) in the open subgroup. No significant difference was observed in the MIE (OR 0.48; 95% CI 0.22-1.02; p = 0.0564; I2 = 0%). Patients performed similarly in pneumonia (OR 1.12; 95% CI 0.57-2.21; p = 0.745; I2 = 34%). In cervical subgroup, anastomosis leakage may be less in DOF (OR 2.42 95% CI 1.26-4.64; p = 0.0651; I2 = 58%), while in thoracic subgroup, there is no obvious difference (OR 0.86 95% CI 0.46-1.61; p = 0.01; I2 = 84.9%). CONCLUSIONS: Anastomotic leakage related to the timing of oral feeding after open esophagectomy, which is more favorable to the DOF regimen. However, timing of oral feeding did not impair anastomotic healing in patients undergoing MIE.

Effects of interfacial specific cations and water molarities on AOT micelle-to-vesicle transitions by chemical trapping: the specific ion-pair/hydration model.

Salt induced micelle-to-vesicle transitions of ionic surfactants depend on the surfactant chain length, headgroup structure, counterion type and concentration, but the interfacial molarities of counterions and water that balance the hydrophobic effect are difficult to determine. In anionic micelles of twin-tailed sodium bis(2-ethylhexyl)sulfosuccinate (AOT), the chemical trapping (CT) method provides estimates of the interfacial molarities of anionic headgroups (RSO3-m) and neutral (H2Om) nucleophiles during salt induced transitions of AOT micelles to vesicles. Product yields were measured by HPLC from the competitive dediazoniation reaction using a specially designed hydrophobic probe, 4-hexadecyl-2,6-dimethylbenzenediazonium cation, 16-ArN2+. The reactions were run at constant concentration of 15 mM AOT mixed with 0 to 50 mM added salts, containing cations of different sizes and valences including tetraalkylammonium cations (MR4+, R = 1-4) and metal cations (M1-3+). Parallel reactions in aqueous salt solutions with a short chain analog, 1-ArN2+, were used as references to calculate interfacial molarities. Aggregates were structurally characterized by TEM and DLS. Typically, interfacial RSO3- molarities increase with added salts from 1 to 2 M and water molarities decrease from about 40 to 20 M with the micelle to vesicle transition. These changes are consistent with the ion-pair/hydration model, in which the added cations form neutral but polar ion-pairs with RSO3- that have a lower demand for hydration and water was released into the surrounding aqueous phase. The extent of ion-pairing increases with cation size, charge and hydrophobicity and decreases with interfacial water molarity, which permits tighter interfacial packing and vesicle formation at lower added salt concentrations.

Adjuvant chemotherapy may improve outcome of patients with non-small-cell lung cancer with metastasis of intrapulmonary lymph nodes after systematic dissection of N1 nodes.

OBJECTIVE: Survival benefit of adjuvant chemotherapy (AC) of patients with intrapulmonary lymph node (IPLN) metastasis (level 12-14) needs investigation. We evaluated the impact of AC on patients whose metastatic nodes were limited to intrapulmonary levels after systematic dissection of N1 nodes. METHODS: First, 155 consective cases of lung cancer confirmed as pathologic N1 were collected and evaluated. Patients received systematic dissection of N2 and N1 nodes. For patients with IPLN metastasis, survival outcomes were compared between those receiving AC and those not receiving AC. RESULTS: In this group, 112 cases (72.3%) had IPLN metastasis and 55 cases (35.5%) had N1 involvement limited to level 13-14 without further disease spread to higher levels. Patients with IPLN involvement had a better prognosis than that of patients with hilar-interlobar involvement. For the intrapulmonary N1 group (level 12-14-positive, level 10-11-negative or unknown, n=112), no survival benefit was found between the AC group and non-AC group [5-year overall survival (OS): 54.6±1.6vs. 50.4±2.4 months, P=0.177]. However, 76 of 112 cases for whom harvesting of level-10 and level-11 nodes was done did not show cancer involvement in pathology reports (level 12-14-positive, level 10-11 both negative), oncologic outcome was better for patients receiving AC than those not receiving AC in this subgroup (5-year OS: 57.3±1.5vs. 47.1±3.2 months, P=0.002). CONCLUSIONS: Oncologic outcome may be improved by AC for patients with involvement of N1 nodes limited to intrapulmonary levels after complete examination of N1 nodes.

Evaluation of whiteness formulas for FWA and non-FWA whites.

Whiteness is an important colorimetric characteristic for surface colors. Currently, the CIE whiteness formula is widely used to characterize the whiteness of a surface in industry, whose limitations have been well documented. In this study, the whiteness appearance of 55 textile samples [43 non-fluorescent whitening agents (FWAs) and 12 FWA samples] were evaluated under six lighting conditions, comprising three levels of correlated color temperature (CCT) (i.e., 3000, 4000, and 6500 K) and two levels of UV radiation (i.e., zero and high), by 12 observers with normal color vision. The results indicated that the CIE whiteness formula with the CAT02 chromatic adaptation transform and the optimized CIE whiteness formula had the best performance in predicting the whiteness of surface colors, regardless of whether FWAs are contained, among the six formulas.

Atorvastatin Protects Myocardium Against Ischemia-Reperfusion Injury Through Inhibiting miR-199a-5p.

OBJECTIVE: This study aimed to evaluate the protective effects of atorvastatin against myocardial ischemia/reperfusion (I/R) injury in cardiomyocytes and its possible underlying mechanism. METHOD: Direct cytotoxic effect of OGD/R on cardiomyocytes with and without atorvastatin pretreatment was evaluated. Effects of atorvastatin on expression of GSK-3ß and miR-199a-5p were determined using RT-PCR and Western blot. In addition, GSK-3ß expression with miR-199a-5p upregulation and downregulation was detected using RT-PCR, Western blot, and immunohistochemistry. RESULTS: Pretreatment with atorvastatin significantly improved the recovery of cells viability from OGD/R (p<0.05). In addition, the atorvastatin pretreatment significantly increased GSK-3ß expression both in mRNA level and protein level and decreased miR-199a-5p expression in mRNA level (p<0.05). Upregulation and downregulation of miR-199a-5p respectively decreased and increased GSK-3ß expression both in mRNA level and protein level. CONCLUSION: These results suggested that atorvastatin provides the cardioprotective effects against I/R injury via increasing GSK-3ß through inhibition of miR-199a-5p.

Characterization of the genotype and integration patterns of hepatitis B virus in early- and late-onset hepatocellular carcinoma.

UNLABELLED: Early-onset hepatocellular carcinoma (HCC) accounts for 15%-20% of total HCC cases in Asia, and the incidence is increasing. The low frequency of cirrhosis and poor prognosis of early-onset HCC suggests that its mechanisms may differ from late-onset HCC. Although hepatitis B virus (HBV) infection is epidemiologically associated with HCC, the role of HBV in early-onset HCC remains poorly understood. Here, we report a comparative study of HBV subgenotypes and integration in early- (≤30) and late-onset (≥70) HBV-associated HCC using a novel high-throughput viral integration detection method. We report that HBV B2 is predominantly present in early-onset HCC. HBV integration is a common phenomenon, both in early- and late-onset HCC, which favors integrating into human repeat regions. Moreover, we found a breakpoint in 8q24 located between c-Myc and plasmocytoma variant translocation 1 (PVT1), which was detected in 12.4% (14 of 113) of early-onset HCCs, but only 1.4% (2 of 145) in late-onset HCCs. HBV integrating this site results in c-MYC, PVT1, and microRNA-1204 overexpression in tumors, thereby potentially contributing to the development of early-onset HCC. CONCLUSION: HBV genotype and integration patterns may be distinct in early-onset HCC. Our results may shed light on HCC risk factors in young HBV carriers. Further studies are needed to elucidate at which time in tumor development this integration event occurs and whether it plays an important, causative role in HCC development or progression.

Is radical mediastinal lymphadenectomy necessary for elderly patients with clinical N-negative non-small-cell lung cancer? A single center matched-pair study.

BACKGROUND: The extent of lymph node dissection during surgery in elderly non-small-cell lung cancer patients remains controversial. We evaluated a cohort of elderly patients with clinical N0 disease who underwent lobectomy to determine if radical mediastinal lymphadenectomy (RML) is justified for the special group. PATIENTS AND METHODS: A single-center database of patients over 70 y old from 2001-2011 was used to conduct a matched-pair analysis. The patients undergoing RML were matched 1:1 with those not (non-radical mediastinal lymphadenectomy group) by age, gender, American Society of Anesthesia score, histology, and clinical T status to assess their postoperative and long-term outcomes. RESULTS: A total of 136 patients could be matched (68 RML and 68 non-radical mediastinal lymphadenectomy). No statistical difference was observed in postoperative mortality and overall morbidity rate between the matched groups (0 versus 1, P > 0.99 and 43 versus 35, P = 0.17). Patients undergoing RML experienced more major morbidities, but no significant difference was achieved (15 versus 7, P = 0.06). No significantly more N-positive diseases were discovered in RML group (N1 and N2 involvement disease: 16 versus 16, P > 0.99 and 10 versus 4, P = 0.09, respectively). RML was associated with a significantly longer cancer-related and disease-free survival (P = 0.02 and P = 0.02). Whereas for clinical IA diseases, significant differences were observed neither in cancer-related nor in disease-free survival (P = 0.67 and P = 0.61). CONCLUSIONS: The performance of RML seemed to result in a tendency of higher major morbidity rate in elderly patients, but to contribute a favorable impact on long-term survival. However, for clinical IA patients the survival benefits were not obtained.

MicroRNA-23a antisense enhances 5-fluorouracil chemosensitivity through APAF-1/caspase-9 apoptotic pathway in colorectal cancer cells.

Current literature provided information that alteration in microRNA expression impacted sensitivity or resistance of certain tumor types to anticancer treatment, including the possible intracellular pathways. The microRNA-23a (miR-23a)-regulated apoptosis in response to the 5-fluorouracil (5-FU)-induced mitochondria-mediated apoptotic pathway was determined in this study. The miR-23a expression in 5-FU-treated and untreated colon cancer cells and tissues was assessed using real-time PCR analysis. To determine the function of miR-23a in the regulation of 5-FU-induced apoptosis, cell-proliferation, cytotoxicity, and apoptosis analyses were performed. Dual luciferase reporter assay was used to identify the apoptosis-related target gene for miR-23a. The activity of caspases-3, -7, and -9 were also assessed in miR-23a antisense and 5-FU treated tumor cells. A xenograft tumor model was established to evaluate the biological relevance of altered miR-23a expression to the 5-FU-based chemotherapy in vivo. We found that the expression of miR-23a was increased and the level of apoptosis-activating factor-1 (APAF-1) was decreased in 5-FU-treated colon cancer cells compared to untreated cells. The activation of the caspases-3 and 7 was increased in miR-23a antisense and 5-FU-treated colon cancer cells compared to negative control. APAF-1, as a target gene of miR-23a, was identified and miR-23a antisense-induced increase in the activation of caspase-9 was observed. The overexpression of miR-23a antisense up-regulated the 5-FU induced apoptosis in colon cancer cells. However, the miR-23a knockdown did not increase the antitumor effect of 5-FU in xenograft model of colon cancer. This study shows that miR-23a antisense enhanced 5-FU-induced apoptosis in colorectal cancer cells through the APAF-1/caspase-9 apoptotic pathway.

Clinical value of hematologic test in predicting tumor response to neoadjuvant chemotherapy with esophageal squamous cell carcinoma.

BACKGROUND: To investigate the relationship between hematologic test results and the predictive effect of regression of esophageal cancer after neoadjuvant chemotherapy (NACT), we analyzed pre-NACT hematologic data and their relationship to tumor regression. METHODS: Thirty-eight consecutive patients with locally advanced squamous cell esophageal carcinoma who had undergone two cycles of paclitaxel/carboplatin NACT were enrolled. On the day prior to the first cycle of chemotherapy, hematologic tests, including routine blood test and biochemical examinations, were recorded. All patients were confirmed to have no history of hepatitis. Surgical resection was performed when clinical restaging showed effective regression. Histopathological examination was routinely performed to evaluate the postoperative effects of chemotherapy. RESULTS: After two cycles of NACT, tumor imaging evaluation showed that 27 of the 38 patients had CR and PR, including 25 patients who underwent radical esophagectomies. Six patients had stable disease and five patients had progressive disease. According to the hematologic test results before NACT, patients with higher white blood cell counts, lymphocyte percentages, mononuclear cell counts, neutrophilic granulocyte counts, and eosinophilic granulocyte counts and lower alanine aminotransferase (ALT) level had a significantly greater opportunity for an effective response. CONCLUSION: Basal host immunologic function and hepatic function are associated with tumor response to NACT in patients with esophageal cancer. These parameters may have a certain predictive efficacy on NACT for esophageal squamous cell carcinoma.