Whole-genome CRISPR screening identifies N-glycosylation as a genetic and therapeutic vulnerability in CALR-mutant MPNs.

Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPNs). Although the biological mechanism by which CALR mutations cause MPNs has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPNs. To identify unique genetic dependencies in CALR-mutant MPNs, we performed a whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (among others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor 2-deoxy-glucose (2-DG) and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared with wild-type cells and normalization of key MPNs disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow as compared with bone marrow derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPNs.

Inferior Turbinate Hypertrophy: A Comparison of Surgical Techniques.

Introduction Nasal obstruction is one of the most frequently reported symptoms in clinical practice. The second most common cause of nasal obstruction is inferior turbinate hypertrophy, a nasal pathology for which surgical treatment is often required. This study aims to determine the most effective surgical method in patients with inferior turbinate hypertrophy (ITH). Materials and methods The study was performed from September 2018 to October 2019 in the Otolaryngology-Head and Neck Surgery Department of the Evangelismos Hospital of Athens. The study population comprised 205 patients that underwent surgery and were monitored in the hospital. Radiofrequency ablation (RFA) was the method used in 73 patients, 68 patients were treated with the microdebrider-assisted turbinoplasty (MAT), and the remaining 64 patients were operated on using electrocautery (EC). Following surgery, postoperative complications were assessed and quantified. Results Overall, 205 patients underwent surgery. The first group (n=73) was operated on using radiofrequency ablation and had a complication rate of 30.1%. Out of 73 patients, 51 recovered without complications. The remaining 22 had complications, consisting of 16 patients with bleeding and six with postnasal drip. The second group (n=68) was treated using the microdebrider method. The complication rate was 26.5%, where 50 patients did not present with any symptoms post-operatively and 18 exhibited symptoms. Specifically, postnasal drip was more prevalent with this method as all 18 patients showed postnasal drip as their complication. The third group (n=64) was treated with electrocautery. Patients in this group had the most complications (n=24), 16 were attributed to postnasal drip and eight to infections, treated promptly with oral antibiotics. The complication rate using this method was 37.5%. Conclusion In our study, the microdebrider-assisted turbinoplasty offered the lowest complication rate, followed by radiofrequency ablation and electrocautery. However, all three methods managed to alleviate the nasal obstruction and treat inferior turbinate hypertrophy. More research is needed as a lack of consensus remains regarding the optimal surgical technique for lower turbinate hypertrophy.

Atypical Retropharyngeal Abscess of Tuberculosis: Diagnostic Reasoning, Management, and Treatment.

Retropharyngeal abscess caused by tuberculosis (TB) is an unusual life-threatening disease. We present the case of a patient, mainly complaining about dysphagia, cephalalgia, and neck pain. History, examination, and laboratory data were inconclusive. Diagnostic imaging revealed retropharyngeal abscess with atypical characteristics. Aspiration through the pharynx was performed. The aspirated fluid sent for microscopic examination by polymerase chain reaction (PCR) gene probe, revealed Mycobacterium tuberculosis (MTB). Subsequently, the patient was treated with a standard nine-month anti-TB chemotherapy. The combination of fine-needle aspiration and antitubercular agents was successful. The aim of the present study is to inform the importance of early diagnosis with targeted therapy.