Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer.

Esophageal cancer (EC) is a main cause of cancer-related deaths. However, genomic alterations and the clinical value of next-generation sequencing (NGS) in advanced or metastatic EC for precision therapy remain largely unclear. Herein, we performed comprehensive analyses on a cohort of 47 individuals with advanced or metastatic EC who underwent NGS between May 2017 and February 2020. Eventually, 227 mutated genes were identified in the cohort. TP53, NQO1, DPYD, GSTM1, XRCC1 and ERCC1 were the most mutated genes and associated with immune cell infiltration, autophagy and hypoxia. Patients who received NGS-guided treatments exhibited better objective remission rate (ORR) (72.22%), disease control rate (DCR) (88.89%), overall survival (OS) (P = .0019) and progression-free survival (PFS) (P = .0077) than those not receiving NGS-guided therapies. The multivariate analyses further demonstrated that the NGS-guided therapy was an independently prognostic factor (OS: hazard radio [HR] 0.31, 95% coincidence interval [CI] 0.1-0.97, P = .04). In conclusion, we depicted a comprehensive mutational landscape of 47 patients with locally advanced or metastatic EC and illustrated the utility of NGS testing to guide clinical management in improving ORR, DCR, OS and PFS.

Hepatocarcinoma cell-derived hepatoma-derived growth factor (HDGF) induces regulatory T cells.

BACKGROUND AND AIMS: It is suggested that regulatory immune cells play a critical role in cancer cell growth by facilitating cancer cells to escape from the immune surveillance. The generation of the immune regulatory cells in cancer has not been fully understood yet. This study aims to investigate the role of the hepatoma-derived growth factor (HDGF) in the generation of regulatory T cells (Treg). METHODS: CCL-9.1 cells (A mouse hepatoma cell line), were cultured. The expression of HDGF in CCL-9.1 cells was assessed by quantitative RT-PCR and Western blotting. The generation of Foxp3(+) T cells was assessed by cell culture and flow cytometry. The immune suppressor function of the Foxp3(+) T cells on CD8(+) T cell activities was assessed by the carboxyfluorescein succinimidyl ester (CFSE)-dilution assay and enzyme-linked immunosorbent assay. RESULTS: The results showed that exposure to PolyIC markedly increased the expression of HDGF in CCL-9.1 cells. Coculture of CCL-9.1 cells and CD4(+) CD25(-) T cells in the presence of PolyIC generated the Forkhead box protein (Foxp)3(+) T cells. The exposure to HDGF increased the expression of Foxp3 and decreased the expression of GATA3 in CD4(+) T cells. After activation, the Foxp3(+) T cells suppressed the CD8(+) T cell proliferation and the release of the cytotoxic cytokines. CONCLUSIONS: Liver cancer cell-derived HDGF can induce Foxp3(+) T cells; the latter has the immune suppressor functions on CD8(+) T cell activities.

[Chinese herbal medicine for patients with mild to moderate Alzheimer disease based on syndrome differentiation: a randomized controlled trial].

BACKGROUND: Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by its gradual progression. At present, the cause and mechanism of AD are yet unclear, and there is no effective therapy for treating it. With development of global aging, the prevalence rate of AD is increasing. The life quality of elderly people is affected severely by AD that is ultimately life-threatening. Recently, study on treating AD with traditional Chinese medicine (TCM) has deepened. OBJECTIVE: To explore the therapeutic effects of a syndrome differentiation-based TCM regime in treating patients with mild to moderate AD for improving cognition, and to evaluate the changes in brain function of AD patients observed by resting-state functional magnetic resonance imaging (fMRI) technique. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Adopting the internationally recognized criteria developed by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association, the clinical trial was conducted on 131 patients with mild to moderate AD from 5 communities and 7 social welfare institutions. Participants were accepted after informed consent was received, and laboratory tests and a head imaging study were conducted. The patients were randomly divided into Chinese medicine group (CMG) (66 cases) or Western medicine group (WMG) (65 cases). Patients in the CMG were treated monthly with Chinese medicine according to syndrome differentiation. Patients in the WMG were treated with donepezil at a dose of 5 mg once daily. The therapeutic course lasted 48 weeks. MAIN OUTCOME MEASURES: The scores of Mini-Mental State Examination (MMSE), Fuld Object-Memory Evaluation (FOM), Block Design (BD) and Digit Span (DS) were used to evaluate the cognitive function; resting-state fMRI was used for observing brain function. The questionnaires and fMRI were performed before and after treatments. RESULTS: The cognitive functions of the patients in the CMG and WMG were improved after treatment. MMSE score was improved significantly in both groups (P<0.05 or P<0.001). After 48 weeks of treatment, 70.91% patients in the CMG had an improved MMSE score and 20% got worse, however, 55.77% patients in the WMG were improved in MMSE score and 34.62% got worse. Scores of FOM denominator and BD increased significantly in both groups; scores of FOM numerator and DS were also increased in the CMG (P<0.05 or P<0.01). The results of fMRI suggested that both Chinese medicine and donepezil treatment improved the connectivity between posterior cingulated gyrus and specific areas in the brain. The influence range of Chinese medicine primarily impacted on the left parietal lobe, being less than the influence range of donepezil, which primarily affected both sides of frontal lobes. CONCLUSION: TCM treatment based on syndrome differentiation is effective in improving cognitive function of patients with mild to moderate AD and increasing the brain function by increasing connectivity between posterior cingulated gyrus and specific areas in the brain.

Gross Tumor Volume Predicts Survival and Pathological Complete Response of Locally Advanced Esophageal Cancer After Neoadjuvant Chemoradiotherapy.

Background: Neoadjuvant chemoradiotherapy (neo-CRT) plus surgery has greatly improved the prognosis of locally advanced esophageal cancer (EC) patients. But which factors may influence the pathological tumor response and long-term survival remains unclear. The purpose of this study was to identify the prognostic biomarkers of locally advanced EC patients receiving neo-CRT. Methods: We reviewed the data of 72 patients with cT2-4N0-3M0 EC who underwent neo-CRT at our hospital. The patients received intensity-modulated radiation therapy with a total radiation dose of 41.4-60.0 Gy. Most patients received platinum + paclitaxel-based combination regimens every three weeks for 2-4 cycles. The recorded data included age, sex, smoking history, alcohol use, histology, tumor location, clinical TNM stage, tumor length, gross tumor volume (GTV), GTV of primary tumor (GTVp), GTV of lymph nodes (GTVn), radiation dose, and number of chemotherapy cycles. Overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR) were analyzed. Results: The 3-year OS and PFS rates of these patients who underwent neo-CRT were 51.14% and 43.28%, respectively. In the univariate analyses, smoking history, clinical stage, GTV, GTVp, and GTVn were significantly associated with OS, whereas alcohol use, GTV, GTVp, and GTVn were significantly associated with PFS. Furthermore, in the multivariate analysis, GTV was an independent prognostic predictor of OS (hazard ratio (HR): 14.14, 95% confidence interval (CI): 3.747-53.33, P < 0.0001) and PFS (HR: 6.090, 95% CI: 2.398-15.47, P < 0.0001). In addition, GTV < 60.50 cm3 compared to > 60.50 cm3 was significantly associated with higher pCR rate (59.3% and 27.8%, respectively, P = 0.038). High dose (> 50 Gy) and increased number of chemotherapy cycles (≥ 3) didn't improve the OS or PFS in patients with GTV > 60.50 cm3. Conclusion: GTV was an independent prognostic factor of long-term survival in EC patients, which may be because GTV is associated with histological response to neo-CRT. Additionally, patients with GTV > 60.50 cm3 didn't benefit from increased radiation dose or increased number of chemotherapy cycles.

[Clinical study on effect of Shenyin Oral Liquid in treating mild cognitive impairment].

OBJECTIVE: To observe the therapeutic effect of Shenyin Oral Liquid (SOL) in relieving mild cognitive impairment (MCI) and decreasing the Alzheimer's disease (AD) transformation rate. METHODS: One hundred and seventeen MCI patients were randomly assigned to the Chinese medicine group (42 cases), the vitamin E group (38 cases) and the placebo group (37 cases). The treatment course was 12 months and a 6-month follow-up was conducted after ending the treatment course. RESULTS: After treatment, the scores of clock drawing test (CDT), nonsensical figure recognition and mini-mental state examination (MMSE) raised significantly in the Chinese medicine group (P < 0.05 or P < 0.01), the activity of acetylcholine esterase in erythrocytic membrane was lower in the Chinese medicine group than that in the placebo group and the Vitamin E group (P < 0.05 or P < 0.01). Six months after the treatment, there were 2 and 5 cases in the placebo group and the vitamin E group which were diagnosed as AD, respectively, and none in the Chinese medicine group. CONCLUSION: SOL has an effect similar to cholinesterase inhibitor, it could improve cognitive function in MCI patients and reduce the AD transformation rate in them.

[Effects of TX0201 abstracted from heart-regulating formula on spatial learning and regulation of Bax mRNA, Bcl-2 mRNA level in brain of rat with Alzheimer's disease].

OBJECTIVE: To research the mechanism of TX0201 abstracted from heart-regulating formula in the treatment of rat with Alzheimer's disease (AD). METHOD: The rat models of AD were induced by A beta(1-40) injected into the bilateral amygdale. All rats were divided into five groups at random, namely control group, model group, heart-regulating formula group, TX0201 group and aricept group. The rats were intragastrically treated with different solution respectively for 20 days. The effect of TX0201 on spatial learning and memory ability of these rat models was investigated with the method of Morris water maze. By using the method of RT-PCR, the expression of apoptosis associated genes (such as Bcl-2 and Bax) in cerebral cortex and hippocampus of rats were examined. RESULT: Heart-regulating formula, TX0201 and aricept could significantly improve the spatial learning and memory ability of rats. Heart-regulating formula could comprehensively redress the abnormal expression of Bax mRNA and Bcl-2 mRNA in cerebral cortex and hippocampus. TX0201 could rectify the abnormal expression of Bax mRNA in cerebral cortex and hippocampus. Aricept could regulate the abnormal expression of Bax mRNA in cerebral cortex. CONCLUSION: TX0201 could ameliorate the learning and memory ability of these model rats by alleviating neuron apoptosis by means of regulating the abnormal expression of Bax mRNA in brain.

MiR-124 enhances cell radiosensitivity by targeting PDCD6 in nasopharyngeal carcinoma.

BACKGROUND: Radiation resistance poses a major clinical challenge in treatment of nasopharyngeal carcinoma (NPC). Studies have shown that the abnormal expression of microRNAs (miRNAs) is associated with radiosensitivity, however, the mechanisms have not been fully elucidated. The aim of this study, therefore, was to investigate whether ectopic expression of miR-124 is correlated with radiosensitivity in NPC. METHODS: In this study, the expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). Cell radiosensitivity was determined by colony formation assay. Target prediction algorithms and luciferase assay were used to confirm the target of miR-124. Tumor xenograft model was performed to understand the functions of miR-124 in vivo. RESULTS: We found that miR-124 was down-regulated in both NPC specimens and NPC cell lines. Ectopic expression of miR-124 increased radiosensitivity of NPC cells. In vivo assays extended the significance of these results, showing that miR-124 overexpression decreased cell resistance to radiation treatment in tumor xenografts. Furthermore, we identified PDCD6 as a novel direct target of miR-124. Functional studies showed that knockdown PDCD6 enhanced cell radosensitivity to irradiation, and PDCD6 could rescue the effect caused by overexpression of miR-124, indicating that PDCD6 is a functional target of miR-124. CONCLUSIONS: MiR-124 enhances cell radiosensitivity by targeting PDCD6, miR-124/PDCD6 axis may facilitate the development of novel targeted therapies for NPC.

[Effect of TX0201 on expression of the apoptosis signal transduction molecule caspase-3 and apoptosis associated genes bcl-2 and bax mRNA in brain tissue of rat analogue model of Alzheimer's disease].

OBJECTIVE: To study the mechanism of TX0201, an effective fraction extracted from Tiaoxin recipe in regulating apoptosis associated genes in brain tissue of rat analogue model of Alzheimer's disease (AD) induced by beta-amyloid protein 25-35 (Abeta 25-35). METHODS: The model of AD was induced by bilateral amygdala injection of Abeta 25-35 to study the spatial memory capacity using Morris water maze test, and by means of RT-PCR and immunohistochemistry assay, the expressions of beta-amyloid precursor protein (APP), apoptosis correlative genes (bcl-2, bax), and apoptosis signal transduction molecule (Caspase-3) in the brain, and the effect of TX0201 on expressions of these genes were examined. RESULTS: In AD model group, the spatial capacity was damaged significantly. Caspase-3 and the expression of APP mRNA and bax/bcl-2 mRNA were increased in the cortex and hippocampus; TX0201 ameliorated all the pathologic changes mentioned above. CONCLUSION: TX0201 could improve the oriented learning and memory capacity in AD rats by decreasing bax/bcl-2 and down-regulating Caspase-3 to reduce neurocyte apoptosis, suggesting that effective regulation of neuron apoptosis associated genes may be one of the mechanisms of TX0201.

[miR-124 regulates radiosensitivity of colorectal cancer cells by targeting PRRX1].

OBJECTIVE: To detect the expression of miR-124 in colorectal carcinoma (CRC) cells and tissue specimens and analyze its association with the radiosensitivity of the cells. METHODS: The expression of miR-124 in CRC cell lines and tissues were detected using qRT-PCR. The effect of miR-124 in modulating cell radiosensitivity was assessed in CRC cells with miRNA-124 overexpression and miRNA-124 knockdown, and bioinformatics prediction and dual luciferase reporter system were employed to identify the direct target of miR-124. RESULTS: s miR-124 expression was down-regulated in CRC cell lines and tissues. CRC cells over-expressing miR-124 showed an obviously enhanced radiosensitivity, whereas miR-124 knockdown resulted in a reduced radiosensitivity of the cells. Bioinformatics prediction and dual luciferase reporter system verified PRRX1 as a direct target of miR-124, which regulated the radiosensitivity of CRC cells by directly inhibiting PRRX1. CONCLUSION: miR-124 can enhance the radiosensitivity of CRC cells by directly targeting PRRX1, which provides a target for improving the therapeutic effect of radiotherapy of CRC.

Down-regualtion of miR-106b induces epithelial-mesenchymal transition but suppresses metastatic colonization by targeting Prrx1 in colorectal cancer.

Accumulating evidence identified that epithelial-mesenchymal transition (EMT) is acquired during progression to metastatic, but whether it is an absolute requirement is still controversial. MiR-106b has been confirmed to promote cancer cell proliferation; however few studies are available on its functions in EMT and metastasis in colorectal cancer (CRC). In this study, we found that knocking down miR-106b induced EMT conferring migratory and invasive properties. MiR-106b knockdown induced cytoskeletal reorganization through staining intracellular F-actin. The expression of Rho GTPases (Rac1 and Cdc42) and Tiam1 was significantly enforced after miR-106b down-regulation. However, miR-106b knocking down could suppress metastatic colonization in vivo. Correspondingly, over expression of miR-106b obtained an opposite effect. We identified Prrx1 was a direct target of miR-106b through using target prediction algorithms and dual-Luciferase reporter assay. Moreover, Moreover, we also found TGF-ß1 could down-regulate miR-106b, and simultaneously miR-106b also influences the expression of TGF-ß1, establishing a negative feedback loop to regulate the expression of Prrx1 together. Taken together, these findings demonstrated that miR-106b knockdown could induce EMT which conferring cells migratory and invasive properties but could not accomplish distant metastatic colonization efficiently.

[Clinical study on treatment of Alzheimer's disease from the viewpoint of Xin and Shen].

OBJECTIVE: To explore the therapeutic mechanism of Tiaoxin Recipe (TXR) and Bushen Recipe (BSR) in treating Alzheimer's disease (AD). METHODS: Sixty patients with AD were divided into 3 groups according to their MMSE and ADL scores before treatment, using randomized block design. They were treated separately with TXR, BSR and Donepezil (Dp) for 12 weeks. The changes of MMSE score, ADL score, neuro-psychology amount table score, including FOM, RVR, DS and BD, as well as the overall operational evaluation before and after treatment were analyzed. RESULTS: The recognition and daily life capacity of patients in the 3 groups were improved after treatment. MMSE score in the TXR group increased from 16.10 +/- 1.94 scores before treatment to 17.90 +/- 2.59 scores after treatment, in the BSR group, from 16.15 +/- 2.16 to 17.50 +/- 2.59, and in the Dp group, from 17.35 +/- 1.90 to 19.60 +/- 3.39, all showed significant difference (all P < 0.01). Change of ADL score showed that in TXR from 43.10 +/- 3.86 to 41.50 +/- 4.40, in the BSR group from 43.30 +/- 4.53 to 41.60 +/- 4.12 and in the Dp group, from 42.95 +/- 3.58 to 40.60 +/- 5.23, which also showed significant difference (P < 0.05 or P < 0.01). Moreover, increase of FOM, RVR and DS score was shown in the TXR and the Dp group, and increase of RVR and BD score was shown in the BSR group with significant difference in comparison of corresponding score before and after treatment, inter-groups comparison showed significant difference of FOM score between the BSR and the Dp group (P < 0.01). Overall operational evaluation (total effective rate) in the TXR group was 70%, in the BSR group 65% and in Dp group 75%, with no significant difference among them. CONCLUSION: TXR and BSR are effective TCM drugs in treating AD.