Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.

Survival prediction for patients with malignant biliary obstruction caused by pancreatic cancer undergoing biliary drainage: the COMBO-PaS model.

BACKGROUND: Patients with pancreatic cancer-caused biliary obstruction (PC-BO) have poor prognosis, but we lack of tools to predict survival for clinical decision-making. This study aims to establish a model for survival prediction among patients with PC-BO. METHODS: A total of 172 patients with PC-BO treated with percutaneous biliary drainage were randomly divided into a training group (n = 120) and a validation group (n = 52). The independent risk factors for overall survival were selected to develop a Cox model. The predictive performance of M stage, hepatic metastases, cancer antigen 199, and the Cox model was determined. Naples prognostic score (NPS), the prognostic nutritional index (PNI), and the controlling nutritional status (CONUT) for 1-month mortality risk were compared with the Cox model. RESULTS: The Cox model was developed based on total cholesterol, direct bilirubin, hepatic metastases, cancer antigen 199, stenosis type, and preprocedural infection (all P < 0.05), which named "COMBO-PaS." The COMBO-PaS model had the highest area under the curves (AUC) (0.801-0.933) comparing with other predictors (0.506-0.740) for 1-, 3-, and 6-month survival prediction. For 1-month mortality risk prediction, the COMBO-PaS model had the highest AUC of 0.829 comparing with NPS, PNI, and CONUT. CONCLUSION: The COMBO-PaS model was useful for survival prediction among patients with PC-BO.

SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation.

The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells.

Med1 inhibits ferroptosis and alleviates liver injury in acute liver failure via Nrf2 activation.

BACKGROUND: Extensive hepatocyte mortality and the absence of specific medical therapy significantly contribute to the unfavorable prognosis of acute liver failure (ALF). Ferroptosis is a crucial form of cell death involved in ALF. In this study, we aimed to determine the impact of Mediator complex subunit 1 (Med1) on ferroptosis and its potential hepatoprotective effects in ALF. RESULTS: Med1 expression is diminished in the liver of lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice, as well as in hepatocytes damaged by H2O2 or TNF-α/D-GalN in vitro. Med1 overexpression mitigates liver injury and decreases the mortality rate of ALF mice by ferroptosis inhibition. The mechanism by which Med1 inhibits erastin-induced ferroptosis in hepatocytes involves the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, Med1 overexpression suppresses the transcription of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the liver of mice with LPS/D-GalN-induced ALF. CONCLUSION: Overall, our research findings indicate that Med1 suppresses ferroptosis and alleviates liver injury in LPS/D-GalN-induced ALF through the activation of Nrf2. These findings substantiate the therapeutic viability of targeting the Med1-Nrf2 axis as a means of treating individuals afflicted with ALF.

Clinicopathological features, treatment modalities, and prognosis of esophageal neuroendocrine carcinoma: A single-center retrospective study.

OBJECTIVES: Esophageal neuroendocrine carcinoma (ENEC) is a rare cancer that is highly malignant and related to a poor prognosis. In this retrospective study we aimed to elucidate the clinical characteristics, diagnosis and management of patients with ENEC and to evaluate the potential prognostic factors. METHODS: Altogether 82 patients diagnosed with ENEC between January 2009 and December 2020 at the Fudan University Shanghai Cancer Center were retrospectively enrolled. Patients' survival was analyzed using the Kaplan-Meier and log-rank methods. Univariate and multivariate analyses and a Cox regression model were used to identify the prognostic factors. RESULTS: The median overall survival (mOS) was 13 months in all patients. Multivariate analysis revealed that advanced tumor stage (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.07-6.66, P = 0.0353), liver (HR 3.36, 95% CI 1.53-7.41, P = 0.0026) and lung metastasis (HR 3.37, 95% CI 1.20-9.51, P = 0.0214) were associated with a poor prognosis. While positive chromogranin A (CgA) expression was related to a favorable outcome (HR 0.21, 95% CI 0.09-0.49, P < 0.001). Also, patients had adjustment of chemotherapy (dose reduction or less than three cycles) were prone to a worse prognosis compared with those did not (HR 4.36, 95% CI 2.10-9.08, P < 0.001). CONCLUSION: In patients with ENEC, advanced cancer stage, adjustment of chemotherapy, liver and lung metastasis were associated with a poor survival, while CgA expression was related to a favorable prognosis.

miR-196a2 C allele is a low-penetrant risk factor for cancer development.

Published data on the association between miR-196a2 T/C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 21 studies including 10,441 cases and 12,353 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with miR-196a2 C allele when all studies were pooled into the meta-analysis (TC vs. TT: OR=1.23, 95% CI=1.11-1.36; CC vs. TT: OR=1.30, 95% CI=1.14-1.48; dominant model: OR=1.25, 95% CI=1.13-1.38). In the subgroup analysis by ethnicity, significantly increased risks were found in Asains (TC vs. TT: OR=1.24, 95% CI=1.10-1.40; CC vs. TT: OR=1.31, 95% CI=1.13-1.52; dominant model: OR=1.26, 95% CI=1.12-1.41) but with bordline statistical significance in Caucasians (TC vs. TT: OR=1.15, 95% CI=1.00-1.31). In the subgroup analysis by cancer type, statistically significantly increased risks were found for breast cancer (TC vs. TT: OR=1.15, 95% CI=1.01-1.31; CC vs. TT: OR=1.30, 95% CI=1.01-1.68; dominant model: OR=1.22, 95% CI=1.00-1.50; and recessive model: OR=1.11, 95% CI=1.01-1.23) and lung cancer (CC vs. TT: OR=1.30, 95% CI=1.10-1.54; and recessive model: OR=1.18, 95% CI=1.02-1.36). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TC vs. TT: OR=1.30, 95% CI=1.13-1.49; CC vs. TT: OR=1.37, 95% CI=1.14-1.66; dominant model: OR=1.32, 95% CI=1.15-1.53) and population-based studies (CC vs. TT: OR=1.19, 95% CI=1.06-1.35; dominant model: OR=1.13, 95% CI=1.01-1.25). Despite some limitations, this meta-analysis suggests that the miR-196a2 C allele is a low-penetrant risk factor for cancer development.

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility.

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR A1298C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC vs. AA, CC vs. AA), dominant model (CC+AC vs. AA), and recessive model (CC vs. AC+AA), respectively. A total of 26 studies including 12,244 cases and 15,873 controls were involved in this meta-analysis. Overall, no significant associations were found between MTHFR A1298C polymorphism and breast cancer risk when all studies pooled into the meta-analysis (AC vs. AA: OR=0.99, 95% CI 0.94-1.05; CC vs. AA: OR 0.99, 95% CI 0.90-1.09; dominant model: OR=0.99, 95% CI 0.95-1.04; and recessive model: OR=0.98, 95% CI 0.90-1.08). In the subgroup analysis by ethnicity or study design, still no significant associations were found for all comparison models. In conclusion, this meta-analysis suggests that the MTHFR A1298C polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.

Non-small-cell lung cancer with epidermal growth factor receptor L861Q-L833F compound mutation benefits from both afatinib and osimertinib: A case report.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been adopted as the standard of care for non-small cell lung cancer (NSCLC) patients harboring EGFR sensitizing mutations. Besides the two common mutations exon 19 deletion and L858R, which together comprise approximately 85% of EGFR mutations in NSCLC, rare EGFR mutations also exist, including point mutations, deletions, and insertions spanning EGFR exons 18-25. However, the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest. CASE SUMMARY: Herein, we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis. The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo. After afatinib failure, the patient received multiple line treatments with chemotherapy. Upon disease progression, the heavily pretreated patient was treated with osimertinib and bevacizumab, and both lung lesion and brain metastases were stable for more than 3 mo. He had an overall survival of 25 mo. CONCLUSION: Our case revealed that both afatinib and the osimertinib + bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833F-L861Q compound mutation. The results provide more therapeutic options for patients with rare compound mutations.

NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis.

To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968-1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938-1.068) or Asians (OR = 1.155, 95% CI = 0.886-1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037-1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886-1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844-1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099-1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility.

The p21 Ser31Arg polymorphism and breast cancer risk: a meta-analysis involving 51,236 subjects.

Published data on the association between p21 Ser31Arg polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between the p21 Ser31Arg polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (Ser/Arg vs. Ser/Ser, Arg/Arg vs. Ser/Ser), dominant model (Arg/Arg + Ser/Arg vs. Ser/Ser), and recessive model (Arg/Arg vs. Ser/Arg + Ser/Ser). A total of 21 studies including 22,109 cases and 29,127 controls were involved in this meta-analysis. Overall, no significant associations were found between p21 Ser31Arg polymorphism and breast cancer risk when all studies pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly increased risk was found for Caucasians (Arg/Arg vs. Ser/Ser: OR 1.496, 95% CI 1.164-1.924; and recessive model: OR 1.492, 95% CI 1.161-1.919). When stratified by study design, statistically significantly elevated risk was found for population-based studies (Ser/Arg vs. Ser/Ser: OR 1.085, 95% CI 1.019-1.156). In conclusion, this meta-analysis suggests that the p21 Ser31Arg polymorphism may be associated with breast cancer development in Caucasian. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding.

Current evidence on the relationship between three polymorphisms in the FGFR2 gene and breast cancer risk: a meta-analysis.

In this article, inconsistency of the association of polymorphisms of fibroblast growth factor receptor 2 (FGFR2) with breast cancer is noted. Three commonly studied FGFR2 polymorphisms including rs1219648 (A > G), rs2420946 (C > T), and rs2981582 (C > T) were selected to explore their association with risk of development of breast cancer by meta-analysis of published case-control studies. The results showed that all these three polymorphisms were significantly associated with altered breast cancer risk in any model (co-dominant, dominant, or recessive model) and in stratification based on ethnicity and study design. In the subgroup analyses for postmenopausal women, significantly increased risks were found for rs1219648 and rs2420946 in any model. This meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of breast cancer. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays.

A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation.

Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM, micropeptide in mitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM-/- mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM-/- mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.

Genome­scale analysis to identify potential prognostic microRNA biomarkers for predicting overall survival in patients with colon adenocarcinoma.

The aim of the present study was to identify potential prognostic microRNA (miRNA) biomarkers for colon adenocarcinoma (COAD) prognostic prediction using the dataset of The Cancer Genome Atlas (TCGA). The genome­wide miRNA sequencing dataset and corresponding COAD clinical information were downloaded from TCGA. Prognosis­related miRNA screening was performed by genome­wide multivariable Cox regression analysis and used for prognostic signature construction. Ten miRNAs (hsa­mir­891a, hsa­mir­6854, hsa­mir­216a, hsa­mir­378d­1, hsa­mir­92a­1, hsa­mir­4709, hsa­mir­92a­2, hsa­mir­210, hsa­mir­940 and hsa­mir­887) were identified as prognostic miRNAs and used for further prognostic signature construction. The 10­miRNA prognostic signature showed good performance in prognosis prediction (adjusted P<0.0001; adjusted hazard ratio, 4.580; 95% confidence interval, 2.783­7.538). In the time­dependent receiver operating characteristic analysis, the area under the curve was 0.735, 0.788, 0.806, 0.806, 0.775 and 0.900 for 1­, 2­, 3­, 4­, 5­ and 10­year COAD overall survival prediction, respectively. Comprehensive survival analysis suggested that the 10­miRNA prognostic signature is an independent prognostic factor in COAD, with a better performance in COAD overall survival prediction than other traditional clinical parameters. Functional enrichment indicated that the corresponding target genes were significantly enriched in multiple biological processes and pathways, including regulation of cell proliferation, cell cycle, cell growth, and Wnt and transforming growth factor­ß signaling pathways. In conclusion, our present study identified a 10­miRNA expression signature that may serve as a potential prognostic biomarker in COAD patients.

Prognostic and predictive value of serum carcinoembryonic antigen levels in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutations and receiving tyrosine kinase inhibitors.

BACKGROUND: Despite the widespread use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced or recurrent non-small cell lung cancer (NSCLC), no biomarkers for predicting the efficacy of EGFR-TKIs in patients with EGFR-sensitive mutations have yet been identified. The purpose of our study was to explore the effect of baseline serum tumor markers in stage IIIB/IV NSCLC patients treated with EGFR-TKIs. METHODS: One hundred and seventy-seven patients with stage IIIB/IV NSCLC who harbored EGFR-sensitive mutations and were treated with EGFR-TKIs were retrospectively reviewed. Their levels of CEA, CYFRA 21-1, NSE and CA199 were measured before treatment with EGFR-TKIs. RESULTS: The response rate for all patients was 54.8%, with a median progression-free survival of 6.6 months and overall survival of 14.8 months. In univariate analyses, patients with CEA levels below the cutoff point (10 ng/ml) had higher RR, better PFS, and better OS than those with CEA levels above 10 ng/mL (RR: 69.2% vs. 43.4%, p= 0.001; mPFS: 7.8 months vs. 5.3 months, p=0.029; mOS: 18.8 months vs. 11.8 months, p=0.000). The baseline serum CEA level was an independent factor for RR (odds ratio [OR] =0.322, p=0.001), PFS (hazard ratio [HR] =1.45, p=0.025), and OS (HR=2.133, p=0.000). CONCLUSION: Our study suggests that baseline serum CEA levels may play a role in predicting the efficacy of EGFR-TKIs in stage IIIB/IV NSCLC patients with EGFR-sensitive mutations who are treated with EGFR-TKIs.

Age-related alterations of neuronal excitability and voltage-dependent Ca2+ current in a spontaneous mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder, characterized by a progressive dysfunction of central neurons, and senescence-accelerated mouse prone 8 (SAMP8), a spontaneous AD mouse model, appears to be an excellent model to investigate the process of AD. Previous studies have indicated that neuronal excitability is impaired in transgenic AD mice. In this study, the cognition of SAMP8 mice was tested using the passive avoidance task and Morris water maze; whole-cell current-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials, and after-hyperpolarization; and the voltage-dependent Ca2+ current in hippocampal slices was measured using whole-cell voltage-clamp recordings. We found that compared to the young mice, the performance in the learning and memory behavior tasks was impaired in aged mice, and the hippocampal CA1 pyramidal neurons of the aged mice showed a significantly depolarized resting membrane potential, increased numbers of action potentials after injection of depolarizing current, and increased after-hyperpolarization after the action potentials. Consistent with the above changes, the voltage-dependent Ca2+ current was larger in aged mice than in young mice. These data suggested that the aged SAMP8 neurons were hyperexcitable, and the alterations in the voltage-dependent Ca2+ current of aged neurons occurred in parallel to the elevation in excitability.

Significance of glucocorticoid receptor expression in patients with non-small cell lung cancer treated with pemetrexed-based chemotherapy.

BACKGROUND: Pemetrexed is the preferred chemotherapy agent in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), but lacks biomarkers predicting its efficacy. Dexamethasone, one of the premedications of pemetrexed, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cells (PBMC) and its role in predicting pemetrexed efficacy. METHODS: In all, 122 patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC was measured before treatment with pemetrexed using real-time PCR was used to detect the levels of GRα and GRß. RESULTS: The response rate for all patients was 38.5%, with a median progression-free survival (PFS) of 5.9 months and overall survival (OS) of 14.3 months. In univariate analyses, patients with a low GRα/GRß ratio in PBMC had higher RR, better PFS, and better OS than those with a high GRα/GRß ratio (RR: 48.2 vs. 30.3%, p = 0.043; mPFS: 6.9 vs. 4.0 months, p < 0.001; mOS: 18.7 vs. 12.2 months, p = 0.005). The baseline GRα/GRß ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95% CI 0.208-0.978; p = 0.044), PFS (HR = 1.584, 95% CI 1.094-2.295; p = 0.015), and OS (HR = 1.761, 95% CI 1.195-2.595; p = 0.004). CONCLUSIONS: Baseline GRα/GRß ratio in PBMC may play a role in predicting the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sq NSCLC patients.

p38 MAPK Participates in the Mediation of GLT-1 Up-regulation During the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning.

Our previous study has proved that the up-regulation of glial glutamate transporter 1 (GLT-1) played an important role in the acquisition of brain ischemic tolerance after cerebral ischemic preconditioning (CIP) in rats. However, little is known about the mechanism involved in the up-regulation of GLT-1 in the process. The present study investigates whether p38 MAPK, ERK1/2, and/or JNK participates in the up-regulation of GLT-1 during the induction of brain ischemic tolerance by CIP. It was found that CIP significantly enhanced the expression of p-p38 MAPK without altering p-ERK1/2 and p-JNK expression in the CA1 hippocampus. Inhibition of p38 MAPK function by its selective inhibitor SB203580 or knockdown p38 MAPK expression by its antisense oligodeoxynucleotides (AS-ODNs) suppressed the induction of brain ischemic tolerance. Furthermore, p38 MAPK was activated earlier than the up-regulation of GLT-1 in the CA1 hippocampus after CIP. Meanwhile, the expression of p-p38 MAPK by astrocytes was increased, and p38 MAPK AS-ODNs dose-dependently inhibited the up-regulation of GLT-1 after CIP. Taken together, it could be concluded that p38 MAPK participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance after CIP.

Primary breast lymphoma: long-term treatment outcome and prognosis.

Between 1980 and 2002, 32 cases diagnosed as primary breast lymphoma were reviewed. Among them, 18 patients were stage I and 14 were stage II. Four patients underwent mastectomy and the remainder underwent lumpectomy. Twenty-eight patients received postoperative chemotherapy and 20 patients received postoperative radiotherapy. After a median follow-up of 76 (range 25 - 245) months, the 5-year overall survival and relapse-free survival was 69.3% and 47.7%, respectively. Ann Arbor stage, International Prognostic Index (IPI) excluding stage, lactic dehydrogenase (LDH) and radiotherapy were significant factors for relapse-free survival. We conclude that younger age and elevated LDH were apparent characters of the patients in our study. IPI excluding stage was a valuable prognostic factor. Combined radiotherapy and chemotherapy appeared to be important for treatment.

PA-MSHA in combination with EGFR tyrosine kinase inhibitor: A new strategy to overcome the drug resistance of non-small cell lung cancer cells.

The inhibition of epidermal growth factor receptor (EGFR) signaling by Gefitinib provides a promising treatment strategy for non-small cell lung cancer (NSCLC); however, drug resistance to Gefitinib and other tyrosine kinase inhibitors presents a major issue. Using NSCLC cell lines with differential EGFR status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth. PC-9, A549, and NCI-H1975 cells were treated with PA-MSHA, Gefetinib, or PA-MSHA plus Gefetinib at different concentrations and times. The effects of the drugs on proliferation, cell cycle distribution and apoptosis were evaluated. The activation of EGFR and apoptotic signaling-related molecules was evaluated by Western blotting in the presence or absence of EGFR siRNA. Tumor growth and pathway signaling activation was assessed by xenografts in nude mice. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in all NSCLC cells tested. The combination of PA-MSHA plus Gefitinib enhanced the growth inhibition, sub-G1 content and apoptosis over that observed with either agent alone. Furthermore, the combination of PA-MSHA plus Gefitinib resulted in caspase-3/caspase-9 cleavage and increased inhibition of EGFR-dependent activation of AKT and ERK phosphorylation. Combination treatment was more effective in reducing tumor size and EGFR activation than either agent alone. These data suggest that PA-MSHA and Gefitinib function additively to suppress the proliferative effects of NSCLC cells of differential EGFR status. The combination of PA-MSHA and Gefitinib provides a potential new strategy to conquer drug resistance for anti-EGFR-targeted therapy of NSCLC.