H2S Alleviates Neuropathic Pain in Mice by Nrf2 Signaling Pathway Activation.

Neuropathic pain is a chronic pain caused by direct damage to the peripheral or central nervous system, characterized by hyperalgesia, allodynia, and spontaneous pain. Hydrogen sulfide (H2S) therapy has been applied for neuropathic pain treatment, although the underlying mechanisms remain unknown. In this study, we sought to ascertain whether H2S therapy could alleviate neuropathic pain in a model of chronic constriction injury (CCI) and, if so, the potential mechanism. A CCI model was established in mice through a spinal nerve ligation method. Intrathecal injection of NaHS was used to treat CCI model mice. The thermal paw withdrawal latency (TPWL) and mechanical paw withdrawal threshold (MPWT) were used for pain threshold evaluation in mice. A series of experiments including immunofluorescence, enzyme-linked immunosorbent assay, electrophysiological test, mitochondrial DNA (mtDNA) quantification, measurement of ATP content, demethylase activity, and western blot were performed to investigate the specific mechanism of H2S treatment in neuropathic pain. Mice with CCI exposure exhibited a decrease in MPWT and TPWL, an increase in IL-1ß and TNF-α expressions, elevated eEPSP amplitude, an upregulation of mtDNA, and a reduction in ATP production, whereas H2S treatment significantly reversed these changes. Furthermore, CCI exposure induced a remarkable increase in vGlut2- and c-fos-positive as well as vGlut2- and Nrf2-positive cells, an increase in Nrf2 located in the nucleus, and an upregulation of H3K4 methylation, and H2S treatment further enhanced these changes. In addition, ML385, a selective Nrf2 inhibitor, reversed the neuroprotective effects of H2S. H2S treatment mitigates CCI-induced neuropathic pain in mice. This protective mechanism is possibly linked to the activation of the Nrf2 signaling pathway in vGlut2-positive cells.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/ß-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability.

BACKGROUND: Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells. METHODS: ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC. RESULTS: Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated ß-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/ß-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/ß-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells. CONCLUSIONS: Our findings elucidate that melatonin mitigates the HDAC7/ß-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1-2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1-14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1-2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

Methionine restriction enhances the chemotherapeutic sensitivity of colorectal cancer stem cells by miR-320d/c-Myc axis.

Chemotherapy resistance of colorectal cancer stem cells (CRC-SCs) has become a major challenge in clinical treatment of cancer. Methionine restriction (MR) enhances the therapeutic effect of chemotherapeutic agents. The aim of this study was to explore the molecular pathways that MR affects the chemotherapeutic sensitivity of CRC-SCs. CD133+ and CD133- SW480 or SW620 cells were isolated by magnetic-activated cell sorting (MACS). Mouse xenograft tumor model was established by subcutaneous inoculation of CD133+ SW480. MTT assay was used to detect cell viability. Phase distribution of cell cycle was detected by flow cytometry. Western blotting was used to detect drug-resistant related protein expression. miR-320d and transcription factor c-Myc expressions were detected by qRT-PCR. The interaction between miR-320d and c-Myc was verified by luciferase assay. CD133+ SW480 and SW620 cells were more resistant to 5-fluorouracil (5-FU) than CD133- cells. In vitro and in vivo experiments showed that 5-FU and MR combined therapy further inhibited CD133+ cell activity and ATP binding cassette subfamily G member 2 (ABCG2) expression, and reduced tumor volume compared with drug administration alone. Interference with miR-320d or overexpression of c-Myc reversed the increased chemotherapeutic sensitivity of CRC-SCs induced by synergistic therapy with 5-FU and MR. miR-320d can target and regulate c-Myc. Interference with c-Myc could reverse the increase in cell viability and ABCG2 expression caused by down-regulation of miR-320d. In conclusion, the combined chemotherapy with MR can enhance the chemotherapeutic sensitivity of CRC-SCs by up-regulation of miR-320d to inhibit c-Myc expression, which lays a molecular basis for MR regulation of chemotherapeutic sensitivity of CRC-SCs.

Exosome-mediated transfer of lncRNA HCG18 promotes M2 macrophage polarization in gastric cancer.

BACKGROUND: Gastric cancer (GC) derived exosomes (Exos) aggravate GC development by facilitating M2 macrophage polarization and long non-coding RNA (lncRNA) HCG18 was highly expressed in GC. This study aimed to investigate whether the exosomal lncRNA HCG18 regulated the M2 macrophage polarization in GC and the possible mechanism. METHODS: The isolated GC cells (GCCs)-Exos were identified using transmission electron microscopy, Nanoparticle Tracking Analysis and Western blot. The GCCs-Exos function was verified by enzyme-linked immunosorbent assay and flow cytometry. Meanwhile, the exosomal lncRNA HCG18 function was determined using thein vitro assays. Furthermore, the underlying mechanism of the exosomal lncRNA HCG18 that regulated M2 macrophage polarization in GC was investigated using dual-luciferase reporter gene assay and RNA pull-down. RESULTS: After the validation of GCCs-Exos, the GCCs-Exos facilitated the M2 macrophage polarization. The in vitro assays confirmed that the exosomal lncRNA HCG18 positively regulated the M2 macrophage polarization. Mechanistically, lncRNA HCG18 bound to miR-875-3p, miR-875-3p bound to KLF4. Furthermore, GCCs-exosomal lncRNA HCG18 elevated the KLF4 expression by decreasing miR-875-3p in macrophages to facilitate M2 macrophage polarization, thus alleviating GC. The in vivo assays clarified that the GCCs-exosomal lncRNA HCG18 restrained the tumor growth of GC induced by M2 macrophages. CONCLUSION: GCCs-exosomal lncRNA HCG18 elevated KLF4 expression by decreasing miR-875-3p in macrophages to facilitate the M2 macrophage polarization.

Transfer of LncRNA CRNDE in TAM-derived exosomes is linked with cisplatin resistance in gastric cancer.

This study explores the role of the long noncoding RNA (LncRNA) CRNDE in cisplatin (CDDP) resistance of gastric cancer (GC) cells. Here, we show that LncRNA CRNDE is upregulated in carcinoma tissues and tumor-associated macrophages (TAMs) of GC patients. In vitro experiments show that CRNDE is enriched in M2-polarized macrophage-derived exosomes (M2-exo) and is transferred from M2 macrophages to GC cells via exosomes. Silencing CRNDE in M2-exo reverses the promotional effect of M2-exo on cell proliferation in CDDP-treated GC cells and homograft tumor growth in CDDP-treated nude mice. Mechanistically, CRNDE facilitates neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1)-mediated phosphatase and tensin homolog (PTEN) ubiquitination. Silencing CRNDE in M2-exo enhances the CDDP sensitivity of GC cells treated with M2-exo, which is reduced by PTEN knockdown. Collectively, these data reveal a vital role for CRNDE in CDDP resistance of GC cells and suggest that the upregulation of CRNDE in GC cells may be attributed to the transfer of TAM-derived exosomes.

Methionine deficiency promoted mitophagy via lncRNA PVT1-mediated promoter demethylation of BNIP3 in gastric cancer.

BACKGROUND: The occurrence of recurrence and metastasis after treatment is a major challenge in the treatment of gastric cancer. This study was based on the methionine (Met)-dependent characteristics of gastric cancer cells to explore the effect of Met deficiency on the occurrence and development of gastric cancer. METHODS: Human gastric cancer cell lines MKN45 and AGS and nude mice model were used to explore how Met affects gastric cancer by regulating lncRNA PVT1. RESULTS: The levels of lncRNA PVT1 in gastric cancer cells and human gastric cancer xenografts of nude mice were down-regulated under the condition of Met deficiency. The cell viability and cell proliferation were declined after MKN45 and SGC-790 cells were cultured in Met-deficient medium. LncRNA PVT1 could affect BNIP3 promoter DNA methylation level through its interaction with DNMT1. Moreover, the silence of lncRNA PVT1 and the up-regulation of BNIP3 level inhibited the gastric cancer cell proliferation. Met deficiency could up-regulate BNIP3 expression by inhibiting the binding of lncRNA PVT1 to DNMT1, and activate mitophagy, thus inhibiting gastric cancer cell proliferation. CONCLUSION: Our study suggested that Met deficiency could down-regulate the expression of lncRNA PVT1, further demethylated the promoter of BNIP3, thus inhibiting the proliferation of gastric cancer cells by activating mitophagy.

Identification of subtype-specific genes signature by WGCNA for prognostic prediction in diffuse type gastric cancer.

BACKGROUND: Gastric cancer is a common malignancy and had poor response to treatment due to its strong heterogeneity. This study aimed to identify essential genes associated with diffuse type gastric cancer and construct a powerful prognostic model. RESULTS: We conducted a weighted gene co-expression network analysis (WGCN) using transcripts per million (TPM) expression data from The Cancer Genome Atlas (TCGA) to find out the module related with diffuse type gastric cancer. Combining Least Absolute Shrinkage and Selection Operator (LASSO) with multi-cox regression, the 10 specific genes risk score model of diffuse type gastric cancer was established. The concordance index (0.97), the area under the respective ROC curves (AUCs) (1-years: 0.98; 3-years: 1; 5-years: 1) and survival difference of high- and low risk groups (p=2.84e-10) of this model in TCGA dataset were obtained. The moderate predicting performance was observed in the independent cohort of GSE15459 and GSE62254. The results of the gene set enrichment analysis (GSEA) using high-and low risk group as phenotype indicated differential expression of tumor-related pathways. CONCLUSION: Thus, we constructed a reliable prognostic model for diffuse type gastric cancer, which should be beneficial for clinical therapeutic decision-making.

TMEM88 modulates the secretion of inflammatory factors by regulating YAP signaling pathway in alcoholic liver disease.

OBJECTIVE: Transmembrane protein 88 (TMEM88), a new protein of increasing concern existed in cell membrane, inhibits the typical Wnt/ß-catenin signaling pathway to play a regulatory role on cell proliferation by binding to Dishevelled-1. Until recently, the connection between TMEM88 and alcoholic liver disease is unknown. In this research, we explored the effect of TMEM88 on the secretion of inflammatory cytokines in ethanol (EtOH)-induced RAW264.7 cells, moreover, the function of YAP signaling pathway in EtOH-induced RAW264.7 cells were investigated. METHODS: We administered TMEM88 adenovirus (ADV-TMEM88) by tail vein injection into C57BL/6J mice in vivo. In vitro, RAW264.7 murine macrophages were stimulated with EtOH and were transfected with pEGFP-C1-TMEM88 and TMEM88 siRNA, respectively, protein expression and mRNA expression of IL-6 and IL-1ß were assessed by Western Blotting and RT-qPCR, respectively. RESULTS: Our group found that the overexpression of TMEM88 led to an up-regulation of IL-6 and IL-1ß secretion, hinting that it had the possibility of linking with the initiation, the development, and the end of inflammation. In addition to that, TMEM88 silencing reduced the secretion of IL-6 and IL-1ß in RAW264.7 cells. Moreover, we demonstrated that the YAP signaling pathway under the action of EtOH was activated by TMEM88. CONCLUSIONS: All in all, these experimental outcomes indicated that TMEM88 had an indispensable impact on EtOH-induced secretion of inflammatory cytokines (IL-6 and IL-1ß) in RAW264.7 cells through YAP signaling pathway.

Disparity in clinical outcomes between pure and combined pulmonary large-cell neuroendocrine carcinoma: A multi-center retrospective study.

OBJECTIVES: The 2015 World Health Organization classification defines pulmonary large-cell neuroendocrine carcinoma (LCNEC) as a high-grade neuroendocrine carcinoma. However, the clinical characteristics and prognostic factors of pure LCNEC and combined LCNEC remain unclear. Hence, we performed a multi-center retrospective study to compare the clinical outcomes of pure versus combined LCNEC. MATERIALS AND METHODS: Data from 381 patients with pulmonary LCNEC admitted to 17 Chinese institutes between 2009 and 2016 were collected retrospectively. Clinical characteristics and prognosis were analyzed among patients receiving adjuvant (adjuvant group; n = 56) and first-line (first-line group; n = 146) chemotherapy, as well as among patients receiving small cell lung cancer (SCLC) and non-SCLC (NSCLC) chemotherapy regimens. The Kaplan-Meier method and multivariable Cox regression were used to identify clinicopathological variables that might influence patient outcomes. RESULTS: Expression levels of neuroendocrine markers (synaptophysin, chromogranin-A, CD56) were associated with patients' prognosis in the total study cohort. In the adjuvant group, median disease-free survival was non-significantly longer for SCLC-based regimens than for NSCLC-based regimens (P = 0.112). In the first-line group, median progression-free survival was significantly longer for SCLC-based regimens than for NSCLC-based regimens (11.5 vs. 7.2 months, P = 0.003). Among patients with combined LCNEC, adenocarcinoma was the most common combined component, accounting for 70.0 % of cases. Additionally, median overall survival was non-significantly shorter for combined LCNEC than for pure LCNEC (P = 0.083). CONCLUSION: The SCLC regimen is a more effective choice, as either first-line or adjuvant chemotherapy, when compared to the NSCLC regimen for LCNEC treatment. Further studies are needed to clarify the survival differences between patients with pure-, and combined LCNEC.

Clinical effectiveness of combined interventional therapy as a salvage modality for unresectable pancreatic carcinoma.

Although different treatment methods have been introduced to treat advanced pancreatic carcinoma, the median overall survival rate remains unsatisfactory. Theoretically, combining different treatment methods should work in synergy to enhance locoregional disease control and improve survival. Therefore, the aim of the present retrospective study was to analyze the effectiveness of combined interventional therapy compared with trans-arterial chemoembolization (TACE) or chemotherapy alone for the treatment of unresectable pancreatic carcinoma. A total of 266 patients who were undergoing treatment for unresectable pancreatic carcinoma between July 2012 and November 2015 were included in the current study. The tumor responses and 3-year overall survival rates of patients treated with combined interventional therapy (TACE combined with iodine-125 seed implantation and/or radiofrequency ablation; CIT group; n=84) were compared with those of patients treated with TACE alone (TACE group; n=59), as well as patients treated with systemic chemotherapy alone (control group; n=123). Patients in the CIT group exhibited significantly improved tumor responses compared with patients in the TACE group (51.89 vs. 30.61%; P=0.028) or control group (51.89 vs. 17.20%; P<0.001). The 3-year overall survival rate of the CIT group was also significantly higher compared with that of the TACE and control groups (P=0.0116 and P=0.0001, respectively). Furthermore, the CIT group exhibited a significantly higher overall survival rate for patients with unresectable metastatic pancreatic cancer compared with the TACE and control groups (P=0.0088 and P<0.0001, respectively), which suggests that a combination of different interventional techniques increases the survival of patients with unresectable pancreatic cancer. No life-threatening complications were observed in any treatment group. In conclusion, combined interventional therapy exhibits a good efficacy and an improved survival rate for unresectable pancreatic cancer compared with TACE alone.

Ectopic liver tissue in the esophagus: A case report.

INTRODUCTION: Ectopic liver (EL) is a rare entity, which is reported to develop at various sites, such as the abdominal cavity, the retroperitoneal cavity, the pleural cavity, and the mediastinum. PATIENT CONCERNS: A 27-year-old previously healthy Chinese man suffered from a discontinuous abdominal pain in the upper abdomen for 2 months. DIAGNOSIS: The upper gastrointestinal endoscopy revealed there was a polypoid mucosal uplift on the distal region of the esophagus near the cardia. INTERVENTIONS: Endoscopic polypectomy was performed. OUTCOMES: Pathology examination showed the liver tissue. CONCLUSION: EL should be excised as it may possibly lead to the development of a malignancy. Endoscopic resection was found to be safe and reliable in this case.

Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1-cAMP Response Element Binding-Brain-Derived Neurotrophic Factor Pathway.

BACKGROUND: Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression. METHODS: Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5). RESULTS: Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB-brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions. CONCLUSIONS: The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.

A Novel Derivative of (-)mycousnine Produced by the Endophytic Fungus Mycosphaerella nawae, Exhibits High and Selective Immunosuppressive Activity on T Cells.

An endophytic fungus, Mycosphaerella nawae ZJLQ129, was isolated from the leaves of the traditional Chinese medicine Smilax china. From the fermentation broth and mycelium, a dibenzofurane compound (-)mycousnine (1) was isolated. Chemical modification of it to the amide derivative (-)mycousnine enamine (2), which is new to science, was found to have high and selective immunosuppressive activity: similar to cyclosporin A, (-)mycousnine enamine (2) selectively inhibited T cell proliferation, suppressed the expression of the surface activation antigens CD25 and CD69 and the formation and expression of the cytokines interleukin-2 as well as interferon γ in activated T cells, but did not show any effect on the proliferation of B cells and cancer cells (PANC-1 and A549) and the activation of macrophages. Furthermore, the cytotoxicity of (-)mycousnine enamine was lower than that of cyclosporin A, and its therapeutic index (TC50/EC50) was 4,463.5, which is five-fold higher than that of cyclosporin A. We conclude that (-)mycousnine enamine (2), the semi-synthestic product prepared from the native product (-)mycousnine (1) of the endophyte M. nawae is a novel effective immunosuppressant showing low toxicity and high selectivity.

Non-Gaussian diffusion imaging for malignant and benign pulmonary nodule differentiation: a preliminary study.

BACKGROUND: Diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) has demonstrated inconsistent results in pulmonary nodule differentiation. Diffusion kurtosis imaging (DKI), which quantifies non-Gaussian diffusion, is believed to better characterize tissue micro-structure than conventional DWI. PURPOSE: To assess the feasibility of DKI in human lungs and to compare its diagnostic value with standard DWI in differentiating malignancies from benign pulmonary nodules. MATERIAL AND METHODS: Thirty-five pulmonary nodules in 32 consecutive patients were evaluated by DKI by using 3b-values of 0, 500, and 1000 s/mm2 and conventional DWI with b values of 0 and 800 s/mm2. Two observers independently evaluated and compared diagnostic accuracy of mean kurtosis (MK) and ADC values in differentiating malignancies from benign pulmonary nodules. The intra- and inter-observer repeatability (intra-class correlation coefficient [ICC]) were also assessed for each derived measures. RESULTS: The diagnostic accuracy, and the area under curve (AUC) in differentiating malignancies from benign pulmonary nodule, were not significantly higher for MK (Obs. 1a: 85.70%, 0.87; Obs. 1b: 80.00%, 0.80; and Obs. 2: 82.80%, 0.91) as compared to ADC (Obs. 1a: 77.14%, 0.81; Obs. 1b: 80.00%, 0.85; and Obs. 2: 77.14%, 0.85 respectively). The intra- and inter-observer agreement (ICC) for malignant and benign lesions was substantial for each reading. CONCLUSION: The initial results of this study indicate the feasibility of DKI in human lungs. However, there was no significant benefit of DKI derived MK values over ADC for malignant and benign pulmonary nodule differentiation.

Rational design of asymmetric red fluorescent probes for live cell imaging with high AIE effects and large two-photon absorption cross sections using tunable terminal groups.

In this work, we report the synthesis of a family of donor-acceptor (D-A) π-conjugated aggregation-induced red emission materials (TPABT, DTPABT, TPEBT and DTPEBT) with the same core 2,2-(2,2-diphenylethene-1,1-diyl)dithiophene (DPDT) and different amounts and different strengths of electron-donating terminal moieties. Interestingly, TPABT and TPEBT, which have asymmetric structures, give obviously higher solid fluorescence quantum efficiencies in comparison with those of the corresponding symmetric structures, DTPABT and DTPEBT, respectively. In particular, the thin film of TPEBT exhibited the highest fluorescence quantum efficiency of ca. 38% with the highest αAIE. Moreover, TPEBT and DTPEBT with TPE groups showed two-photon absorption cross-sections of (δ) 1.75 × 103 GM and 1.94 × 103 GM at 780 nm, respectively, which are obviously higher than the other two red fluorescent materials with triphenylamine groups. Then, the one-photon and two-photon fluorescence imaging of MCF-7 breast cancer cells and Hela cells, and cytotoxicity experiments, were carried out with these red fluorescent materials. Intense intracellular red fluorescence was observed for all the molecules using one-photon excitation and for TPABT using two-photon excitation in the cell cytoplasm. Finally, TPEBT is biocompatible and functions well in mouse brain blood vascular visualization. It is indicated that these materials can be used as a specific stain fluorescent probe for live cell imaging.

RESILIENCE THEORY AND ITS IMPLICATIONS FOR CHINESE ADOLESCENTS.

Over the past 20 years, resilience theory has attracted great attention from both researchers and mental health practitioners. Resilience is defined as a process of overcoming the negative effects of risk exposure, coping successfully with traumatic experiences, or avoiding the negative trajectories associated with risks. Three basic models of resilience have been proposed to account for the mechanism whereby promotive factors operate to alter the trajectory from risk exposure to negative consequences: compensatory model, protective model, and inoculation model. Assets and resources are two types of promotive factors found to be effective in decreasing internalizing and externalizing problems. Considering the protective or compensatory role of assets and resources in helping youth be resilient against negative effects of adversity, resilience could be applied to Chinese migrant and left-behind children who are at risk for internalizing (e.g., depression, anxiety) and externalizing problems (e.g., delinquent behaviors, cigarette and alcohol use). Additionally, psychological suzhi-based interventions, a mental health construct for individuals that focuses on a strengths-based approach, can be integrated with resilience-based approach to develop more balanced programs for positive youth development.

Pemetrexed induced a durable response in heavily pretreated metastatic extramammary Paget's disease.

PURPOSE: Extramammary Paget's disease (EMPD) is a rare neoplasm with only a limited number of cases reported in the literature. Little was known about the availability of systemic chemotherapy for metastatic EMPD. METHODS: We report one case of heavily pretreated EMPD with multiple organ metastases and successfully treated by pemetrexed. RESULT: The tumor was progression after multi-line therapy including erlotinib, radiotherapy, combined chemotherapy and radioactive particles implantation. Pemetrexed monotherapy was applied and progression free survival of more than 5 months with partial remission (PR) response was achieved. Only 1 time of grade 3 neutropenia was observed during the pemetrexed chemotherapy. CONCLUSION: Due to the significant response and tolerability in the present case, pemetrexed monotherapy was recommended as a potent candidate for patients with advanced EMPD.

Bevacizumab concomitant with chemotherapy is effective in treating Chinese patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). METHODS: Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. RESULTS: The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. CONCLUSIONS: Bevacizumab concomitant with chemotherapy is effective and the related toxicity can be well tolerated in Chinese patients with NSNSCLC.