Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer.

DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I (via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.

Prognostic significance of mean platelet volume in patients with lung cancer: a meta-analysis.

OBJECTIVE: The mean platelet volume (MPV) is a measure of platelet size, and it is considered a surrogate marker of platelet activation. Because the correlation between platelet count/size and lung cancer prognosis remains unclear, this meta-analysis comprehensively evaluated the prognostic significance of MPV among patients with lung cancer. METHODS: A systematic search of PubMed, Embase, Google Scholar, and additional sources of relevant studies were conducted with no language restrictions from inception to 7 May 2021. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS), as well as their hazard ratios (HR) and 95% confidence intervals (CIs), were pooled to evaluate the relationship between MPV and survival. The study protocol was registered on PROSPERO. RESULTS: Eleven studies involving 2421 patients with lung cancer were included in our analysis. Nine studies including only patients with non-small cell lung cancer were included in the meta-analysis. Our analysis revealed no significant associations of MPV with OS (HR = 1.09, 95% CI = 0.84-1.41) and DFS/PFS (HR = 1.13, 95% CI = 0.58-2.20). CONCLUSION: Pretreatment MPV levels did not display prognostic significance in patients with NSCLC. Large-scale prospective studies and a validation study considering ethnicity and lung cancer staging are warranted.

Early life stressful experiences escalate aggressive behavior in adulthood via changes in transthyretin expression and function.

Escalated and inappropriate levels of aggressive behavior referred to as pathological in psychiatry can lead to violent outcomes with detrimental impact on health and society. Early life stressful experiences might increase the risk of developing pathological aggressive behavior in adulthood, though molecular mechanisms remain elusive. Here, we provide prefrontal cortex and hypothalamus specific transcriptome profiles of peripubertal stress (PPS) exposed Balb/c adult male mice exhibiting escalated aggression and adult female mice resilient to such aberrant behavioral responses. We identify transthyretin (TTR), a well known thyroid hormone transporter, as a key regulator of PPS induced escalated aggressive behavior in males. Brain-region-specific long-term changes in Ttr gene expression and thyroid hormone (TH) availability were evident in PPS induced escalated aggressive male mice, circulating TH being unaltered. Ttr promoter methylation marks were also altered being hypermethylated in hypothalamus and hypomethylated in prefrontal cortex corroborating with its expression pattern. Further, Ttr knockdown in hypothalamus resulted in escalated aggressive behavior in males without PPS and also reduced TH levels and expression of TH-responsive genes (Nrgn, Trh, and Hr). Escalated aggressive behavior along with reduced Ttr gene expression and TH levels in hypothalamus was also evident in next generation F1 male progenies. Our findings reveal that stressful experiences during puberty might trigger lasting escalated aggression by modulating TTR expression in brain. TTR can serve as a potential target in reversal of escalated aggression and related psychopathologies.

The impact of heat and inflow wind variations on vertical transport around a supertall building - The One Vanderbilt field experiment.

The impact skyscrapers have on wind flow remains poorly characterized, thus affecting atmospheric dispersion predictions in dense urban centers. A new mobile observatory equipped with remote sensors controlled by a smart sampling protocol was developed to collect high-resolution (18 m, 15 s) observations throughout the atmospheric layer below 1.5 km. A series of four deployments was performed around the One Vanderbilt skyscraper (H1 = 427 m) located in Manhattan, NY to document wind flow and temperature in canyons with relatively high width-to-depth ratios (H2/W ~ 1.2-7.5; H2 being the height of the adjacent building) and steepness (H1/H2= 2.1-11.2) and that under a range of inflow wind and solar heating conditions. A series of flow features were common to all case studies with head-on winds. A stagnation point was observed 2/3 of the way up the impeded portion of the One Vanderbilt, pointing to the importance of the upwind building height in controlling vertical air flow. In the canyons parallel to the flow, three sets of mirroring counterrotating vortices were detected pointing to the fact that H2 is not as important a parameter in controlling flow in canyons parallel to the inflow wind. Plumes of rapidly rising air were detected near building heat vents under both 10 m s-1 and 3 m s-1 inflow wind conditions, at night and in the morning respectively. This suggests that anthropogenic heat may be an important energy source especially in the absence of solar heating. In the presence of solar heating, a systematic tendency for upward flow was observed above H1. We associate this pattern to the presence of rising thermals, a common mechanism for planetary boundary layer growth. Below H2, complete flow reversal (relative to mechanically driven circulations) was detected ~20 % of the time, showing evidence of dominant thermal effects even under 7 m s-1 inflow wind conditions.