Discovery of a far-red carbazole-benzoindolium fluorescent ligand that selectively targets mitochondrial DNA and suppresses breast cancer growth.

G-quadruplex (G4) formation was considered to be more prevalent in the mitochondrial DNA (mtDNA) of cancer cells compared with normal cells. Stabilization of these G4s may induce mtDNA instability and cause mitochondrial dysfunction and subsequent cell death, which may be treated as a new strategy for cancer treatment. However, few ligands were developed to target mtG4s, leaving a huge room to improve. In this study, we designed and synthesized a series of carbazole-based ligands, among which, BKN-1 was identified as the most promising mitochondrial targeting fluorescent ligand with far-red emission. Then, we demonstrated that BKN-1 may robustly interact with mtG4s via a variety of biophysical, biological experiments. Subsequently, we proved that BKN-1 may cause mtDNA loss, disrupt mitochondrial integrity, decrease ATP level and trigger unbalanced ROS, thereby leading to apoptosis and autophagy. Finally, we verified that BKN-1 had good anti-tumor activity in both cellular and in vivo models. Altogether, this study provided a dual-function ligand that may not only track the formation of mtG4s but also induce mitochondrial dysfunction, which may be developed into an applicable chemical tool for investigating the structure and function of mtG4s, and moreover, an effective therapeutic agent for cancer interference.

Fibromatosis-like metaplastic carcinoma of the breast: Two case reports.

BACKGROUND: Fibromatosis-like metaplastic carcinoma is classified as a rare type of metaplastic carcinoma of the breast by the 2012 WHO pathological and genetic classification criteria for breast tumors, which takes hyperplastic spindle cells as the main component and is often misdiagnosed as benign stromal proliferative lesions or benign mesenchymal tumors of the breast because of its mild morphology. Here, we collected the clinical data of 2 cases of fibromatosis-like metaplastic carcinoma of the breast and performed pathomorphological observation and immunohistochemical staining of the surgically resected specimens. According to the clinical features, imaging features, immunophenotype, diagnosis and differential diagnosis of 2 cases of fibromatosis-like metaplastic carcinoma of the breast, it was further differentiated. CASE SUMMARY: Case 1: A 56-year-old postmenopausal female was admitted due to "right breast mass for over 1 year and local ulceration for over 1 mo". Physical examination showed a mass with a diameter of 4.5 cm × 5.5 cm palpable at 2.5 cm from the nipple at 1 o'clock in the right breast. The skin on the surface of the mass ruptured about 3 cm, with a small amount of exudation and bleeding, less clear boundary, hard texture, fair activity, without obvious tenderness. No obvious abnormality was palpable in the left breast. No enlarged lymph nodes were palpable in the bilateral axillae and bilateral supraclavicular region. After removing the mass tissue, it was promptly sent to the pathology department for examination. Case 2: Female, 52-years-old, premenopausal, admitted due to "right breast mass for more than 3 mo". Physical examination showed a 4.0 cm × 4.0 cm diameter mass palpable at 2.0 cm of the nipple in the lower outer 7 o'clock direction of the right breast, with less clear boundary, hard texture, fair activity, no significant tenderness, no palpable significant abnormalities in the left breast, and no palpable enlarged lymph nodes in the bilateral axillae and bilateral supraclavicular region. The mass was resected and sent for pathological examination. Postoperative pathological examination revealed fibromatosis-like metaplastic carcinoma of the breast in both patient 1 and patient 2. No systemic therapy and local radiotherapy were performed after surgery, and no tumor recurrence or metastasis was observed. CONCLUSION: Fibromatosis-like metaplastic carcinoma of the breast is a rare subtype of metaplastic carcinoma that is often misdiagnosed, and the diagnosis relies on medical history collection, complete sampling, and full use of immunohistochemical assessment. The risk of lymph node and distant metastasis is low, and the current treatment is based on complete surgical resection. The efficacy of systemic radiotherapy and chemotherapy is not clear.

Prediction of Prognosis and Chemotherapeutic Sensitivity Based on Cuproptosis-Associated lncRNAs in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma.

Cervical cancer is the fourth most common cancer. The 5-year survival rate for metastatic cervical cancer is less than 10%. The survival time of patients with recurrent cervical cancer is approximately 13-17 months. Cuproptosis is a novel type of cell death related to mitochondrial respiration. Accumulative studies showed that long non-coding RNAs (lncRNAs) regulated cervical cancer progression. Compressive bioinformatic analysis showed that nine cuproptosis-related lncRNAs (CRLs), including C002128.2, AC002563.1, AC009237.14, AC048337.1, AC145423.1, AL117336.1, AP001542.3, ATP2A1-AS1, and LINC00426, were independently correlated with the overall survival (OS) of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients. The time-dependent area under curve value reached 0.716 at 1 year, 0.718 at 3 years, and 0.719 at 5 years. Notably, CESC patients in the low-risk group had increased immune cell infiltration and expression of several immune checkpoints, which indicated that they may benefit more from immune checkpoint blockade therapy. In addition, we also used the model for drug sensitivity analysis. Several drug sensitivities were more sensitive in high-risk patients and showed significant correlations with the risk models, such as Bortezomib_1191, Luminespib_1559, and Rapamycin_1084, suggesting that these drugs may be candidate clinical drugs for patients with a high risk of CESC. In summary, this study further explored the mechanism of CRLs in CESC and provided a more optimized prognostic model and some insights into chemotherapy of CESC.

Enhancing Circulation and Tumor Accumulation of Carboplatin via an Erythrocyte-Anchored Prodrug Strategy.

The short circulatory half-lives and low tumor accumulation of carboplatin greatly limit the drug's efficacy in vivo. Herein, we address these challenges by using a prodrug strategy and present the rational design of a novel platinum(IV) anticancer prodrug that can hitchhike on erythrocytes. This prodrug, designated as ERY1-PtIV , can bind to erythrocytes efficiently and stably, possessing a circulatory half-life 18.5 times longer than that of carboplatin in mice. This elongated circulatory half-life enables platinum to accumulate at levels 7.7 times higher than with carboplatin, with steady levels in the tumors. As a consequence, the ERY1-PtIV prodrug is proved to exhibit significantly enhanced antitumor activity and reduced side effects compared with carboplatin. Collectively, our novel approach highlights an efficient strategy to utilize intrinsic erythrocytes as auto-binding carriers to enhance the tumor accumulation and subsequent antitumor efficacy of platinum drugs.

Efficacy of Solitaire AB stent-release angioplasty in acute middle cerebral artery atherosclerosis obliterative cerebral infarction.

BACKGROUND: In both national and international studies, the safety and effectiveness of treatment with the Solitaire stent in patients with ischemic stroke caused by acute large vessel occlusion were good, and the disability rate was significantly reduced. However, there are currently only a few reports on the differences in endovascular treatment for different etiological classifications, especially in the anterior cranial circulation, aorta atherosclerotic stenosis, and acute thrombosis. AIM: To investigate the efficacy of Solitaire AB stent-release angioplasty in patients with acute middle cerebral artery atherosclerosis obliterative cerebral infarction. METHODS: Twenty-five patients with acute middle cerebral atherosclerosis obliterative cerebral infarction were retrospectively enrolled in this study from January 2017 to December 2019. The Solitaire AB stent was used to improve anterior blood flow to maintain modified cerebral infarction thrombolysis [modified thrombolysis in cerebral infarction (mTICI)] at the 2b/3 level or above, the stent was then unfolded and released. RESULTS: All 25 patients underwent successful surgery, with an average recanalization time of 23 min. One patient died of cerebral hemorrhage and cerebral herniation after the operation. The National Institutes of Health Stroke Scale (NIHSS) scores immediately after surgery (7.5 ± 5.6), at 24 h (5.5 ± 5.6) and at 1 wk (3.6 ± 6.7) compared with the preoperative NIHSS score (15.9 ± 4.4), were significantly different (P < 0.01). One case of restenosis was observed 3 mo after surgery (the stenosis rate was 50% without clinical symptoms), the modified Rankin scale scores were 0 points in 14 cases (56%), 1 point in 4 cases (16%), 2 points in 2 cases (8%), 3 points in 3 cases (12%), 4 points in 1 case (4%), and 6 points in 1 case (4%). CONCLUSION: In acute middle cerebral artery atherosclerosis obliterative cerebral infarction, when the Solitaire AB stent is unfolded and the forward blood flow is maintained at mTICI level 2b/3 or higher, stent release may be a safe and effective treatment method; however, long-term observation and a larger sample size are required to verify these findings.

Expression Profiles Reveal Involvement of VEGF, IGF1, BIRC5, and MMP1 in Vulvar Carcinogenesis.

OBJECTIVE: The objective of this study was to identify key genes and shed light on the underlying molecular mechanisms of vulvar squamous cell carcinoma (VSCC). METHODS: Bioinformatic software was utilized for the identification and characterization of key differentially expressed genes (DEGs) from microarrays GSE63678 and GSE38228, which contain VSCC and normal vulvar tissue data. These microarrays were obtained from Gene Expression Omnibus (GEO). Immunohistochemical assays (55 VSCC and 50 normal vulvar tissues) were utilized to validate the expression of VEGF, IGF1, BIRC5, and MMP1 screened from the identified DEGs. SPSS 18.0 software was used for statistical analyses of the relationships between IGF1, BIRC5, VEGF, MMP1 expression levels and patient clinicopathological characteristics. RESULTS: A total of 141 DEGs were identified, among which 18 genes were closely correlated with the biological characteristics of VSCC. Four of the 18 genes (VEGF, IGF1, BIRC5, and MMP1) screened from the GEO database were markedly enriched in pathways in cancer (P < 0.05), and could be considered key genes in VSCC based on KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis in DAVID (Database for Annotation, Visualization and Integrated Discovery).The expression levels of these 4 hub genes, determined by immunohistochemical assays, were consistent with the bioinformatics results. Higher expression of IGF1 showed significant association with well-differentiated carcinomas (P = 0.017).BIRC5 expression levels showed a positive correlation with clinical stage (P = 0.039); compared with those in menopause for over 10 years, patients in menopause for less than 10 years at the time of diagnosis tended to have significantly higher expression of BIRC5 (P = 0.003). VEGF and MMP1 expression levels were not correlated with any of the tested clinicopathological characteristics. CONCLUSION: VEGF, IGF1, BIRC5, and MMP1 were identified as being associated with VSCC using integrated bioinformatic methods, which may provide important insights into the pathogenesis of this disease and help to identify new biomarkers.