ABSTRACT
BACKGROUND: The cell cycle is tightly regulated by checkpoints, which play a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anticancer treatments, allowing for DNA repair prior to cell division. Manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies. METHODS: In this study, we conducted a forward genome-wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. RESULTS: Our findings revealed that canonical DNA repair pathways, including the Ataxia-telangiectasia mutated (ATM)/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of PKMYT1, in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between alkylating agents and a Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. CONCLUSIONS: Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as an effective strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes.
Subject(s)
Antineoplastic Agents, Alkylating , DNA Damage , G2 Phase Cell Cycle Checkpoints , Temozolomide , Xenograft Model Antitumor Assays , Humans , Animals , Temozolomide/pharmacology , G2 Phase Cell Cycle Checkpoints/drug effects , Mice , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , DNA Damage/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effects , CRISPR-Cas Systems , Mice, Nude , Cell Line, Tumor , Tumor Cells, Cultured , Drug Resistance, Neoplasm/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , DNA Repair/drug effectsABSTRACT
BACKGROUND: Reports find that magnetic resonance elastography (MRE) and shear wave elastography (SWE) can classify intracranial tumors according to stiffness. However, systematic syntheses of these articles are lacking. In this report, a systematic review and meta-analysis was performed to evaluate whether SWE and MRE can predict meningioma and glioma grades. METHODS: PubMed and Scopus were searched between February 10, 2022. and March 2, 2022. using manual search criteria. Eight out of 106 non-duplicate records were included, encompassing 84 patients with low-grade tumors (age 42 ± 13 years, 71% female) and 92 patients with high-grade tumors (age 50 ± 13 years, 42% female). Standardized mean difference in stiffness between high-grade and low-grade tumors were measured using a forest plot. The I2, χ2, and t tests were performed, and bubble plots were constructed to measure heterogeneity. An adapted QUADAS-2 scale evaluated study quality. Additionally, a funnel plot was constructed, and an Egger's intercept test determined study bias. RESULTS: Low-grade tumors were stiffer than high-grade tumors (Cohen's D = -1.25; 95% CI -1.88, -0.62). Moderate heterogeneity was observed (I2 = 67%; P = 0.006) but controlling for publication year (I2 = 0.2%) and age (I2 = 0.0%-17%) reduced heterogeneity. Included studies revealed unclear or high bias for the reference standard and flow and timing (>50%). CONCLUSIONS: Elastography techniques have potential to grade tumors intraoperatively and postoperatively. More studies are needed to evaluate the clinical utility of these technologies.
ABSTRACT
Overlapping surgery (OS) is a common practice in neurosurgery that has recently come under scrutiny. This study includes a systematic review and meta-analysis on articles evaluating the effects of OS on patient outcomes. PubMed and Scopus were searched for studies that analyzed outcome differences between overlapping and non-overlapping neurosurgical procedures. Study characteristics were extracted, and random-effects meta-analyses were performed to analyze the primary outcome (mortality) and secondary outcomes (complications, 30-day readmissions, 30-day operating room returns, home discharge, blood loss, and length of stay). Mantel-Haenszel tests were completed for binary outcomes, whereas the inverse variance tests were conducted for continuous outcomes. Heterogeneity was measured using the I2 and X2 tests. The Egger's test was conducted to evaluate publication bias. Eight of 61 non-duplicate studies were included. Overall, 21,249 patients underwent non-OS (10,504 female) and 15,863 patients underwent OS (8393 female). OS was associated with decreased mortality (p = 0.002), 30-day returns to OR (p < 0.001), and blood loss (p < 0.001) along with increased home discharges (p < 0.001). High heterogeneity was observed for home discharge (p = 0.002) and length of stay (p < 0.001). No publication bias was observed. OS was not associated with worse patient outcomes compared to non-OS. However, considering multiple sources of limitation in the methodology of the included studies (such as limited number of studies, reports originating from mostly high-volume academic centers, discrepancy in the definition of "critical portion(s)" of the surgery across studies, and selection bias), extra caution is advised in interpretation of our results and further focused studies are warranted.
