Mitochondrial calcium uniporter activates TFEB-driven autophagy to promote migration of breast cancer cells.

Objectives: Tumor metastasis is the leading cause of death in breast cancer (BC) patients and is a complicated process. Mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, has been reported to be associated with tumorigenesis and metastasis. The molecular mechanisms of MCU contributing to the migration of BC cells are partially understood. This study investigated the role of MCU in BC cell metastasis and explored the underlying mechanism of MCU-mediated autophagy in BC cell migration. Materials and Methods: The Kaplan-Meier plotter database was used to analyze the prognostic value of MCU mRNA expression. Western blotting was used to examine the expression level of MCU in 4 paired BC and adjacent normal tissues. The cellular migration capability of BC was measured by transwell migration assay and wound healing assay. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression levels of autophagy-related markers. The effects of MCU activation or inhibition on TFEB nuclear translocation in BC cells were detected by laser scanning confocal microscopy. Results: Expression of MCU was found to be negatively correlated with BC patient prognosis in the Kaplan-Meier plotter database. Compared with the adjacent normal tissues, MCU was markedly up-regulated in the BC tissues. MCU overexpression promoted cellular migration, activated autophagy, and increased TFEB nuclear translocation in BC cells, whereas its knockdown produced the opposite effects. Conclusion: MCU activates TFEB-driven autophagy to promote BC cell metastasis and provides a potential novel therapeutic target for BC clinical intervention.

A monoclonal antibody against basic fibroblast growth factor attenuates cisplatin resistance in lung cancer by suppressing the epithelial-mesenchymal transition.

Objectives: To investigate the underlying mechanisms of how the basic fibroblast growth factor monoclonal antibody (bFGFmAb) attenuates cisplatin (DDP) resistance in lung cancer using A549 cells and cisplatin-resistant A549 cells (A549/DDP). Methods: Cancer cell proliferation, cell viability, and 50% inhibitory concentration (IC50) of cisplatin were assessed. Transwell assays were utilized to evaluate the invasion activity of tumor cells in response to treatment. Epithelial-to-mesenchymal transition markers and drug resistance proteins were analysed using Western blots. Results: We demonstrate that the bFGFmAb inhibits the proliferation and invasion of both A549 and A549/DDP cells. The bFGFmAb increases cisplatin sensitivity of both A549 and A549/DDP cells as evidenced by an increase in the IC50 of cisplatin in A549 and A549/DDP cells. Furthermore, bFGFmAb significantly increases the expression of E-cadherin, whilst decreasing the expression of N-cadherin and bFGF in both cell lines, thereby showing inhibition of epithelial-to-mesenchymal transition. In addition, we demonstrate that bFGFmAb significantly reduces the expression of the lung resistance protein. Conclusions: Our data suggests that the humanized bFGFmAb is a promising agent to attenuate cisplatin resistance in NSCLC. The underlying mechanism for this effect of bFGFmAb may be associated with the inhibition of epithelial-to-mesenchymal transition and reduced expression of lung resistance protein.

Post-Diagnosis use of Antioxidant Vitamin Supplements and Breast Cancer Prognosis: A Systematic Review and Meta-Analysis.

Antioxidant vitamin supplements (AVSs) are widely used among breast cancer survivors. Whether post-diagnosis use of AVSs would impair cancer survival is unclear. To assess the association between breast cancer survival and post-diagnosis AVSs use. We performed a literature search using PubMed, Cochrane Library, and Embase from their inception to October 1, 2020. Studies that investigated the association between breast cancer survival and post-diagnosis AVS use included. The AVSs included 1 or more of the following: vitamin A, C, or E. The meta-analysis included 8 studies with 17,062 patients. There was no significant difference between AVS use or not after diagnosis (HR 0.92, 95% CI 0•82-1•03) or during chemotherapy (HR 1.15, 95% CI 0.78-1.68) in overall survival (OS). Whenever during chemotherapy or after diagnosis, AVS users had a worse prognosis in the later studies. There was no significant inverse association between post-diagnosis vitamin A or E supplements use and OS. Vitamin C intake after breast cancer diagnosis was significantly associated with better OS (HR 0.84, 95% CI 0.76-0.93). Our findings suggest that post-diagnosis AVSs use would not worsen breast cancer survival, while vitamin C use after diagnosis might benefit OS. The discrepancy of survivals associated with post-diagnosis AVS use between earlier and later studies may cast doubt on the recommendation on guidelines. RCTs with large sample sizes are needed.

Is nab-paclitaxel better than conventional taxanes as neoadjuvant therapy for breast cancer? A meta-analysis.

OBJECTIVE: This study compared the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with conventional taxanes as neoadjuvant chemotherapy for breast cancer. METHODS: We searched the literature using PubMed, the Cochrane Library, and Web of Science from their inception to December 15, 2019 based on predetermined inclusion and exclusion criteria. The relevant studies compared pathologic complete response (pCR) and adverse event rates. RESULTS: The meta-analysis included five studies and 2335 patients. Compared with conventional taxanes, neoadjuvant chemotherapy with nab-paclitaxel was associated with a higher pCR rate (odds ratio [OR] = 1.39, 95% confidence interval [CI] = 1.16-1.67), especially among patients with triple-negative breast cancer or Ki67 indices of >20%. Pooled outcomes also revealed better event-free survival in the nab-paclitaxel group (hazard ratio = 0.69, 95% CI = 0.57-0.85). However, all-grade (OR = 2.17, 95% CI = 1.38-3.40) and grade ≥3 peripheral sensory neuropathy (OR = 3.92, 95% CI = 2.44-6.28) were more frequent in the nab-paclitaxel group. CONCLUSIONS: This meta-analysis implied that nab-paclitaxel more effectively improved pCR than conventional taxanes. Nab-paclitaxel may have greater benefits in patients with triple-negative breast cancer. However, additional attention is required for the early diagnosis and management of peripheral sensory neuropathy.

PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges.

Unprecedented efficacy of chimeric antigen receptor (CAR) T cell therapy in the treatment of hematologic malignancies brings new hope for patients with many cancer types including solid tumors. However, the challenges for CAR-T cell therapy in eradicating solid tumors are immense. To overcome these seemingly intractable hurdles, more "powerful" CAR-T cells with enhanced antitumor efficacy are required. Emerging data support that the anti-tumor activity of CAR-T cells can be enhanced significantly without evident toxicity through simultaneous PD-1 disruption by genome editing. This review focuses on the current progress of PD-1 gene disrupted CAR-T cells in cancer therapy. Here we discuss key rationales for this new combination strategy and summarize the available pre-clinical studies. An update is provided on human clinical studies and available registered cancer clinical trials using CAR-T cells with PD-1 disruption. Future prospects and challenges are also discussed.

Validation of a breast cancer nomogram to predict lymphedema in a Chinese population.

BACKGROUND: Upper arm lymphedema (LE) is a common complication after axillary lymph node dissection (ALND) in breast cancer patients. This retrospective cohort study aimed to validate a published nomogram to predict the risk of LE in the Chinese breast cancer patients. METHODS: A total of 409 breast cancer patients who underwent breast cancer surgery and ALND (level I and II) were identified. Cox regression analysis was used to identify the risk factors for LE. The nomogram predictive of LE of breast cancer was evaluated by receiver-operating curve analysis, calibration plots, and Kaplan-Meier analysis in our study population. RESULTS: With a median follow-up of 68 months, the 5-year cumulative incidence of LE was 22.3%. Higher body mass index (hazard ratio [HR] = 1.06, 95% CI: 1.00-1.13), neoadjuvant chemotherapy (HR = 3.76, 95% CI: 2.29-6.20), larger extend of axillary surgery (level I/II/III versus level I/II: HR = 2.39, 95% CI: 1.30-4.37), and radiotherapy (HR = 4.90, 95% CI: 1.90-12.5) were independently associated with LE. The AUC value of the nomogram was 0.706 (95% CI: 0.648-0.752). A high-risk subgroup of patients defined by nomogram had significantly higher cumulative risk of LE than those in the low-risk subgroups (P < 0.01). The calibration plots revealed that the nomogram was well calibrated (Hosmer-Lemeshow test, P = 0.0634). CONCLUSIONS: The nomogram to predict the risk of LE in breast cancer patients with ALND has been validated to be discriminative and accurate. More studies are needed to evaluate the impact of other factors (lifestyle, behaviors, and so forth) on the performance of the nomogram.