Discovery of a proliferation essential gene signature and actin-like 6A as potential biomarkers for predicting prognosis and neoadjuvant chemotherapy response in triple-positive breast cancer.

BACKGROUND: Patients with triple-positive breast cancer (TPBC) have a higher risk of recurrence and lower survival rates than patients with other luminal breast cancers. However, there are few studies on the predictive biomarkers of prognosis and treatment responses in TPBC. METHODS: Proliferation essential genes (PEGs) were acquired from clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) technology, and cohorts of patients with TPBC were obtained from public databases and our cohort. To develop a TPBC-PEG signature, Cox regression and least absolute shrinkage and selection operator regression analyses were applied. Functional analyses were performed with gene set enrichment analysis. The relationship between candidate genes and neoadjuvant chemotherapy (NACT) sensitivity was explored via real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) on the basis of clinical samples. RESULTS: Among 900 TPBC-PEGs, 437 showed significant differential expression between TPBC and normal tissues. Three prognostic PEGs (actin-like 6A [ACTL6A], chaperonin containing TCP1 subunit 2 [CCT2], and threonyl-TRNA synthetase [TARS]) were identified and used to construct the PEG signature. Patients with high PEG signature scores exhibited a worse overall survival and lower sensitivity to NACT than patients with low PEG signature scores. RT-qPCR results indicated that ACTL6A and CCT2 expression were significantly upregulated in patients who lacked sensitivity to NACT. IHC results showed that the ACTL6A protein was highly expressed in patients with NACT resistance and nonpathological complete responses. CONCLUSIONS: This efficient PEG signature prognostic model can predict the outcomes of TPBC. Furthermore, ACTL6A expression level was associated with the response to NACT, and could serve as an important factor in predicting prognosis and drug sensitivity of patients with TPBC.

Efficacy and safety of neoadjuvant therapy for triple-negative breast cancer: a Bayesian network meta-analysis.

BACKGROUND: Numerous studies have concentrated on neoadjuvant therapies for treating triple-negative breast cancer (TNBC) that improve the pathological complete response (pCR) rate but remain controversial. We conducted a network meta-analysis (NMA) to objectively explore the efficacy and safety of different neoadjuvant regimens. METHODS: Phase II/III randomized clinical trials that compared different neoadjuvant therapies for TNBC were included. NMA and pairwise meta-analysis were performed using WinBUGS (version 1.4.3) and Review Manager 5.3. RESULTS: Forty-four studies with 8459 patients met the eligibility criteria. The NMA of pCR showed that programmed cell death Protein-1 and programmed cell death Ligand-1 inhibitors (PD-1/PD-L1), bevacizumab (Bev), zoledronic acid (ZOL), and platinum salts plus poly polymerase inhibitors (Pt+PARPi) may be favorable for TNBC neoadjuvant therapy. Chemotherapy combined with platinum salts or nanoparticle albumin-bound paclitaxel (Nab-p) has additional beneficial effects. However, neo-type drugs may also have increased toxicity. CONCLUSION: PD-1/PD-L1, Bev, ZOL, and Pt+ PARPi-containing regimens improved the pCR rate compared to traditional chemotherapy, including anthracyclines and taxanes. Chemotherapy with platinum salts or Nab-p improved the pCR rate. Nevertheless, the balance between efficacy and toxicity should be evaluated rigorously. PD-1/PD-L1-containing regimens appear to be the most favorable for TNBC neoadjuvant therapy, with good efficacy and tolerance.

LINC00092 Modulates Oxidative Stress and Glycolysis of Breast Cancer Cells via Pyruvate Carboxylase-Mediated AKT/mTOR Pathway.

Background: The discovery of noncoding RNAs (ncRNAs) offers new options for cancer-targeted therapy. This study is aimed at exploring the regulatory function of LINC00092 on breast cancer (BC) oxidative stress and glycolysis, along with internal mechanism concerning pyruvate carboxylase (PC). Methods: Bioinformatics analysis was used to explore LINC00092 (or friend leukemia virus integration 1 (FLI1)) expression on BC progression, as well as oxidative stress and glycolysis in BC. After LINC00092 overexpression or silence, BC cell viability, proliferation, migration, invasion, oxidative stress, glycolysis, and AKT/mTOR pathway were detected. Following 2-DG, SC79, or MK2206 treatment, effects of LINC00092 on BC cells were measured. Moreover, regulatory activity of LINC00092 in PC expression was analyzed. Whether PC participated in the modulation of LINC00092 on BC cell functions was explored. Results: LINC00092 was lowly expressed in BC and negatively related to BC progression. FLI1 bound to LINC00092 promoter to positively modulate LINC00092. LINC00092 overexpression inhibited BC cell proliferation, migration, invasion, oxidative stress, glycolysis, and AKT/mTOR pathway and likewise suppressed BC growth in vivo. Silence of LINC00092 had opposite influences. 2-DG partially reversed the LINC00092 silence-resulted increase of BC cell proliferation. SC79 alleviated the function of LINC00092 overexpression on BC cell functions. MK2206 had the contrary influence of SC79. Besides, LINC00092 bound to PC to modulate ubiquitination degradation of PC protein. PC took part in the influences of LINC00092 on BC cell functions. Conclusions: LINC0092 modulates oxidative stress and glycolysis of BC cells via the PC-mediated AKT/mTOR pathway, which is possibly a target for BC diagnosis and therapy.

Analysis of Stemness and Prognosis of Subtypes in Breast Cancer Using the Transcriptome Sequencing Data.

The stem characteristics of tumor cells have been proposed in theory very early, and we can use the signature of gene expression to speculate the stemness of tumor cells. However, systematic studies on the stemness of breast cancer as well as breast cancer subtypes, and the relationship between stemness and metastasis and prognosis, are still lacking. In the present research, using the transcriptome data of patients with breast cancer in the TCGA database, a stemness prediction model was utilized to derive the stemness of the patients' tumors. We compared the stemness values among different subtypes and the differences with metastasis. COX regression was employed to evaluate the correlation between stemness value as well as prognosis. Using the Lasso-penalized Cox regression machine learning model, we obtained the gene signature of the basal subtype that is related to stemness and can also predict the prognosis of the patient. Patients can be stratified into two groups of high and low stemness, corresponding to good and poor prognosis. Based on further prediction of tumor infiltration by CIBERSORT and prediction of drug response by a connectivity map, we found that the difference in stemness between these two groups is associated with the activation of tumor-killing immune cells and drug response. Our findings can promote the understanding and research of subtypes of basal breast cancer and provide corresponding molecular markers for clinical detection and therapy.

Altered Brain Functional Connectivity at Resting-State in Patients With Non-arteritic Anterior Ischemic Optic Neuropathy.

Purpose: To investigate the possible changes in functional connectivity (FC) in patients with non-arteritic anterior ischemic optic neuropathy (NAION) using resting-state functional MRI (fMRI). Methods: Thirty-one NAION patients and 31 healthy controls were recruited and underwent resting-state fMRI scans. Regions of interest (ROIs) were defined as bilateral Brodmann's area 17 (BA17). FC analysis was performed between the ROIs and the rest of the brain regions, and the between group comparisons of FC were performed. We conducted correlation analysis between the FC changes and the clinical variables in NAION patients. Results: Compared with healthy controls, patients with NAION showed significantly decreased FC between the left BA17 and the right inferior frontal gyrus, left caudate nucleus. As for the right BA17, patients exhibited significantly increased FC with the left olfactory gyrus and decreased FC with the right superior frontal gyrus (SFG), right insula. Moreover, FC values between the right insula and the right BA17 were positively correlated with the right side of mean sensitivity in the central visual field (r = 0.52, P < 0.01) and negatively correlated with the right side of mean defect in the central visual field (r = -0.55, P < 0.01). Conclusion: Our study indicated that patients with NAION showed significantly abnormal functional reorganization between the primary visual cortex and several other brain regions not directly related to visual function, which supports that NAION may not only be an ophthalmic disease but also a neuro-ophthalmological disease.

An immunohistochemical panel of three small ubiquitin-like modifier genes predicts outcomes of patients with triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease. Developing new candidate biomarkers for chemotherapy response and possible therapeutic targets has become an urgent clinical need. Small ubiquitin-like modifiers (SUMOs) mediate post-translational modifications (SUMOylation) has been shown to be involved in numerous biological processes. However, the role of SUMOylation in TNBC has yet to be elucidated. METHOD: The mRNA expression of SUMO1/2/3 was analyzed by the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO) databases (N=412). We also evaluated the SUMO1/2/3 protein expression in 212 TNBC patients using immunohistochemical (IHC) staining method. A classifier with Least absolute shrinkage and selection operator (LASSO) Cox regression model was then built based on the associations between the expression of SUMO1/2/3 proteins and the disease-free survival (DFS) of TNBC patients. RESULTS: Elevated SUMO1/2/3 levels were indicated to be associated with a poorer overall survival (OS) and DFS for TNBC patients. With the LASSO model, we built a classifier based on the IHC scores of SUMO1/2/3 proteins and named it the 'SB classifier'. Patients with SB classifier-defined high score were found to have an unfavorable response to chemotherapy [hazard ratio (HR) 4.04, 95% confidence interval (CI): 2.14-7.63; P<0.0001]. A nomogram was then developed to identify which patients might benefit from chemotherapy. Finally, our results also suggested that the activation of SUMOylation pathway in TNBC might be induced by MYC signaling. CONCLUSIONS: We constructed a reliable prognostic and predictive tool for TNBC patients treated with chemotherapy, which could facilitate individualized counseling and management.

Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis.

AIMS: Currently, there are many approaches available for neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer that improve therapeutic efficacy but are also controversial. We conducted a two-step Bayesian network meta-analysis (NMA) to compare odds ratios (ORs) for pathologic complete response (PCR) and safety endpoints. METHODS: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and online abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched comprehensively and systematically. Phase II/III randomised clinical trials for targeted therapy in at least one arm were included. RESULTS: A total of 9779 published manuscripts were identified, and 36 studies including 10,379 patients were finally included in our analysis. The NMA of PCR showed that dual-target therapy is better than single-target therapy and combination chemotherapy is better than monochemotherapy. However, anthracycline did not bring extra benefits, whether combined with dual-target therapy or single-target therapy. On the other hand, the addition of endocrine therapy in the HER2-positive, hormone receptor (HR)-positive subgroup might have additional beneficial effects but without significant statistical difference. By performing a conjoint analysis of the PCR rate and safety endpoints, we found that 'trastuzumab plus pertuzumab' and 'T-DM1 containing regimens' were well balanced in terms of efficacy and toxicity in all target regimens. CONCLUSION: In summary, trastuzumab plus pertuzumab-based dual-target therapy with combination chemotherapy regimens showed the highest efficacy of all optional regimens. They also achieved the best balance between efficacy and toxicity. As our study showed that anthracycline could be replaced by carboplatin, we strongly recommended TCbHP as the preferred choice for neoadjuvant treatment of HER2-positive breast cancer. We also look forward to the potential value of T-DM1 in improving outcomes, which needs further study in future trials.

Abnormal Regional Spontaneous Neural Activity in Nonarteritic Anterior Ischemic Optic Neuropathy: A Resting-State Functional MRI Study.

Objective: To explore altered regional neuronal activity in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and its correlation with clinical performances using the regional homogeneity (ReHo) method, which is based on resting-state functional magnetic resonance imaging (fMRI). Method: Thirty-one patients with NAION (20 males, 11 females) and 31 age- and sex-matched normal controls (NCs) (20 males, 11 females) were enrolled in the study. All patients underwent ophthalmic examination, including eyesight, intraocular pressure measurement, optimal coherence tomography (OCT), visual field analysis, and fMRI scans. After ReHo was calculated, we investigated group differences in results between the patients and NCs. We analyzed the relationship between ReHo values for different brain regions in patients with NAION and intraocular pressure, visual field analysis, and OCT. A receiver operating characteristic (ROC) curve was used to assess the diagnostic ability of the ReHo method. Results: Compared with NCs, patients with NAION exhibited higher ReHo values in the left middle frontal gyrus, left middle cingulate gyrus, left superior temporal gyrus, and left inferior parietal lobule. Additionally, they exhibited lower ReHo values in the right lingual gyrus, left putamen/lentiform nucleus, and left superior parietal lobule. ReHo values in the left superior parietal lobule were negatively correlated with right retinal nerve fiber layer values (r = -0.462, P = 0.01). The area under the ROC curve for each brain region indicated that the ReHo method is a credible means of diagnosing patient with NAION. Conclusion: NAION was primarily associated with dysfunction in the default mode network, which may reflect its underlying neural mechanisms.

The Expression, Clinicopathologic Characteristics, and Prognostic Value of Androgen Receptor in Breast Cancer: A Bioinformatics Analysis Using Public Databases.

The role of androgen receptor (AR) in breast cancer has been unveiled in succession for the past few years. In this study, we conducted a comprehensive analysis based on four online public databases of data from many previous studies. We found that the expression of AR is significantly related to age, histological grade, and subtype but not to lymph node status. The low expression level of AR is strongly associated with poor recurrence-free survival, especially with poor distance metastasis-free survival in luminal A patients, but inverse in HER2 (human epidermal growth factor receptor-2) enriched patients. AR might be a biomarker of chemosensitivity in the basal subtype. Besides, the expression of melanophilin (MLPH) is distinctly in accordance with that of AR. AR could play diverse roles in different subtypes of breast cancer.

Eco-friendly preparation of large-sized graphene via short-circuit discharge of lithium primary battery.

We proposed a large-sized graphene preparation method by short-circuit discharge of the lithium-graphite primary battery for the first time. LiCx is obtained through lithium ions intercalation into graphite cathode in the above primary battery. Graphene was acquired by chemical reaction between LiCx and stripper agents with dispersion under sonication conditions. The gained graphene is characterized by Raman spectrum, X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Atomic force microscope (AFM) and Scanning electron microscopy (SEM). The results indicate that the as-prepared graphene has a large size and few defects, and it is monolayer or less than three layers. The quality of graphene is significant improved compared to the reported electrochemical methods. The yield of graphene can reach 8.76% when the ratio of the H2O and NMP is 3:7. This method provides a potential solution for the recycling of waste lithium ion batteries.