Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer.

Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.

Squamous cell carcinoma associated with endometriosis in the uterus and ovaries: A case report.

BACKGROUND: Endometriosis is a common benign gynecological disease that causes dysmenorrhea in women of childbearing age. Malignant tumors derived from endometriosis are rarely reported and are found in only 1% of all patients with endometriosis. Here, we report a well-differentiated squamous cell carcinoma (SCC) caused by squamous metaplasia of endometriosis that co-occurred in the uterus and ovaries. CASE SUMMARY: A 57-year-old postmenopausal woman had a 6-month history of irregular uterine bleeding. The uterus and adnexa were examined by computed tomography, and there were two solid cystic masses in the pelvis and right adnexa. Histological findings of surgical specimens showed well-differentiated SCC arising from squamous metaplasia of ectopic endometrial glands in the uterus and ovaries. The patient received chemotherapy after surgery and was followed up for 3 mo without metastasis. CONCLUSION: The continuity between ectopic endometrial glands and SCC supports that SCC originates from ectopic endometrial glands with metaplasia towards squamous epithelium.

Effectiveness of acupuncture for treatment of diabetic peripheral neuropathy.

BACKGROUND: This study will assess the effectiveness and safety of acupuncture for the treatment of patients with diabetic peripheral neuropathy (DPN). METHODS: We will comprehensively search electronic databases of MEDLINE, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and China National Knowledge Infrastructure from their inception to July 1, 2019. We will also search grey literature to avoid missing any potential studies. Randomized controlled trials related to acupuncture for the treatment of DPN will be included. All record literatures are searched without language limitation. Two researchers will independently carry out research selection, data extraction, and research quality evaluation. We will perform RevMan 5.3 software for statistical analysis. RESULTS: Primary outcomes consist of severity of neuropathy and pain intensity. Secondary outcomes include diabetes mellitus duration, body mass index, HbA1c level, blood glucose levels, and adverse events. CONCLUSION: The findings of this study will summarize recent evidence for the effectiveness and safety of acupuncture for the treatment of patients with DPN. ETHICS AND DISSEMINATION: We will not analyze individual data, thus no ethic approval is needed. The results of this study are expected to be published at a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019139635.

[Relationship between Chemotactic Factor CCL5 and Diabet-associated Diffuse Large B Cell Lymphoma].

OBJECTIVE: To explore whether the chemotactic factor CCL5 is the major factor of diffuse large B cell lymphoma (DLBCL) induced by diabetes or not. METHODS: The normal human B cells and DLBCL cells were cultured in vitro; the RT-PCR was used to detect their CCL5 mRNA expression, the human DLBCL cell line and mouse-derived DLBCL cell line A20 were cultured in vitro by using glucose at 5 and 30 mmol/L, respectively, then their CCL5 mRNA expression was detected by PT-PCR; the diabetic mouse model was constructed through peritoneal injection of streptozotocin at low dose in the BALB/c mice; the cell lines with stably high and low expression of CCL5 were established via lentiviral transfection and the cell lines with low and high expression of CCL5 were subcutaneously injected into diabetic mice and mice with normal blood sugar level. According to blood sugar level, the experimental mice were divided into 2 groups: diabetic group (A group) and normal blood sugar group as control (B group); then according to CCL5 expression level, the A group and B group were divided as well into high expression group (A1 group and B1 group) and low expression group (A2 group and B2 group), respectively, the tumor-formation rate, tumor-formation time, tumor size and texture were analyzed, respectively; the CCL5 expression was detected by using HE staining of tumor tissue and immunohistochemical method. RESULTS: The expression of CCL5 mRNA in human DLBCL cell line cultured in vitro was higher than that in normal B cells (P < 0.05); the expressions of CCL5 mRNA in human DLBCL cells cultured in high sugar concentration in vitro and mouse DLBCL cells were higher than those in cells cultured in low sugar concentration (P < 0.05). The tumor-formation rates in diabetic mice injected with high and low expression of CCL5 cell line A20 were 93.3% in A1 group and 60% in A2 group; the their tumor-formation time was 7.0 ± 0.85 days in A1 group and 9.5 ± 2.8 days in A2 group, while the tumor formation rates in mice with normal blood sugar level were 20% in B1 group and 20% in B2 group, and their tumor-formation time was 12 ± 1.3 days and 14 ± 2.5 days respectively; the CCL5 expression level in tumor tissue of diabetic mice was higher than that in tumor tissue of mice with normal blood sugar level. CONCLUSION: The high blood glucose level can casase increase of DLBCL risk and promote the tumor growth; the chemotactic factor CCL5 may play an important role in the growth and migration of DLBCL caused by diabetes mellitus.

Lipoxin A4 suppresses lipopolysaccharide-induced hela cell proliferation and migration via NF-κB pathway.

Uterine cervical carcinoma (UCC) is one of the most common malignant tumors in females, and UCC has a close relationship with chronic cervicitis. As the endogenous "braking signal," lipoxins can regulate anti-inflammation and the resolution of inflammation. We investigated the effect of lipoxin A4 (LXA4) on the proliferation, apoptosis, and migration in lipopolysaccharide (LPS)-stimulated Hela cells. We demonstrated that LXA4 could significantly suppress p53, cyclin D1 expression, and migration of LPS-stimulated Hela cells via nuclear factor-κB (NF-κB) pathway, and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4). We presented evidence for a novel role of LXA4 on the proliferation and migration in LPS-stimulated Hela cells, and FPR2/ALX was involved in the procedures. These results showed that LXA4 could be a possible candidate for UCC therapy, and blocking the activation of NF-κB would be an effective drug target.

The effect of non-pharmacological staged interventions on fatigue and dyspnoea in patients with chronic obstructive pulmonary disease: a randomized controlled trial.

The aim of this study was to examine the effect of non-pharmacological staged interventions on fatigue and dyspnoea in patients with chronic obstructive pulmonary disease. A randomized controlled trial was conducted with 64 patients in a tertiary hospital in China from 2010 to 2011. Patients were randomly assigned to the control group (n = 32), who received routine care, and the intervention group (n = 32), who received additional non-pharmacological staged interventions. The Multidimensional Fatigue Inventory and the five-grade Medical Research Council dyspnoea scale were used to collect data at baseline and after 6 weeks. Compared with the control group, patients in the intervention group had significantly lower scores on general fatigue (P < 0.001), physical fatigue (P < 0.001), reduced activity (P < 0.001) and reduced motivation (P = 0.03) and had better relief of dyspnoea (P = 0.02). Our study showed that non-pharmacological staged interventions were effective in relieving fatigue and dyspnoea in patients with chronic obstructive pulmonary disease.

[Expression of miR-9 in B lymphocytes and B cell lymphomas cell lines and its significance].

OBJECTIVE: To investigate the expression of miR-9 in B lymphocytes, B cell lymphoma and classical Hodgkin's lymphoma (cHL) cell lines and its significance. METHODS: CD19(+) B lymphocytes were sorted from normal lymph node by magnetic beads. Total cellular micro-RNA was extracted from cHL cell line L428, B cell lymphoma cell lines Ly1 and Ly10 (diffuse large B cell lymphoma), Raji cells (Burkitt's lymphoma) and CD19(+) B lymphocytes, respectively. These micro-RNAs were separately transformed into cDNA by reverse transcription. The expression levels of miR-9 were measured by fluorescence quantitative PCR. In situ hybridization was used to detect the expression of miR-9 in cell lines. RESULTS: The expression of miR-9 was high in L428 cells (104.44 ± 1.61), and low in cell lines of B cell lymphoma (Ly1: 2.17 ± 0.38; Ly10: 1 ± 0.015; Raji: 2.65 ± 0.89), and extremely low in CD19(+) B lymphocytes (0.0026 ± 0.00040). Compared with that in the other cell lines, the expression of miR-9 in L428 cells was statistically significant (P < 0.05). miR-9 localized in the cytoplasm diffusely and strongly in L428, but scattered and slightly with some prominent distribution around the nuclear membranes in Ly1 and Ly10, and only weakly in Raji. CONCLUSIONS: miR-9 highly expressed in cHL cell line and might be a molecular marker for diagnosis and treatment of cHL.

Expression of ß-catenin and cyclin D1 in epidermal stem cells of diabetic rats.

The healing of diabetic wounds represents a formidable clinical challenge, and the molecular mechanisms involved in diabetic wound healing are far from clear. In this study, we investigated the expression of ß-catenin and cyclin D1 in the epidermal stem cells (ESCs) of diabetic rats, and explored whether the reduction of ß-catenin and its downstream target in ESCs, cyclin D1, lead to poor wound healing in diabetes mellitus (DM). We found that, compared to the controls, the ESCs of diabetic rats were markedly reduced, the clone formation efficiency of the ESCs was markedly lower, and the mRNA and protein expression of ß-catenin and cyclin D1 was significantly decreased. These findings suggest that the low expression of ß-catenin and cyclin D1 may reduce the activity of ESCs from diabetic rats, which might be one of the important mechanisms of delayed wound healing in DM.

Correlation of seven biological factors (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma.

OBJECTIVE: To explore correlation of seven apoptosis-related proteins (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma (ALCL). METHODS: Using immunohistochemistry and immunofluorescence double staining methods, the expressions of these seven apoptosis-associated proteins were studied to clarify their relationship with clinical outcomes of 36 ALK+ and 25 ALK-systemic ALCL patients enrolled between 1996 and 2006. The relationship of these apoptosis-regulating proteins with NPM-ALK status was also evaluated with the tyrosine inhibitor herbimycin A (HA) in vitro by immunocytochemistry, Western blotting and flow cytometric assays. RESULTS: The presence of Hsp90α-, MDM2-, Bax-, Cytochrome C, and Cleaved caspase3-positive tumor cells was found significantly different in ALK+ and ALK-ALCLs, which was correlated with highly favorable clinical outcome. The Bcl-2- and p53-positive tumor cells were found in groups of patients with unfavorable prognosis. Inhibition of NPM-ALK by HA could reactivate the p53 protein and subsequent apoptosis-related proteins and therefore induced apoptosis in ALK+ ALCL cells. CONCLUSION: Our results suggest that these seven proteins might be involved in apoptosis regulation and associated with clinical outcome of ALK+ systemic ALCLs. We also reveal a dynamic chain relation that NPM-ALK regulates p53 expression and subsequent apoptosis cascade in ALK+ ALCLs.