Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including ...genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.
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•Genome instability driven by aneuploidy can facilitate chemoresistance•Chemoresistant cells are characterized by recurrent karyotypes•Resistance to chemotherapy is dictated by changes in gene copy number•Chemoresistance is achieved through altered expression of specific proteins
Ippolito et al. show that induction of chromosome mis-segregation leads to increased karyotypic heterogeneity that could be exploited by cancer cells to survive during chemotherapy. Chemoresistant cells harbor recurrent karyotypes, which impose gene copy-number changes and consequent altered expression of specific proteins crucial for chemoresistance.
Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that ...aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.
Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates ...the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O
transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages.
Abstract
Introduction
Apical hypertrophic cardiomyopathy (ApHCM) compared with normal HCM is less frequent, it's more associated with atrial fibrillation (AF) and it has different sudden cardiac ...death (SCD) risk factors. Authoritative recommendations and guidelines on diagnosis, family screening and especially patient risk stratification don't exist. Taking decisions on ICD implantation can sometimes be challenging.
Patient presentation
A 66-year-old male with a history of arterial hypertension was admitted to our cardiology department because during the last night, while he was driving his car, he would have lost consciousness having a car accident. He rapidly felt well even though he doesn't remember what happened a few minutes shortly before and immediately after the event. No witnesses. Due to traumatic chest pain he went to emergency department where an electrocardiogram was performed with evidence of negative T waves and ST-segment depression on V3-V6 leads.
Diagnosis and management
Physical examination didn't show anything relevant. On heart ultrasound he had normal left ventricle ejection fraction with apical hypertrophy (maximum thickness 18 mm). He underwent coronary angiography which showed normal coronaries. During hospitalization a cardiac magnetic resonance was performed; it described apical hypertrophy with some small areas of intra-myocardium delayed enhancement in apex wall. During hospitalizations no arrhythmic alarms were detected.
Discussion
Pharmacological and electrical treatment options are based on classic HCM aiming to reduce symptoms, incidence of atrial fibrillation, ventricular arrhythmias, and sudden death. Concerning ApHCM, left ventricular outflow tract obstruction is usually absent and therefore pharmacological therapeutic benefits may be lower than in classic HCM. Regarding sudden death prevention, we evaluate ICD implantation according to ESC 5-y HCM SCD risk score which doesn't include potential risk markers for SCD in ApHCM such as apical aneurysm, midcavity gradient and midventricular obstruction with SCD risk underestimation. By the way it's still the most used score being aware that could lead to ICD underutilization. In our case, according to HCM risk score 1.74%, negative family screening, no arrhythmic events for 15 days hospitalization, no previous transient loss of consciousness (TLOC) and dynamics of the car accident, we decided to follow-up the patients in our cardiomyopathies outpatient clinic explaining the TLOC with a sleep disorder.
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