Impact of o-aryl halogen effects on ethylene polymerization: steric vs. electronic effects.

Ligand steric hindrance and electronic effects play a crucial role in late-transition metal-catalyzed olefin polymerization. In this research, a series of o-aryl halogenated α-diimine ligands bearing bulky dibenzhydryl substituents, along with their corresponding nickel catalysts, have been synthesized and thoroughly characterized. The nickel catalysts demonstrated very high activity in ethylene polymerization, achieving a high rate of up to 107 g mol-1 h-1. The produced polyethylenes displayed a broad spectrum of molecular weights (12.2-871.7 kg mol-1) but maintained consistent branching densities (50-82/1000 C) when polymerized at a fixed temperature with different nickel catalysts. Notably, the polymerization temperature has a significant influence on both the molecular weight and branching density of the resulting polyethylene. Higher temperatures led to the formation of polyethylenes with lower molecular weights and increased branching densities. Interestingly, the o-aryl halogens significantly impact the molecular weight of the polyethylene. The size of the halogen substituents primarily determines the molecular weight of the polyethylene. However, in terms of branching density, the steric and electronic effects of these substituents appear to counteract each other. In addition, the branched high molecular weight polyethylenes from the bromine and chlorine substituted nickel catalysts are excellent polyethylene thermoplastic elastomers with high strain at break values (688-2478%) and high strain recovery values (42-62%).

Apatinib weakens proliferation, migration, invasion, and angiogenesis of thyroid cancer cells through downregulating pyruvate kinase M2.

Thyroid cancer (TC) is the most frequent malignancy of the endocrine system. Apatinib, as an anti-angiogenic agent, has been applied in the therapy of several cancers. However, the function and mechanism of Apatinib in TC have not been clearly elucidated. After processing with Apatinib alone or combined PKM2 overexpression plasmids, cell proliferation, migration, and invasion were analyzed by EdU staining, CCK-8, wound healing, and Transwell. Meanwhile. HUVECs were incubated with the conditioned medium prepared from cell culture medium, and tube formation and VEGFR2 expression in HUVECs were examined using tube formation and immunofluorescence (IF) assays. Besides, we established a nude mouse xenograft model by lentivirus-mediated PKM2 shRNAs, and tested the growth of tumors; the pathological structure was analyzed with H&E staining. And the expressions of N-cadherin, Vimentin, E-cadherin, PKM2, VEGFA, VEGFR2, and Ki67 were determined by immunohistochemistry or Western blot. Apatinib could prominently suppress proliferation, migration, invasion, and HUVEC tube formation in SW579 and TPC-1 cells. Besides, we discovered that Apatinib had a significant inhibitory role on the expression of pyruvate kinase M2 (PKM2) in TC cells. And PKM2 overexpression also could notably reverse Apatinib-mediated inhibition of TC progression. Moreover, PKM2 shRNAs were applied to TC xenografts, resulting in significant reduction in tumor volume and suppression of angiogenesis-related protein expression. In summary, Apatinib has a regulatory role in TC progression, and Apatinib can block cancer cell angiogenesis by downregulating PKM2. This will provide a theoretical basis for therapy of TC.

Facilitating combined biopsy and percutaneous microwave ablation of pulmonary ground-glass opacities using lipiodol localisation.

OBJECTIVES: Whether preoperative localisation is necessary and valuable for the microwave ablation (MWA) of small pulmonary lesions with ground-glass opacity (GGO) remains unclear. This study aimed to explore the role of the Chiba needle and lipiodol localisation techniques in facilitating MWA and biopsy. METHODS: This retrospective before-after study included patients with GGOs who underwent conventional MWA and biopsy treatment in our hospital between January 2018 and December 2019 (group A) or who underwent the Chiba needle and lipiodol localisation treatment before MWA and biopsy between January 2020 and December 2020 (group B). The characteristics of each patient and GGO lesion were collected and analysed to evaluate the safety and effectiveness of the localisation technique. RESULTS: A total of 122 patients with 152 GGOs and 131 patients with 156 GGOs underwent MWA and biopsy in groups A and B, respectively. The primary technique efficacy rate of MWA differed significantly between the two groups (A vs. B: 94.1% vs. 99.4%; p = 0.009). The positive biopsy rate in the two groups was determined by the difference (A vs. B: 93.4% vs. 98.1%; p = 0.042). The incidence of complications did not increase in group B. CONCLUSIONS: Compared with the unmarked group, the Chiba needle and lipiodol localisation technique improved the positive rate of biopsy and the initial effective rate of MWA, without significantly increasing the complication rate. KEY POINTS: • The localisation of the Chiba needle and lipiodol could improve the positive biopsy rate and the initial effective rate of MWA. • The localisation of the Chiba needle and lipiodol does not affect the subsequent MWA and biopsy and does not increase the incidence of pneumothorax and haemorrhage.

Hypophysitis: A rare but noteworthy immune-related adverse event secondary to camrelizumab therapy.

The programmed cell death 1 (PD-1) inhibitor - camrelizumab - is a promising agent for the treatment of several malignancies. Secondary hypophysitis has been reported in patients treated with the other PD-1 inhibitors such as nivolumab and pembrolizumab. However, camrelizumab-related hypophysitis has not yet been described. Herein, we report three cases of hypophysitis secondary to camrelizumab therapy. Case 1 was a 60-year-old male patient with non-small-cell lung carcinoma, who was diagnosed with central adrenal insufficiency associated with hypophysitis after 11 cycles of camrelizumab treatment (200 mg every 2 weeks). Glucocorticoid therapy rapidly improved his symptoms. Case 2 was a 68-year-old male patient with hepatocellular carcinoma who received ten cycles of camrelizumab (200 mg every 2 weeks) plus apatinib (250 mg daily), before the diagnosis of hypophysitis. Steroid therapy was also efficacious. Case 3 was a 69-year-old male patient diagnosed with renal carcinoma. After eight cycles of camrelizumab therapy (200 mg every 2 weeks) combined with oral apatinib (250 mg daily), the patient presented with hypophysitis, which responded well to glucocorticoid therapy. These results suggest a caution for hypophysitis in patients treated with camrelizumab.

Synchronous Microwave Ablation Combined With Cisplatin Intratumoral Chemotherapy for Large Non-Small Cell Lung Cancer.

Background: Microwave ablation (MWA) and intratumoral chemotherapy (ITC) are useful for treating tumors in animal models; however, their clinical use in patients with large non-small cell lung cancer (NSCLC) remains unknown. This retrospective study aimed to evaluate preliminary outcomes of MWA + ITC for large NSCLC. Methods: From November 2015 to April 2020, a total of 44 NSCLC patients with a mean lesion diameter of 6.1 ± 1.5 cm were enrolled and underwent synchronous MWA + ITC procedures. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were progression-free survival (PFS), complications, overall survival (OS), and associated prognostic factors. Results: The median follow-up time was 19.0 months. At the 1-month CT scan, complete tumor ablation was observed in 47.7% of cases. Median LPFS was 12.1 months; 1-, 2-, and 3-year LPFS rates were 51.2%, 27.9%, and 13.6%, respectively. A shorter LPFS was significantly associated with large lesions (HR 1.23, 95% CI 1.02-1.49; p = 0.032). Median PFS was 8.1 months; 1-, 2-, and 3-year PFS rates were 29.5%, 18.2%, and 9.1%, respectively. LPFS was significantly superior to PFS (p = 0.046). Median OS was 18.8 months. The 1-, 2-, 3-, and 5-year OS rates were 65.9%, 43.2%, 26.4%, and 10.0%, respectively. In univariate comparisons, high performance status (PS) score, smoking, and larger lesions were significantly correlated with poor survival. In multivariate analysis, advanced age, higher PS score, higher stage, larger lesion, and prior systematic treatment were independent prognostic factors for shorter OS. Adverse events were well tolerated and all patients recovered after appropriate intervention. Conclusions: MWA + ITC is a safe and effective new modality of local treatment for large NSCLC and can significantly prolong LPFS.

A study of microwave ablation for small cell lung cancer.

Purpose: To reveal the survival and safety of percutaneous microwave ablation (MWA) combined with chemoradiotherapy (CRT) in treating small cell lung cancer (SCLC). Materials and Methods: Clinical data of 48 SCLC patients who underwent MWA were retrospectively collected; survival and incidence of major complications were analyzed. Results: Totally, 48 SCLC patients underwent 51 MWA procedures. The median overall survival (OS) for all SCLC was 27.0 months (95% confidence interval 22.4-31.6 months). The OS of limited-stage (LS-SCLC) was longer than the extensive-stage (ES-SCLC) (median 48.0 months vs. 25.0 months, P = 0.022). The OS of SCLC with tumor diameter ≤3.0 cm was longer than that of tumor diameter >3.0 cm (median 48.0 months vs. 27.0 months, P = 0.041). For LS-SCLC, the 1-, 2-, 3-, and 5-year survival rate was 91.67%, 72.22%, 66.67%, and 61.11%, respectively. For ES-SCLC, the 1-, 2-, and 3-year survival rates were 83.33%, 50.0%, and 8.33%. Major complications included pneumothorax needing tube placement (29.4%), rarely arrhythmia (2.0%), empyema (2.0%), pulmonary fungal infection (2.0%), and shingles (2.0%). Conclusion: For SCLC patients, who received MWA combined with CRT, OS of LS-SCLC and tumor diameter ≤3.0 cm was better than that of the ES-SCLC and tumor diameter >3.0 cm. For inoperable SCLC, MWA was safe.

Safety Risk Analysis of a New Design of Basalt Fiber Gabion Slope Based on Improved 3D Discrete Element Method and Monitoring Data.

Gabion has been extensively used in retaining walls and slope protection. This study carries out a safety risk analysis of a new structure combining basalt fiber reinforcement (BFR) and the traditional gabion structure. The micro-parameters of BFR and soil were calibrated by using the 3D discrete element method after the tensile test of BFR was completed. The mechanical property of the gabion unit was investigated by using a refined model and a numerical test of uniaxial compression. This work developed a simplified method to simulate the seepage effect. The stress condition and sliding displacement between gabions were also investigated. Deformation, stress, and porosity were all used to evaluate the stability of the new type of gabion slope. According to this study, BFR has a tensile strength of 68.22 MPa, and the safety factor increased by 25.68% after using these BFR gabions. The damage is mainly manifested by bending the BFRs and the dislocation of the gabion units, as the slope does not slip. It is indicated this novel gabion structure has a lower safety risk compared to traditional ones, and thus can be popularized and used in retaining walls and slope protection.

CT-guided microwave ablation in patients with lung metastases from breast cancer.

BACKGROUND: Computed tomography (CT)-guided percutaneous microwave ablation (MWA) is a very common ablation method that shows a good local tumor control rate in primary and secondary lung tumors. At present, few reports have explored the safety and efficacy of MWA for lung metastases from breast cancer. METHODS: From January 2012 to January 2018, 32 breast cancer patients with 46 pulmonary metastases received CT-guided percutaneous MWA. The study was approved by the local institutional review board. The clinical efficacy and complications of MWA were investigated. RESULTS: The median follow-up time was 32 months and the main effective rate was 97.8% (45/46). Five of 46 lesions had local progression (10.9%), with a median progression time of 10 months. The 1-, 3-, and 5-year overall survival (OS) rates were 96.9%, 53.3%, and 17.8%, respectively. The median OS time was 36 months. Among 46 MWA treatments, 11 (23.9%) had massive pneumothorax, two (4.3%) had massive pleural effusion, and two (4.3%) had a pulmonary infection. CONCLUSION: CT-guided percutaneous MWA may be safe and effective for treating lung metastases from breast cancer.

Intestinal bacteria are potential biomarkers and therapeutic targets for gastric cancer.

The diagnostic and therapeutic role of intestinal microbiota in gastric carcinogenesis remains unclear. In this study, feces from gastric cancer patients and healthy people were sequenced for microbiota analysis, and the correlation between fecal bacteria and the occurrence of gastric cancer was explored. The ß-diversity results showed that microbial compositions varied between gastric cancer patients and healthy people. Interestingly, the dissection of microbial structure revealed that all facultative anaerobic genera with relatively high abundances expanded significantly in gastric cancer patients. The succeeding correlation analysis demonstrated a distorted interaction of intestinal bacteria in gastric cancer. The application of some differential bacteria, Desulfovibrio, Escherichia, Faecalibacterium or Oscillospira, as biomarkers to predict gastric cancer could all reach an accuracy of 0.900 or above. The shift in Desulfovibrio was specifically verified by qPCR in newly collected fecal samples, and the patients with stage IV gastric cancer were identified to have significantly more Desulfovibrio than those with stage I, II and III gastric cancer. The possible role of Desulfovibrio in gastric cancer was assessed with H2S-treated HT-29 cells, and the results showed that H2S induced NO, IL-1ß and IL-18 production, which is important for inflammation promotion and can be delivered through the bloodstream. This study suggests a correlation of intestinal microbiota and the development of gastric cancer.

A feasibility and safety study of computed tomography-guided percutaneous microwave ablation: a novel therapy for multiple synchronous ground-glass opacities of the lung.

Purpose: The present study retrospectively evaluated the feasibility, safety, and short-term efficacy of computed tomography (CT)-guided percutaneous microwave ablation (MWA) to treat multiple synchronous ground-glass opacities (GGOs) of the lung.Materials and Methods: From October 2016 to May 2019, 33 patients (9 males and 24 females, mean age: 59.6 ± 10.0 years) with multiple GGOs (103 GGOs with mean size 12.3 ± 6.3 mm) were enrolled in this study. Patients underwent 66 procedures of CT-guided percutaneous MWA. The feasibility, safety, local progression-free survival, and overall survival were evaluated.Results: The technical success and technique efficacy rate were 100% and no MWA procedure-related deaths were reported. The median follow-up period was 18.1 (range: 6.8-37.7) months. Major complications included pneumothorax (11/66, 16.7%), pleural effusion (2/66, 3.0%), pneumonia (3/66, 4.5%), and nerve injury (1/66, 1.5%), which were well controlled by appropriate treatment. Minor complications included pneumothorax (38/66, 57.6%), pleural effusion (43/66, 65.2%), hemoptysis (13/66, 19.7%), subcutaneous emphysema (4/66, 6.1%), and hemothorax (2/66, 3.0%). Currently, all patients are alive without local progression or tumor recurrence, despite the relatively insufficient follow-up time.Conclusion: CT-guided percutaneous MWA for the treatment of multiple synchronous lung GGOs is feasible, safe, and efficacious over short-term follow-up. It may also be employed as an alternative approach for nonsurgical candidates. A longer follow-up is warranted to evaluate the oncologic outcomes.

CD82 supports survival of childhood acute myeloid leukemia cells via activation of Wnt/ß-catenin signaling pathway.

BACKGROUND: Stem cell marker CD82 plays a vital role in the oncogenesis and progression of acute myelogenous leukemia (AML), especially in sharing properties of leukemia stem cells (LSCs). The Wnt/ß-catenin pathway is required for the development of LSCs in AML. The present study aimed to validate whether CD82 supports the survival of LSCs in pediatric AML via activation of Wnt/ß-catenin signaling pathway. METHODS: CD82 expression and its correlation with molecules downstream of Wnt/ß-catenin pathway in samples from pediatric AML patients were analyzed. Forced or downregulated expression of CD82 in AML cells was evaluated for the effects of CD82 on cell proliferation, cycle regulation, apoptosis, and adriamycin chemoresistance and to validate the underlying mechanism. RESULT: Aberrant expression of CD82 in pediatric AML patients was found. CD82 messenger RNA expression correlated positively with downstream molecules of Wnt/ß-catenin pathway in AML children. Knockdown of CD82 induced apoptosis, suppressed growth, and decreased adriamycin chemoresistance in AML cells. CD82 accelerated ß-catenin nuclear location and then stimulated the expression of downstream molecules of Wnt/ß-catenin pathway. CONCLUSION: CD82 regulates the proliferation and chemotherapy resistance of AML cells via activation of the Wnt/ß-catenin pathway, which suggest that the CD82 may be a potential therapeutic target in AML children.

Comparison of two iodine-125 brachytherapy implant techniques for the treatment of lung tumor: Preplanning and intraoperative planning.

PURPOSE: To compare preplanning and intraoperative planning methods of lung tumor brachytherapy based on postimplant CT images and dosimetric outcomes. METHODS AND MATERIALS: Detailed postimplant evaluations of iodine-125 seed implants were performed in 15 patients using a preplanning technique and in 15 patients treated with an intraoperative planning technique. The implant details, dosimetric parameters, and implant quality indices were compared. Furthermore, the dose to the lung and the incidence of complications were compared. RESULTS: The planning target volume was similar in both groups (p = 0.496). The median V100%, V150%, and V200% values (the percent of the planning target volume receiving 100%, 150%, and 200% of the prescription dose) for the intraoperative planning technique were 95.65%, 76.47%, and 59.80%, respectively. The median V100%, V150%, and V200% values for the preplanning methodology were 88.86%, 69.23%, and 28.30%, respectively (p < 0.01). The median values of the coverage index, c1, conformity index, and plan quality index were higher in the intraoperative planning group than in the preplanning group (p < 0.05). The overdose volume index and dose nonhomogeneity ratio were higher in the intraoperative group (p < 0.05), and the dose homogeneity index was lower in the intraoperative group (p < 0.05) than in the preplanning group. No significant differences were observed in the reference dose (VREF), external index, or lung doses between the two groups. The incidences of pneumothorax and hemoptysis were minimal in both groups. CONCLUSION: These data showed that the intraoperative planning method was superior to the preplanning method for the treatment of lung tumors.

Dosimetric comparison of CT-guided iodine-125 seed stereotactic brachytherapy and stereotactic body radiation therapy in the treatment of NSCLC.

This study aimed to assess the dosimetric differences between iodine-125 seed stereotactic brachytherapy (SBT) and stereotactic body radiation therapy (SBRT) in the treatment of non-small cell lung cancer (NSCLC). An SBT plan and an SBRT plan were generated for eleven patients with T1-2 NSCLC. Prescription of the dose and fractionation (fr) for SBRT was 48Gy/4fr. The planning aim for SBT was D90 (dose delivered to 90% of the target volume)≥120Gy. Student's paired t test was used to compare the dosimetric parameters. The SBT and SBRT plans had comparable PTV D90 (104.73±2.10Gyvs.107.64±2.29Gy), and similar mean volume receiving 100% of the prescription dose (V100%) (91.65% vs.92.44%, p = 0.410). The mean volume receiving 150% of the prescribed dose (V150%) for SBT was 64.71%, whereas it was 0% for SBRT. Mean heterogeneity index (HI) deviation for SBT vs. SBRT was 0.73 vs. 0.19 (p<0.0001), and the mean conformity index (CI) for SBT vs. SBRT was 0.77 vs. 0.81 (p = 0.031). The mean lung doses (MLD) in SBT were significantly lower than those in SBRT (1.952±0.713 vs. 5.618±2.009, p<0.0001). In conclusion, compared with SBRT, SBT can generate a comparable dose within PTV, while the organs at risk (OARs) only receive a very low dose. But the HI and CI in SBT were lower than in SBRT.

[Vascular endothelial growth factor secreted by breast cancer cells plays a critical role in the formation of pre-metastatic niche in the mouse lung].

OBJECTIVE: To explore the formation of pre-metastatic niche in the mouse lung and to study the underlying molecular mechanisms whereby primary breast carcinoma-derived factors mediate recruitment of bone marrow-derived cells (BMDCs) and affect the formation of pre-metastatic lung environment before the arrival of tumor cells. METHODS: Mammary carcinoma 4T1 cells were inoculated into the mammary gland to construct mouse model of breast cancer. Confocal microscopy was used to detect the recruitment of BMDCs in the pre-metastatic lungs. The expression of factors in the mouse sera and 4T1 cell culture media was assayed using RayBio Custom mouse cytokine antibody array kit. The mice were injected daily with recombinant VEGF for 7 consecutive days to observe the effect of VEGF on BMDCs recruitment in the mouse lung. RESULTS: No BMDCs were observed in the lungs of control and 4T1-tumor-bearing mice on day 0. On day 7 and 14, clusters of BMDCs observed in the lungs of 4T1-tumor-bearing mice were 8.7±2.2/objective field and 48.8±3.2/objective field, respectively, significantly higher than those in the control mice (1.1±0.8/objective field and 3.1±1.7/objective field) (P<0.05 for both). Confocal microscopic observation found that metastatic breast cancer cells preferentially facilitate BMDCs recruitment sites in the pre-metastatic mouse lungs. The levels of VEGF, GM-CSF, and IL-6 in the serum of 4T1-tumor-bearing mice were significantly increased compared with those in the control group (P<0.05 for all). However, VEGF was detected only in the culture media of 4T1 cells. The amount of BMDCs in the mouse lung tissue was (22.8±3.6)/objective field in the VEGF group and (3.1±0.4)/objective field in the control group (P<0.05). There were 36.8±5.4 metastatic foci in the lung tissue of VEGF group and 12.6±2.2 in the control group (P<0.05). CONCLUSIONS: The results of this study demonstrate that primary breast cancer cells can alter the lung microenvironment during the pre-metastatic phase and induce the formation of pre-metastatic niche. Primary tumor cell-derived VEGF may be a crucial factor responsible for the formation of pre-metastatic niche.

Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells.

BACKGROUND: Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL). Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α) activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. METHODS: T-ALL cell lines (Jurkat, Sup-T1) transfected with HIF-1α or Notch1 small interference RNA (siRNA) were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. RESULTS: Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2) and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. CONCLUSIONS: Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation, invasion and chemoresistance in T-ALL. Pharmacological inhibitors of HIF-1α or Notch1 signalling may be attractive interventions for T-ALL treatment.

Support vector machines coupled with proteomics approaches for detecting biomarkers predicting chemotherapy resistance in small cell lung cancer.

The aim of this study was to identify serum protein fingerprints of small cell lung cancer (SCLC) and potential biomarkers related to chemotherapy resistance of SCLC with surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS). A total of 60 SCLC patients and 48 age- and sex-matched healthy individuals were enrolled. The chemotherapy regimen was cisplatin plus etoposide. All patients received two cycles of chemotherapy. Serum protein profiles were detected using SELDI-TOF MS and the spectra were analyzed with support vector machines (SVMs). Western blotting was performed to verify the results of SELDI-TOF MS. Three top scored peaks, at m/z of 6269, 9043 and 13124 Da, were finally selected as potential biomarkers for detection of SCLC. The SVM classifier separated the SCLC from the healthy samples in the blind test, with a sensitivity of 92.4% and a specificity of 92.5%. For the 56 eligible chemotherapy patients, 4 had a complete response (7.14%), 39 patients had a partial response (69.6%), 9 patients had a stable disease (16.1%) and 4 patients had a progressive disease (7.14%). The model constructed using two protein peaks with m/z of 8830 and 10468 Da separated the chemotherapy-resistant group from the chemotherapy-sensitive group with a sensitivity of 80.0% and a specificity of 80.0%. Initial protein database searching identified 10468 Da as S100-A9 which was confirmed by western blotting. The present results suggest that the combination of SELDI-TOF MS with SVM may provide a useful means in the search for serum biomarkers for predicting chemotherapy resistance in patients with SCLC.

Hyper-activation of WNT/ß-catenin signaling pathway mediates anti-tumor effects of histone deacetylase inhibitors in acute T lymphoblastic leukemia.

Histone deacetylase inhibitors (HDACis) are promising agents for the treatment of acute T lymphoblastic leukemia (T-ALL). However, the underlying mechanisms remain to be elucidated. Based on a recent study showing that HDACis were able to modulate WNT/ß-catenin signaling, we further investigated the influence of HDACis on WNT/ß-catenin signaling in T-ALL cells and modulation of WNT/ß-catenin signaling in mediating anti-leukemic effects of HDACis. Results from Western blotting, immunocytochemistry and a luciferase reporter assay consistently suggested that two HDACis, valproic acid (VPA) and suberoyl bishydroxamic acid (SBHA), augmented WNT/ß-catenin signaling in T-ALL cells. Meanwhile, VPA and SBHA dramatically inhibited cell growth, blocked G2/M cell cycle progression and increased p21(WAF1) expression. In addition, the levels of cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) were elevated, indicating induction of apoptosis. Furthermore, flow cytometry and Western blot for cleaved PARP showed that targeting ß-catenin with shRNA attenuated the apoptosis induced by VPA and SBHA. These data demonstrate that HDACis exert profound anti-leukemic effects partly by augmentation of WNT/ß-catenin signaling. Using HDACis to modulate WNT/ß-catenin signaling could be an attractive new strategy for the treatment of T-ALL.

Aberrant expression and clinical correlation of Notch signaling molecules in breast cancer of Chinese population.

AIMS: Notch signaling molecules play crucial roles in cell proliferation and apoptosis, yet their function in breast cancer remains unclear. METHODS: Samples and clinical data from 62 breast cancer patients were collected. After total RNA isolation, reverse transcription polymerase chain reaction was applied to analyze the expression of Notch receptors (Notch1, Notch3 and Notch4) and ligands (DLL4 and JAG1), and their clinical association. Immunohistochemical analysis was used to detect the intracellular domain of Notch1 (Notch1-IC) expression. RESULTS: Notch1 was the dominant receptor while DLL4 was the dominant ligand. The Notch molecules expression pattern for infiltrating ductal carcinoma (IDC) was similar to that for infiltrating lobular carcinoma (ILC) except for JAG1, while Notch1 standard coefficients in ILC were statistically higher than that in IDC. Immunohistochemical results showed that Notch1-IC protein expression paralleled the mRNA level. Breast cancer patients' clinical parameters suggested that Notch1 expression was higher in stage II disease and lower in more advanced stages. The Notch3 positive rate was higher in patients with lower levels of Notch1, and the Notch3 positive rate was lower in patients with higher levels of Notch1. No apparent correlation of Notch molecules with estrogen receptor (ER), progesterone receptor (PR) was found. Though high Notch1 and Notch3 RNA levels tended to correlate with c-erbB2 expression, no statistical significance was found. CONCLUSION: Notch molecules are useful biomarkers in breast cancer especially for Notch1 and DLL4, and Notch1 is expressed differently in different stages of human breast cancer.

RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer.

Notch signaling plays a critical role in determining cell fate such as proliferation, differentiation, and apoptosis. Accumulating evidence indicates that aberrant Notch signaling has tumor-promoting function in breast cancer. We hypothesized that Notch signaling may be a potential therapeutic target for human breast cancer. To address this issue, we down-regulated the expression of the Notch-1 receptor by siRNA in human breast cancer cells. We found that the down-regulation of Notch-1 signaling caused cancer cell growth inhibition by apoptosis induction. The effect of the down-regulation of Notch-1 may be through the inactivation of NF-kappaB. In addition, the down-regulation of Notch-1 signaling increased chemosensitivity to doxorubicin and docetaxel. Our results suggested that Notch signaling may be a promising target for breast cancer treatment.

Aberrant expression of Notch signaling molecules in patients with immune thrombocytopenic purpura.

To investigate the role of Notch signaling pathway in immune thrombocytopenic purpura (ITP), we measured the expression of 11 Notch pathway molecules in ITP patients and evaluated their clinical relevance. Real-time reverse transcriptase polymerase chain reaction results showed there was aberrant expression of some Notch molecules in ITP. Notch1 and Notch3 expression elevated, while Notch2 decreased statistically in ITP patients. As for Notch ligands, only DLL1 was found downregulated in ITP. The expression of Notch target gene, Hes1, was also upregulated. In accordance with the mRNA level, Notch1 and Hes1 protein expression was also found elevated by Western blot. Immunocytochemistry showed that Notch1 expressed highly in the cytomembrane, cytoplasm, and part of cellular nucleus for ITP while weak in cytomembrane for controls, and Hes1 of ITP was found expressed higher in cellular nucleus than that of controls. Our findings suggest that the aberrant expression profile of Notch pathway may be involved in ITP, and blockage of Notch1 pathway is likely a promising therapeutic concept.