Citations

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)–facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)–mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.

Background: The role of minute ventilation/carbon dioxide production ( / CO2) slope, a ventilation efficiency marker, in predicting short-term and long-term health outcomes for patients with nonsmall-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated. Material and Methods: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of / CO2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/ CO2 slope was estimated using the receiver operating characteristics curve. Internal validation was completed through bootstrap resampling. Results: A cohort of 895 patients [median age (interquartile range), 59 (13) years; 62.5% male] was followed for a median of 40 (range, 1–85) months. Throughout the study, there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/ CO2 slopes, respectively [weighted incidence rate difference per 1000 person-years, 29.21 (95% CI, 7.30–51.12)]. A E/ CO2 slope of greater than or equal to 31 was associated with shorter RFS [hazard ratio for relapse or death, 1.38 (95% CI, 1.02–1.88), P=0.04] and poorer OS [hazard ratio for death, 1.69 (1.15–2.48), P=0.02] compared to a lower / CO2 slope. A high E/ CO2 slope increased the risk of perioperative morbidity compared with a low E/ CO2 slope [odds ratio, 2.32 (1.54–3.49), P<0.001]. Conclusions: In patients with operable NSCLC, a high E/ CO2 slope was significantly associated with elevated risks of poorer RFS, OS, and perioperative morbidity.

Abstract BACKGROUND: Rituximab (RTX) has been previously reported as directed treatment in patients with connective-tissue disease-related interstitial lung diseases (CTD-ILD). A systematic assessment of treatment effect size on pulmonary function outcomes and related adverse effects in patients with CTD-ILD has not been previously reported.METHODS: We performed a systematic review and meta-analysis of published reports from PubMed, Embase, and Cochrane Libraries. Randomized and non-randomized controlled trials, case-control, cohort, and case series (with five or more cases) containing individual pulmonary function data and adverse effects were included. Study endpoints were pre and post treatment change in percent predicted forced vital capacity (FVC %) and diffusion capacity for carbon monoxide (DLCO%), along with reported drug-related adverse events. RESULTS: Twenty studies totaling 411 patients were identified with 14 included in the meta-analysis of pulmonary function and six in the descriptive review. Random effects meta-analysis of pre and post-treatment pulmonary function findings demonstrated increases in FVC% (n =296) (mean difference (MD) 4.57%, [95% CI 2.63-6.51]) and DLCO% (n = 246) (MD 5.0% [95% CI 2.71-7.29]) after RTX treatment. RTX treatment-related adverse effects were reported in 13.6% of the pooled cohort. CONCLUSIONS: A systematic assessment of post-treatment effect size suggests a potential role for RTX in stabilizing or improving lung function in patients with CTD-ILD, with a modest but not insignificant adverse effect profile.

Abstract The role of thoracic CT (computerized tomography) in monitoring disease course of COVID-19 is controversial. The purpose of this study is to investigate the risk factors and predictive value of deterioration on repeatedly performed CT scan during hospitalization. All COVID-19 patients treated in our isolation ward, from January 22, 2020 to February 7, 2020, were reviewed. Patients included were categorized into RD (Radiological Deterioration) group or NRD (No Radiological Deterioration) group according to the manifestation on the CT routinely performed during the hospitalization. All clinical data and CT images were analyzed. Forty three patients were included in our study. All are moderate cases with at least 4 CT scans each. Eighteen (42.9%) patients had radiological deteriorations which were all identified in CT2 (the first CT after admission). Patients in RD group had lower leukocyte count (P = .003), lymphocyte count (P = .030), and higher prevalence (P = .012) of elevated C-reactive protein (CRP) at admission. NRD patients had a lower prevalence of reticulations (P = .034) on baseline CT (CT1, performed within 2 days before admission) and a longer duration between symptom onset and the time of CT2 (P < .01). There was no significant difference in hospital stay or fibrotic change on CT4 (follow-up CT scan performed 4 weeks after discharge) between 2 groups. Shorter duration between symptom onset and CT2 time (odds ratio [OR], 0.436; 95% confidence interval: 0.233–0.816; P < .01) and lower leukocyte count in baseline evaluation (OR, 0.316; 95% CI: 0.116–0.859; P < .05) were associated with increased odds of radiological deterioration on CT image during hospitalization. For moderate COVID-19 patients, the value of routinely performed CT during the treatment is limited. We recommend avoiding using CT as a routine monitor in moderate COVID-19 patients.

Background: Bronchial carcinoid often appears hypervascular on bronchoscopic visualization and may be associated with hemoptysis. The diagnostic yield and bleeding complications associated with bronchoscopic biopsy of bronchial carcinoid tumors remain unclear. Materials and Methods: Patients with bronchial carcinoid tumors that were bronchoscopically visualized and biopsied at our tertiary referral medical center, over an 8-year period from 2010 to 2017, were retrospectively identified and reviewed to assess diagnostic yield and bleeding complications. Correlations with patient characteristics and carcinoid tumor features were analyzed. Results: Forty-nine patients were included (57% female). Tumors were predominantly (71%) located in proximal airways (mainstem and lobar bronchi). Bronchoscopic biopsy was diagnostic in 45 patients (92%). Thirteen patients (27%) experienced moderate (n=12, 25%) or severe (n=1, 2%) bleeding. Among these, 6 tumors (46%) had a vascular appearance and 4 patients (31%) had experienced recent hemoptysis. However, neither vascularity nor hemoptysis was associated with bleeding at biopsy (P=0.68 and 0.73, respectively). Carcinoid tumors were classified as typical in 79% and atypical in 21% with no difference in diagnostic yield or bleeding risk (P=0.28 and 0.92, respectively). Tumor size was also not associated with increased diagnostic yield or bleeding risk (P=0.54 and 0.39, respectively). Conclusion: Bronchoscopic biopsy of endobronchial carcinoid is associated with a high diagnostic yield and severe bleeding is rarely encountered. Diagnostic yield and bleeding seemed independent of vascular tumor appearance or history of recent hemoptysis.

Significance Obesity is a major public health problem affecting physical and emotional well-being. Although lifestyle-based programs can help with weight loss, avoiding weight regain is nearly impossible because of persistent hormonal adaptations. Here, in mouse models, we explored a more effective strategy using viral gene transfer of butyrylcholinesterase (BChE) to control the appetite-mediating hormone acyl-ghrelin. We found that a single injection of BChE vector led to a lifetime high enzyme expression and lower circulating acyl-ghrelin. This same treatment suppressed postdieting hyperphagia, corrected metabolic lesions, and lowered weight regain. This outcome confirms the impact of the BChE-ghrelin axis on body weight and indicates that BChE gene transfer could be a successful strategy for long-term control of obesity and the “metabolic syndrome.”

Recent research shows that butyrylcholinesterase (BChE) is not simply a liver enzyme that detoxifies bioactive esters in food and medications. In fact, in pursuing other goals, we recently found that it has an equally important role in regulating the peptide hormone ghrelin and its impact on hunger, obesity, and emotions. Here, we present and examine means of manipulating brain BChE levels by viral gene transfer, either regionally or globally, to modulate ghrelin signaling for long-term therapeutic purposes and to set the stage for exploring the neurophysiological impact of such an intervention.

Despite numerous reports of relationships between weight gain and butyrylcholinesterase (BChE), this enzyme's role in the genesis of obesity remains unclear, but recent research points to strong links with ghrelin, the “hunger hormone.” The availability of BChE knockout (KO) mice provides an opportunity to clarify the causal relationship between BChE and obesity onset. We now find that young KO mice have abnormally high plasma ghrelin levels that slowly decline during long-term high-fat feeding and ultimately drop below those in wild-type mice. On such a diet, the KO mice gained notably more weight, more white fat, and more hepatic fat than wild-type animals. In addition to a greater burden of hepatic triglycerides, the livers of these KO mice show distinctly higher levels of inflammatory markers. Finally, their energy expenditure proved to be lower than in wild-type mice despite similar activity levels and increased caloric intake. A gene transfer of mouse BChE with adeno-associated virus vector restored nearly all aspects of the normal phenotype. Our results indicate that BChE strongly affects fat metabolism, has an important impact on fat accumulation, and may be a promising tool for combating obesity.

Significance Butyrylcholinesterase (BChE), a common plasma enzyme, has been known for decades but its real physiological roles are just beginning to emerge. Although BChE eliminates the neurotransmitter acetylcholine, it is not vital for locomotion, cognition, or other cholinergic functions. Nevertheless, we now find that circulating BChE has a large impact on aggressive behavior in mice that is attributable to its ability to inactivate ghrelin, a peptide hormone involved in hunger, feeding, and stress. A key observation was decreased fighting among group-housed male mice overexpressing BChE after viral gene transfer. In contrast, BChE knockout mice exhibited increased fighting. These effects mirrored changes in plasma levels of active ghrelin. Controlling them might offer therapeutic potential for certain behavioral disorders.