CD56 regulates human NK cell cytotoxicity through Pyk2

Human natural killer (NK) cells are defined as CD5

CD56 regulates human NK cell cytotoxicity through Pyk2

Human natural killer (NK) cells are defined as CD56+CD3. Despite its ubiquitous expression on human NK cells the role of CD56 (NCAM) in human NK cell cytotoxic function has not been defined. In non-immune cells, NCAM can induce signaling, mediate adhesion, and promote exocytosis through interactions with focal adhesion kinase (FAK). Here we demonstrate that deletion of CD56 on the NK92 cell line leads to impaired cytotoxic function. CD56-knockout (KO) cells fail to polarize during immunological synapse (IS) formation and have severely impaired exocytosis of lytic granules. Phosphorylation of the FAK family member Pyk2 at tyrosine 402 is decreased in NK92 CD56-KO cells, demonstrating a functional link between CD56 and signaling in human NK cells. Cytotoxicity, lytic granule exocytosis, and the phosphorylation of Pyk2 are rescued by the reintroduction of CD56. These data highlight a novel functional role for CD56 in stimulating exocytosis and promoting cytotoxicity in human NK cells

Otolaryngology Away Subinternships: An Analysis of the Application Process and Survey of Current Applicants' Perspectives

Objective: To assess the availability and uniformity of application information for away subinternships and survey 4th-year medical students on their experiences obtaining away subinternships in otolaryngology-head and neck surgery (OHNS) during the 2022 to 2023 application cycle. Study Design: Cross-sectional study. Setting: Online survey. Methods: The Association of American Medical College's Visiting Student Learning Opportunities (VSLO) program was queried for information on OHNS away subinternship applications. A survey assessing 4th-year medical students' perceptions of the away subinternship application process was distributed via OHNS residency program directors and Otomatch. Results: Of 129 OHNS residency programs, 103 (80%) offered away subinternship opportunities on VSLO. Variability in application release dates (January 18 to June 3, 2022), offer release dates (January 27 to August 7, 2022), and estimated cost (22-5,500 dollars) were found. The most common application requirements were a transcript (98.1%) and a CV/resume (90.3%). There were 64 survey respondents, for a 13% response rate. The most common concerns include applying to too few programs (80%) and not knowing offer release dates (77%). The most common stressors include choosing a number of programs to which to apply (48%) and cost (35%). The majority (76%) reported difficulty finding updated information on program websites. Among the proposed changes, the greatest support was found for having all applications on VSLO (88%), uniform application release date (84%), and uniform application requirements (82%). Conclusion: The OHNS away subinternship application process is a significant source of anxiety for medical students due to the tremendous variability in application and acceptance procedures. Having all applications on VSLO, uniform application requirements, and uniform application opening and offer release dates would better facilitate this process.</p

Systemic Bevacizumab for Severe Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP) is the most common benign pediatric laryngeal neoplasm. Various adjuvant medical therapies have failed to reliably decrease surgical frequency in this challenging airway disease. Recently, systemic bevacizumab has shown promise in advanced, treatment-resistant papillomatosis. We describe the use of systemic bevacizumab in two children with severe RRP unresponsive to other therapies. Voice and breathing improved dramatically in both patients with minimal side effects. Both patients have not required surgery in 24 months and 16 months, respectively. Systemic bevacizumab is a promising long-term treatment for severe RRP, with oncology playing an important role in patient care

Human NK cell deficiency as a result of biallelic mutations in MCM10

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage–response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function