Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1a, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1a upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression.Significance: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.
Background The impact of residency training on academic productivity and a career in academic plastic surgery remains uncertain. Previous literature has explored the influence of training institutions on academic careers in surgery. The aims of the study were to assess research productivity during plastic surgery residency training and to illustrate how differences in training programs impact resident research productivity. Methods Academic plastic surgery faculty that graduated in the past 10 years were identified through an Internet search of all Accreditation Council for Graduate Medical Education–accredited residency and fellowship training programs. Research productivity was compared based on h-index, number, and quality of peer-reviewed articles published during residency. Results Three hundred seventy-five academic plastic surgeons were identified and produced 2487 publications during residency. The 10 most productive training institutions were Johns Hopkins, Georgetown, University of Michigan, Stanford, University of California Los Angeles, Northwestern, Harvard, New York University, University of Pennsylvania, and Baylor. Academic productivity was higher among integrated residents (integrated = 8.68 publications, independent = 5.49 publications, P < 0.0001). The number of publications positively correlated to faculty size (r = 0.167, P = 0.0013), National Institute of Health (NIH) funding (r = 0.249, P < 0.0001), residency graduation year (r = 0.211, P < 0.0001), and negatively correlated with Doximity ranking (r = −0.294, P < 0.0001). H-index was positively correlated with number of publications (r = 0.622, P < 0.0001), faculty size (r = 0.295, P < 0.0001), and NIH funding (r = 0.256, P < 0.0001) and negatively correlated with Doximity ranking (r = −0.405, P < 0.0001) and residency graduation year (r = −0.163, P < 0.0001). Conclusions Our study has found that there is an elite cohort of programs that are the most productive research institutions. Resident research productivity is higher among integrated residents, recent graduates, and programs that are larger in size, with a higher Doximity ranking and NIH funding. This study can guide medical students and future applicants who are interested in a career in academic plastic surgery in the selection of programs that match their career aspirations.
Background: The submucous cleft palate can be overt or occult and may require surgical repair. The double-opposing Z-plasty (Furlow repair) is the authors’ center’s preferred approach. This study evaluated complication rates, differences in outcome between overt and occult types, and patient factors associated with surgical failure. Methods: This retrospective study reviewed documentation on all patients who underwent Furlow Z-plasty for submucous cleft palate at a single center between 2004 and 2018. Speech pathology was quantified using the Pittsburgh Weighted Speech Score. Results: A total of 351 patients were included (125 overt and 226 occult cases). Furlow Z-plasty was successful (postoperative Pittsburgh Weighted Speech Score <7 without recommendation for secondary speech surgery) in 291 patients (82.1 percent). Apart from those requiring secondary surgery, there were no documented complications. Occult-type patients were 7.5 years old at palatoplasty with a speech score of 14.1; overt-type patients were 6.5 years old with a score of 15.7. Postoperative speech scores were similar for both groups. Secondary speech surgery patients had a higher preoperative score (16.9 versus 14.2). Age at time of palatoplasty and submucous cleft palate type were not predictive of the need for secondary surgery. Syndromic patients had higher preoperative and postoperative speech scores (15.6 and 7.5, respectively) than nonsyndromic patients (14.3 and 4.3) and needed secondary surgery more often (24.4 percent versus 9.2 percent). V-shaped velar vaulting on preoperative assessment was present in 92 percent of occult-type patients. Conclusions: Furlow palatoplasty is a safe and effective means of repairing submucous cleft palate. Patients with the occult type presented later with a lower Pittsburgh Weighted Speech Score. High preoperative speech score and syndromic status were associated with the need for secondary speech surgery. V-shaped velar vaulting is a reliable sign of occult submucous cleft palate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
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