Faculty Bibliography

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell mediated anti-tumor immunity but many patients do not respond and a significant proportion develops inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1 triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1-targeting therapeutic approaches.

Sequential activation of neurons has been observed during various behavioral and cognitive processes, but the underlying circuit mechanisms remain poorly understood. Here, we investigate premotor sequences in HVC (proper name) of the adult zebra finch forebrain that are central to the performance of the temporally precise courtship song. We use high-density silicon probes to measure song-related population activity, and we compare these observations with predictions from a range of network models. Our results support a circuit architecture in which heterogeneous delays between sequentially active neurons shape the spatiotemporal patterns of HVC premotor neuron activity. We gauge the impact of several delay sources, and we find the primary contributor to be slow conduction through axonal collaterals within HVC, which typically adds between 1 and 7.5 ms for each link within the sequence. Thus, local axonal "delay lines" can play an important role in determining the dynamical repertoire of neural circuits.

IMPORTANCE/OBJECTIVE:Foreign body (FB) aspiration into the airway is a significant cause of pediatric morbidity and mortality, yet the clinical presentation is diverse and dynamic. There are conflicting recommendations which pre-procedural findings support performing a bronchoscopy, the gold standard for diagnosis and removal of FBs, however a procedure that entails general anesthesia and possible risks. OBJECTIVE:Decision whether to proceed to a bronchoscopy may be challenging. Our goal was to enhance decision-making by analyzing the diagnostic values of the different pre-procedural findings in this setting. DATA SOURCES/METHODS:A comprehensive search was performed in PUBMED, EMBASE and Cochrane Review databases to find studies from the last 19 years that reported pre-procedural history, physical examination and radiological findings in patients who had bronchoscopies. STUDY SELECTION/METHODS:Studies were included of pediatric populations if they contained bronchoscopy results (positive and negative for foreign body) with a breakdown according to pre-intervention findings. DATA EXTRACTION AND SYNTHESIS/METHODS:Titles and abstracts retrieved from our search were screened. Thereafter, full-texts were carefully reviewed and selected for inclusion if the aforementioned criteria were met. PRISMA guidelines for systematic review and meta-analyses were followed. MAIN OUTCOME(S) AND MEASURE(S)/UNASSIGNED:Cumulative weighted prevalence, sensitivity, specificity, positive and negative predictive values of each pre-procedural finding were calculated, as well as for the "classic triad" (history of an acute event, wheezing, and unilateral decreased breath sounds). Calculation for other combinations of findings, or optimally, constructing a weighted score based on all the findings for each specific patient were not possible to perform, as the specific data breakdown is rarely reported. RESULTS:Fifteen studies met inclusion criteria, totaling 5606 patients who underwent bronchoscopies. All studies but one were single center based and all except one were retrospective. No single finding has both positive and negative predictive values over 50%. The "classic triad" has 90% specificity, however only 35% sensitivity. CONCLUSIONS:The data is very heterogeneous with regard to pre-procedural findings and how best to guide treatment according to them. This meta-analysis provides cumulative weighted metrics for each finding, to optimize decision-making for the individual patient. Future reporting of data should be enhanced, so that combinations of findings for a specific patient can be used to optimize management. LEVEL OF EVIDENCE/METHODS:4.

Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.

PURPOSE/OBJECTIVE:/day × 21 days of a 28-day cycle. RESULTS:/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. CONCLUSION/CONCLUSIONS:/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

This erratum notifies the readers of the Dysphagia journal of an error in the original published version of this manuscript. In that manuscript, a previously available open source spreadsheet tool was used to calculate the position of the posterior laryngeal air column on lateral view videofluoroscopic images as a proxy for the bottom of the pharynx. We have subsequently been made aware of an error in the mathematical formula built into the spreadsheet, which resulted in a reversal of the results for the X and Y planes of measurement. This erratum provides corrections to the results and interpretations of the original manuscript.

Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.

BACKGROUND:Virtual surgical planning has contributed to technical advancements in free fibula flap mandible reconstruction. The authors present the largest comparative study on the latest modification of this technology: the use of patient-specific, preoperatively customized reconstruction plates for fixation. METHODS:A retrospective chart review was performed on all patients undergoing mandibular reconstruction with virtually planned free fibula flaps at a single institution between 2008 and 2018. Patient demographics, perioperative characteristics, and postoperative outcomes were reviewed. Reconstructions using traditional fixation methods were compared to those using prefabricated, patient-specific reconstruction plates. RESULTS:A total of 126 patients (mean age, 48.5 ± 20.3 years; 61.1 percent male) underwent mandibular reconstruction with a free fibula flap. Mean follow-up time was 23.5 months. A customized plate was used in 43.7 percent of cases. Reconstructions with patient-specific plates had significantly shorter total operative times compared with noncustomized fixation methods (643.0 minutes versus 741.7 minutes; p = 0.001). Hardware complications occurred in 11.1 percent of patients, with a trend toward a lower rate in the customized plate group (5.5 percent versus 15.5 percent; p = 0.091). Multivariate regression showed that the use of customized plates was a significant independent predictor of fewer overall complications (p = 0.03), shorter operative time (p = 0.014), and shorter length of stay (p = 0.001). CONCLUSIONS:Compared to traditional fixation methods, patient-specific plates are associated with fewer complications, shorter operative times, and reduced length of stay. The use of customized reconstruction plates increases efficiency and represents the latest technological innovation in mandibular reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, III.