Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer.

Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.

Clinical application status and prospect of the combined anti-tumor strategy of ablation and immunotherapy.

Image-guided tumor ablation eliminates tumor cells by physical or chemical stimulation, which shows less invasive and more precise in local tumor treatment. Tumor ablation provides a treatment option for medically inoperable patients. Currently, clinical ablation techniques are widely used in clinical practice, including cryoablation, radiofrequency ablation (RFA), and microwave ablation (MWA). Previous clinical studies indicated that ablation treatment activated immune responses besides killing tumor cells directly, such as short-term anti-tumor response, immunosuppression reduction, specific and non-specific immune enhancement, and the reduction or disappearance of distant tumor foci. However, tumor ablation transiently induced immune response. The combination of ablation and immunotherapy is expected to achieve better therapeutic results in clinical application. In this paper, we provided a summary of the principle, clinical application status, and immune effects of tumor ablation technologies for tumor treatment. Moreover, we discussed the clinical application of different combination of ablation techniques with immunotherapy and proposed possible solutions for the challenges encountered by combined therapy. It is hoped to provide a new idea and reference for the clinical application of combinate treatment of tumor ablation and immunotherapy.

[Preparation of Modified Watermelon Biochar and Its Adsorption Properties for Pb(â ¡)].

In this study, watermelon rind was used as a raw material to modify watermelon rind biochar (MBC) with ammonium sulphate[(NH4)2S] for adsorption of Pb(Ⅱ) ions. The effects of solution pH, adsorption time, adsorbent addition amount, initial mass concentration of Pb(Ⅱ) ions, and ionic strength on the adsorption of Pb(Ⅱ) ions were investigated. The results show that the saturated adsorption time was 5 h, the optimum pH of the adsorption reaction was 6, and when the initial mass concentration of Pb(Ⅱ) ions were 1000 mg·L-1, and the amount of adsorbent was 2.0 g·L-1. The maximum adsorption amount of MBC to Pb(Ⅱ) ions can reach 97.63 mg·g-1, which is significantly higher than unmodified watermelon husk biochar (BC). The adsorption of Pb(Ⅱ) ions by modified watermelon biochar was in accordance with the Langmuir isotherm adsorption model and the pseudo second-order kinetic model, which proves that adsorption is dominated by monolayer chemical adsorption. The desorption of MBC after adsorption of Pb(Ⅱ) ions was carried out using a sodium hydroxide solution to study the reusability of MBC, and the adsorption amount was still 64.74 mg·g-1 in the sixth cycle. Characterization and analysis of adsorbents by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, nitrogen adsorption, scanning electron microscopy-energy spectroscopy, zeta potential analysis, and X-ray diffraction (XRD) were carried out, which showed that the adsorption mechanism is mainly that MBC oxygen- and MBC sulfur-containing groups adsorb Pb(Ⅱ) through complexation and precipitation. Therefore, ammonium sulfide modified watermelon rind biochar can be used as a highly efficient lead adsorbent.

Ligustrazine reverts anthracycline chemotherapy resistance of human breast cancer by inhibiting JAK2/STAT3 signaling and decreasing fibrinogen gamma chain (FGG) expression.

Chemotherapy resistance is a major challenge for breast cancer treatment. It is necessary to elucidate the mechanisms of anthracycline resistance to develop new chemosensitizers for breast cancer. In this study, we explored the effects of ligustrazine (TMP) on reverting anthracycline resistance of breast cancer cells, as well as its related mechanisms. Clinical significance of fibrinogen gamma chain (FGG) expression was also analyzed in breast cancer tissues. We provided evidence that breast tumor cell derived FGG participated in anthracycline chemoresistance of breast cancer. Further, TMP reverted epirubicin resistance by inhibiting JAK2/STAT3 signaling and decreasing FGG expression. Meanwhile, the elimination of cancer stem cell was observed in TMP treated chemoresistant breast cancer cells. Clinical analysis demonstrated that patients with FGG expressing breast cancer showed a dramatically low response to anthracycline-based chemotherapy and poor survival. Our data collectively indicated that FGG was an independent detrimental factor for anthracycline based chemotherapy for breast cancer patients. TMP was a novel chemosensitizer for FGG-induced anthracycline chemoresistance in breast cancer treatment.

Annexin A13 predicts poor prognosis for lung adenocarcinoma patients and accelerates the proliferation and migration of lung adenocarcinoma cells by modulating epithelial-mesenchymal transition.

This study aimed to investigate the role of ANXA13 in lung adenocarcinoma (LUAD) growth, migration, and the underlying mechanisms. Firstly, in the TCGA dataset for LUAD, ANXA13 is found to be highly expressed in patients with LUAD and high expression of ANXA13 predicted poor outcomes in LUAD patients. Consistently, the data of qRT-PCR showed that the expression of ANXA13 was higher in LUAD cell lines (Calu-3, LTEP-a-2, and NCI-H1395) than that in normal lung cell line BEAS2B. Then, we performed gain- and loss of function of ANXA13 in NCI-H1395 and Calu-3 cells, respectively. The results displayed that deficiency of ANXA13 suppresses cell proliferation, invasion, and migration in Calu-3 cells and overexpression of ANXA13 augments cell proliferation, invasion, and migration in NCI-H1395 cells. Finally, it was found that silencing of ANXA13 obviously raised the protein expression levels of E-cadherin and reduced the protein levels of N-cadherin, Vimentin, and Snail in Calu-3 cells whereas overexpression of ANXA13 obviously receded the protein expression levels of E-cadherin and enhanced the protein levels of N-cadherin, Vimentin, and Snail in NCI-H1395 cells. This study analyzed the biological effects of ANXA13 in LUAD cells, indicating that ANXA13 could regard as a therapeutic target for LUAD.

Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients with progressive disease after all available standard therapies need new medication for further treatment. Famitinib is a small-molecule multikinase inhibitor, with promising anticancer activities. This multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial was designed to evaluate the safety and efficacy of famitinib in mCRC. METHODS: Famitinib or placebo was administered orally once daily. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality-of-life (QoL), and safety. RESULTS: Between July 18, 2012 and Jan 22, 2014, a total of 167 patients were screened, and 154 patients were randomized in a 2:1 ratio to receive either famitinib (n = 99) or placebo (n = 55). The median PFS was 2.8 and 1.5 months in the famitinib and placebo groups (hazard ratio = 0.60, 95% confidence interval = 0.41-0.86, P = 0.004). The DCR was 59.8% and 31.4% (P = 0.002) and the ORR was 2.2% and 0.0% (P = 0.540) in the famitinib and placebo groups, respectively. The most frequent grade 3-4 adverse events were hypertension (11.1%), hand-foot syndrome (10.1%), thrombocytopenia (10.1%), and neutropenia (9.1%). Serious adverse events occurred in 11 (11.1%) patients in the famitinib group and 5 (9.1%) in the placebo group (P = 0.788). The median OS of the famitinib and placebo groups was 7.4 and 7.2 months (P = 0.657). CONCLUSION: Famitinib prolonged PFS in refractory mCRC patients with acceptable tolerability. Trial registration This study was registered on ClinicalTrials.gov (NCT01762293) and was orally presented in the 2015 ASCO-Gastrointestinal Symposium.

Associations between body mass index and the risk of mortality from lung cancer: A dose-response PRISMA-compliant meta-analysis of prospective cohort studies.

BACKGROUND: Whether body mass index (BMI) is associated with the risk of mortality from lung cancer (LC) is controversial, and the shape of dose-response relationship on this topic is not well-established. Thus, a dose-response meta-analysis was performed to clarify this association. METHODS: A search of PubMed and EMBASE was conducted, and 2-stage random-effect dose-response model was used to yield summary relative risks and its shape. RESULTS: Fifteen prospective cohort studies were eligible for inclusion criteria. The combined relative risks per 5 kg/m in BMI for risk of LC mortality is 0.94 (95% confidence interval] 0.92-0.96), and nonlinear association was found (Pnonlinearity < .0001), which indicated that compared with higher BMI, lower BMI showed higher LC mortality risk. Subgroup analyses revealed that this obesity paradox remained regardless of number of cases, follow-up duration, and study location, but this relationship was not observed among nonsmokers. CONCLUSION: A nonlinear association between BMI and the risk of LC mortality was found, and higher BMI participants have a lower risk of LC death than slim people.

Sodium intake, salt taste and gastric cancer risk according to Helicobacter pylori infection, smoking, histological type and tumor site in China.

AIM: The risk factors mostly strongly associated with gastric cancer are gastric bacteria Helicobacter pylori and diet. Using a case-control study among residents in Jinan, we examined the association between the salt taste and gastric cancer according to H. pylori infection, smoking and histological type as well as tumor site. METHODS: This population-based case-control study included 207 cases and 410 controls. Data on potential risk factors of gastric cancer were obtained by interview of cases and controls with a questionnaire, salt taste preference was measured for all subjects, and IgG antibodies to H. pylori were applied to assess infection. Risk measures were determined using unconditional logistic regression. RESULTS: The proportions of salt taste at intervals of 1.8-7.2 g/L and ≥ 7.2 g/L were significantly higher in cases than controls, with ORs of 1.56 (1.23-3.64) and 2.03 (2.12- 4.11), respectively, subjects with high salt intake having an elevated risk for gastric cancer when infected with H. pylori. Significant modification by smoking and tumor site was observed across the different measures of salt intake, the highest salt taste showed higher cancer risk in ever smokers or with non-cardia cancers. CONCLUSION: Our study supports the view that high intake of sodium is an important dietary risk factor for gastric cancer, with a synergistic effect found between salt and H.pylori and smoking, dependent on the tumor site.