Discovery of Novel Lin28 Inhibitors to Suppress Cancer Cell Stemness.

Lin28 is a pluripotency factor that regulates cancer cell stem-like phenotypes to promote cancer development and therapy-resistant tumor progression. It acts through its cold shock domain and zinc knuckle domain (ZKD) to interact with the Let-7 pre-microRNA and block Let-7 biosynthesis. Chemical inhibition of Lin28 from interacting with Let-7 presents a therapeutic strategy for cancer therapy. Herein, we present the computer-aided development of small molecules by in silico screening 18 million compounds from the ZINC20 library, followed by the biological validation of 163 predicted compounds to confirm 15 new Lin28 inhibitors. We report three lead compounds, Ln7, Ln15, and Ln115, that target the ZKD of both Lin28A and Lin28B isoforms and block Lin28 from binding Let-7. They restore Let-7 expression and suppress tumor oncogenes such as SOX2 in cancer cells and show strong inhibitory effects on cancer cell stem-like phenotypes. However, minimal impacts of these compounds were observed on Lin28-negative cells, confirming the on-target effects of these compounds. We conclude from this study the discovery of several new Lin28 inhibitors as promising candidate compounds that warrant further drug development into potential anticancer therapies.

Incidental finding of severe hyperkalemia in a patient with end-stage renal disease during video-assisted lung lobectomy: A case report.

Patients with end-stage renal disease are at risk of developing hyperkalemia and acidosis, both of which have disastrous sequelae during elective video-assisted thoracic surgery for lung cancer. Herein, we present a case where severe hyperkalemia and combined acidosis were incidentally found in a 68-year-old man with the end-stage renal disease after establishing one-lung ventilation during video-assisted lobectomy. There was no significant instability of vital signs, abnormality of perioperative electrocardiography, or malignant arrhythmia. Therefore, we arranged for related management promptly, and the surgery was relatively smooth. This incidental intraoperative hyperkalemia was thought to have resulted from one-lung ventilation and hypercarbia and/or metabolic acidosis. More frequent arterial blood gas analysis and aggressive blood potassium control during video-assisted thoracic surgery should be considered for patients with end-stage renal disease.

A Comparison of McGrath Videolaryngoscope versus Macintosh Laryngoscope for Nasotracheal Intubation: A Systematic Review and Meta-Analysis.

BACKGROUND: In this study, it was shown that the routine use of McGrath videolaryngoscopy may improve intubation success rates. The benefits to using a videolaryngoscope in nasotracheal intubation were also demonstrated. However, no solid evidence concerning the effectiveness of the use of McGrath videolaryngoscopes in nasotracheal intubation has previously been reported. As a result, we questioned whether, in adult patients who underwent oral and maxillofacial surgeries with nasotracheal intubation (P), the use of a McGrath videolaryngoscope (I) compared with a Macintosh laryngoscope (C) could reduce the intubation time, improve glottis visualization to a score of classification 1 in the Cormack-Lehane classification system, and improve the first-attempt success rate (O). The secondary outcomes measured were the rate of the use of Magill forceps and the external laryngeal pressure (BURP) maneuver used. METHODS: An extensive literature search was conducted using databases. Only randomized controlled trials that compared the McGrath videolaryngoscopy and Macintosh laryngoscopy techniques in nasotracheal intubation in adult patients were included. RESULTS: Five articles met the inclusion criteria and were included in the final analysis (n = 331 patients). The results showed a significant decrease in intubation time and a higher rate of classification 1 scores in the Cormack-Lehane classification system, but no difference in the first-attempt success rates were found between the McGrath group and the Macintosh group. Decreases in the rate of the use of Magill forceps and the use of the external laryngeal pressure maneuver were also found in the pooled analysis. With regard to the overall risk of bias, the selected trials were classified to have at least a moderate risk of bias, because none of the trials could blind the operator to the type of laryngoscope used. CONCLUSIONS: Our analysis suggests that the use of a McGrath videolaryngoscope in nasotracheal intubation resulted in shorter intubation times, improved views of the glottis and similar first-success rates in adult patients who received general anesthesia for dental, oral, maxillofacial, or head and neck cancer surgery, and also reduced the use of Magill forceps and the BURP maneuver.

Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy.

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2-DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

LIN28B promotes the development of neuroendocrine prostate cancer.

Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.