Platelet-derived growth factor subunit-B mediating the effect of dickkopf-1 on acute myocardial infarction risk: a two-step Mendelian randomization study.

Previous studies have indicated a potential connection between plasma levels of Dickkopf-1 (DKK1) and platelet-derived growth factor subunit-B (PDGF-B) with the development of atherosclerosis. However, the causal relationship between DKK1, PDGF-B, and the risk of acute myocardial infarction (AMI) is yet to be established. To address this research gap, we conducted Mendelian randomization (MR) and mediation analyses to investigate the potential mediating role of PDGF-B in the association between DKK1 and AMI risk. Summary statistics for DKK1 (n = 3,301) and PDGF-B (n = 21,758) were obtained from the GWAS meta-analyses conducted by Sun et al. and Folkersen et al., respectively. Data on AMI cases (n = 3,927) and controls (n = 333,272) were retrieved from the UK Biobank study. Our findings revealed that genetic predisposition to DKK1 (odds ratio [OR]: 1.00208; 95% confidence interval [CI]: 1.00056-1.00361; P = 0.0072) and PDGF-B (OR: 1.00358; 95% CI: 1.00136-1.00581; P = 0.0015) was associated with an increased risk of AMI. Additionally, genetic predisposition to DKK1 (OR: 1.38389; 95% CI: 1.07066-1.78875; P = 0.0131) was linked to higher PDGF-B levels. Furthermore, our MR mediation analysis revealed that PDGF-B partially mediated the association between DKK1 and AMI risk, with 55.8% of the effect of genetically predicted DKK1 being mediated through genetically predicted PDGF-B. These findings suggest that genetic predisposition to DKK1 is positively correlated with the risk of AMI, and that PDGF-B partially mediates this association. Therefore, DKK1 and PDGF-B may serve as promising targets for the prevention and treatment of AMI.

Anlotinib in patients with relapsed or refractory thymic epithelial tumors: a study of 50 cases.

The optimal pharmaceutical regimen for advanced thymic epithelial tumors (TETs) remains controversial when first-line chemotherapy fails. This retrospective study aims to evaluate the efficacy and safety of anlotinib treatment for patients with relapsed and refractory TETs. Patients with progressive disease after failure of platinum-based chemotherapy were enrolled in this study. Anlotinib was orally taken once a day at an initial dose of 12 mg (10 mg when body weight <60 kg). The cycle was repeated every 3 weeks (2 weeks of treatment followed by 1-week rest). Objective response rate (ORR) and progression-free survival (PFS) were recorded as primary endpoints. There were 50 patients enrolled in this study from October 2018 to June 2021 at a median age of 50 (range 23-79) years old. Patients with thymoma and thymic carcinoma were 33 (66%) and 17 (34%), respectively. The ORR in thymoma and thymic carcinoma patients were 33% (11/33) and 41% (7/17), respectively. The median PFS (mPFS) was 7 (95% CI, 5.9-10.2) months in thymoma patients and 6 (95% CI, 4.6-9.3) months in the thymic carcinoma group. Eleven patients experienced dose reduction due to toxicities, among whom, eight patients discontinued treatment even after dose reduction. Six patients with thymoma showed myasthenia gravis deterioration during treatment, and two of them died of myasthenia gravis crisis. Anlotinib is active in patients with advanced TETs refractory to routine chemotherapy. Prescription of anlotinib to patients with myasthenia gravis should be made cautiously.

Bevacizumab in combination with paclitaxel and platinum for previously treated advanced thymic epithelial tumors.

There are no optimal regimens for advanced thymic epithelial tumors (TETs) when frontline chemotherapy fails. In this study, we aimed to assess the activity of Bevacizumab in combination with a routine chemotherapeutic regimen. Patients with advanced TETs who had failed after previous chemotherapy were enrolled in this study. Paclitaxel (160 mg/m2) and cisplatin (70 mg/m2) or carboplatin (area under the curve, 6) plus Bevacizumab (7.5 mg/kg) were intravenously injected on day 1.The treatment was repeated every 3 weeks until the disease progressed or intolerable toxicities occurred. Between March 2018 and August 2020, a total of 49 patients (21 thymoma and 28 thymic carcinoma) received the new treatment. There were 28 men and 21 women with a median age of 50 years (range: 21-73 years). The median number of cycles was 3 (range: 1-6) per patient. The objective response rate (ORR) for all patients was 43% (21/49). The ORRs for thymoma and thymic carcinoma were 24% and 57%, respectively. The median progression-free survival for thymoma and thymic carcinoma was 6 and 8 months, respectively. Hematological toxicities were the main side effects. Paclitaxel and platinum plus Bevacizumab showed promising effects in refractory or relapsed advanced TETs without severe toxicity. Even when applied as salvage therapy, this regimen resulted in a better ORR than frontline chemotherapy.

CXCR4 protects bone marrow-derived endothelial progenitor cells against hypoxia through the PI3K/Akt signaling pathway.

The present study aimed to investigate the regulatory mechanism of chemokine (C-X-C motif) receptor 4 (CXCR4) on endothelial progenitor cells (EPCs) through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway under hypoxic conditions. Mononuclear cells were isolated from the bone marrow (BM) of young Sprague-Dawley (SD) rats. Bone marrow-derived endothelial progenitor cells (BM-EPCs) were characterized by using Dil-labeled acetylated low-density lipoprotein (Dil-ac-LDL) and fluorescein isothiocyanate-labeled UEA (FITC-UEA-1). Phenotype identification of BM-EPCs was based on red cytoplasm and green cytomembrane. Flow cytometry was employed to examine the markers CD14, CD34, and KDR. Expression level of the EPC-specific surface marker CD14 was found to be negative, while the expression level of CD34 and KDR was positive. In addition, CXCR4 was stably overexpressed in BM-EPCs after transfection with adenovirus-CXCR4. Cell proliferation, migration and apoptosis abilities were measured through the application of CCK-8, followed by Transwell and flow cytometry assays. The expression level of CXCR4, PI3K and Akt was determined by reverse transcription-quantitative PCR and western blotting assays. Functional experiments demonstrated that hypoxia inhibited BM-EPC proliferation and migration, while accelerating BM-EPC apoptosis. Additionally, CXCR4 was found to promote proliferation and migration, and suppress apoptosis in BM-EPCs with or without hypoxia treatment. Evidence also demonstrated that CXCR4 markedly upregulated the expression levels of PI3K and Akt. Furthermore, PI3K inhibitor (LY294002) and CXCR4 inhibitor (AMD3100) effectively inhibited the proliferation, migration and resistance to apoptosis of CXCR4-mediated BM-EPCs under hypoxic conditions.

Intensity Modulated Radiation Therapy for Pleural Recurrence of Thymoma: A Prospective Phase 2 Study.

PURPOSE: This study aimed to evaluate the efficacy and safety of intensity modulated radiation therapy (IMRT) for pleural recurrence of thymoma that was not suitable for surgery and had progressed after chemotherapy. MATERIALS AND METHODS: From February 2012, consecutive patients with pleural recurrence of thymoma were prospectively enrolled. Due to dose restrictions to normal tissue (lung, liver, and kidney), 3 different levels of radiation doses (30 Gy, 40 Gy, and 50 Gy) were prescribed for pleural lesions of different sizes and locations, with a daily fraction dose of 2 Gy. The objective response rate, local control time (LCT), overall survival time, and toxicity were recorded, respectively. RESULTS: By August 2016, 31 patients had completed the IMRT treatment. There were 21 male and 10 female patients, with a median age of 49 (range, 22-70) years. B3 thymoma was the major (62%) tumor subtype observed. During the median follow-up of 48 (24-70) months, the objective response rate was 97%, and the median LCT was 49 (95% confidence interval, 40.4-58.1) months. However, 29 (93.5%) patients developed out-of-field recurrence, among whom 10 (32%; 30 Gy, n = 7; 40 Gy, n = 3) developed both out-of-field and in-field recurrence. The median progression-free survival was 19 months, and no in-field recurrence occurred in the 50 Gy group. Moreover, a higher dose was related to a longer LCT. No toxicities higher than a grade 4 occurred after IMRT within the normal-tissue dose limitation. The 5-year overall survival of the patients was 81%. CONCLUSIONS: IMRT for pleural recurrence may act as an alternative treatment when surgery is not feasible, with a higher dose resulting in a longer LCT. In this study, out-of-field recurrence was considerably common, but repeated IMRT for new recurrence should be cautiously carried out due to the high risk of radiation-induced pneumonitis.

S-1 salvage chemotherapy for stage IV thymic carcinoma: a study of 44 cases.

BACKGROUND: Thymic carcinoma (TC) is a rare mediastinal tumor, and patients with stage IV TC have a poor prognosis. No optimal chemotherapeutic regimen has yet been established. In this study, we evaluated the efficacy and safety of S-1 as a salvage mono-therapy in stage IV TC. METHODS: Patients with histologically confirmed stage IV TC were enrolled in this study when front-lined chemotherapy failed. S-1 capsules were orally taken twice a day. The daily dose was prescribed in three levels (80, 100, 120 mg) based on body surface area (BSA). One cycle of treatment consists of 4 weeks of drug use and 2 weeks of rest. The cycle was repeated until tumor progressed or intolerable toxicity occurred. The response rate, progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. RESULTS: Forty-four patients with stage IV TC were included between January 2013 and July 2017. Squamous cell carcinoma accounted for 84% of cases (37/44). There were 22 males and 22 females with a median age of 57 years (27-78 years). S-1 was prescribed at a dose of 80 mg for 18 (41%) patients, 100 mg for 17 patients (38%), and 120 mg for 9 patients (21%). The median number of cycles of administrated per patient was 3 [1-32]. Among 44 patients, 13 (30%) achieved a partial response, 22 (50%) remained stable disease, and 9 (20%) showed a rapid progression. With a median follow-up time of 14 months, the median PFS and OS of the whole group were 6 (95% CI, 7.0-13.9) months and 15 (95% CI, 13.2-21.6) months, respectively. For the 13 patients who showed response to S-1, the median PFS was 22 (95% CI, 15.5-30) months. Anorexia was the most common side effect, but all cases were mild. Other toxicities of grade ≥3 were bone marrow suppression (n=6) and rash (n=1). No drug-related deaths occurred. CONCLUSIONS: S-1 is a safe and effective treatment for stage IV TC as a salvage monotherapy. It is especially effective in disease control when the tumor shows response to S-1.

Outcome of nonsurgical treatment for locally advanced thymic tumors.

BACKGROUND: Surgical resection remains the mainstay of treatment for patients with early-staged thymic tumors, while chemotherapy is most commonly used in stage IV cases. As for locally advanced thymic tumors, especially those unsuitable for surgery, the optimal therapy is still controversial. Thus, we conducted this retrospective study by comparing three nonsurgical treatment modalities to find some clues. METHODS: Three treatment modalities were used in 42 patients from October 2000 to December 2010, including radiotherapy (RT) alone, sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT). Objective response rate (ORR), overall survival (OS) and toxicity of the three regimens were compared accordingly. RESULTS: The ORR in all 42 patients was 61.9%, and 5-year OS was 46%. The ORR of RT, SCRT and CCRT were 43.8%, 50% and 87.5%, respectively (RT vs. SCRT, P=0.692; RT vs. CCRT, P=0.009; SCRT vs. CCRT, P=0.051). The 5-year OS of RT, SCRT and CCRT were 30%, 50% and 61.9%, respectively. (RT vs. SCRT, P=0.230; RT vs. CCRT, P=0.011; SCRT vs. CCRT, P=0.282). Eleven patients developed neutropenia of grade 3-4, with 7 in CCRT group and 4 in SCRT, respectively. Nine patients experienced esophagitis of grade 3 with 2 in RT, 3 in SCRT and 4 in CCRT. There were also two cases of grade 3 radiation induced pneumonitis in CCRT group. No life-threatening side effects were noted. CONCLUSIONS: When used to treat locally advanced thymic tumors unsuitable for surgery, CCRT performed more favorably than RT alone or SCRT in both tumor response and long time survival, but probably with the increasing risk of pulmonary damage. CCRT may offer the best chance of disease control in the management of locally advanced disease.

Pleurotus nebrodensis polysaccharide (PN-S) enhances the immunity of immunosuppressed mice.

In the present study, the effects of Pleurotus nebrodensis polysaccharide (PN-S) on the immune functions of immunosuppressed mice were determined. The immunosuppressed mouse model was established by treating the mice with cyclophosphamide (40 mg/kg/2d, CY) through intraperitoneal injection. The results showed that PN-S administration significantly reversed the CY-induced weight loss, increased the thymic and splenic indices, and promoted proliferation of T lymphocyte, B lymphocyte, and macrophages. PN-S also enhanced the activity of natural killer cells and increased the immunoglobulin M (IgM) and immunoglobulin G (IgG) levels in the serum. In addition, PN-S treatment significantly increased the phagocytic activity of mouse peritoneal macrophages. PN-S also increased the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and nitric oxide (NOS) in splenocytes. qRT-PCR results also indicated that PN-S increased the mRNA expression of IL-6, TNF-α, INF-γ, and nitric oxide synthase (iNOS) in the splenocytes. These results suggest that PN-S treatment enhances the immune function of immunosuppressed mice. This study may provide a basis for the application of this fungus in adjacent immunopotentiating therapy against cancer and in the treatment of chemotherapy-induced immunosuppression.

The polysaccharide isolated from Pleurotus nebrodensis (PN-S) shows immune-stimulating activity in RAW264.7 macrophages.

A novel Pleurotus nebrodensis polysaccharide (PN-S) was purified and characterized, and its immune-stimulating activity was evaluated in RAW264.7 macrophages. PN-S induced the proliferation of RAW264.7 cells in a dose-dependent manner, as determined by the MTT assay. After exposure to PN-S, the phagocytosis of the macrophages was significantly improved, with remarkable changes in morphology being observed. Flow cytometric analysis demonstrated that PN-S promoted RAW264.7 cells to progress through S and G2/M phases. PN-S treatment enhanced the productions of interleukin-6 (IL-6), nitric oxide (NO), interferon gamma (INF-γ), and tumor necrosis factor-α (TNF-α) in the macrophages, with up-regulation of mRNA expressions of interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), interferon gamma(INF-γ) and tumor necrosis factor-α (TNF-α) being observed in a dose-dependent manner, as measured by qRT-PCR. In conclusion, these results suggest that the purified PN-S can improve immunity by activating macrophages.

[Studies on relationship between the expression of hTNF-alpha gene and photosynthesis in Anabaena sp. IB02].

The effects of illumination on growth of Anabaena sp. IB02 and hTNF-alpha expression were studied. Photosynthetic activity, PS I and PS II activity of Anabaena sp. IB02 were assayed. Illumination enhanced the growth of Anabaena sp. IB02 and hTNF-a expression. Some relations were observed between hTNF-alpha expression and ture photosynthesis activity, PS I, PS II activity of Anabaena sp. IB02. Significant differences of the photosynthetic activity of host were detected simultaneously when hTNF-a expressed: the respiration rate increased (-68%), the light saturation point descended (+66%), all these suggested that the metabolic charge of host were increased and grow faster than wild type under low illumination.