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ImportanceSurvival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans.ObjectiveTo evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC.Design, Setting, and ParticipantsThis retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022.Main Outcomes and MeasuresOverall survival (OS).ResultsThe study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS.Conclusions and RelevanceThis retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

Genomic aberrations comprise hallmarks of multiple myeloma (MM), a plasma cell malignancy with an overall poor prognosis. MM is heterogeneous and has different molecularly-defined subtypes according to varying clinical and pathological features. Hyperdiploidy or non-hyperdiploidy has usually been identified as early initiating genetic events that can be followed by secondary aberrations, including copy number changes, secondary translocations, and different epigenetic modifications, which cause immortalization of plasma cell and disease progression. Even though recent advances in drug discovery have offered new perspectives of treatment, MM remains incurable. However, understanding the molecular complexity of MM would allow patients to get precision treatment. Our review focuses on current evidence in myeloma biology with special attention to genomic and molecular variations.

The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase. These lipohexapeptides contain a biaryl structural motif reminiscent of glycopeptide antibiotics. We herein describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly. Unlike its enzymatic counterparts in glycopeptide biosynthesis, AryC converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. This activity enables chemo-enzymatic assembly of arylomycin A2 that combines the advantages of liquid- and solid-phase peptide synthesis with late-stage enzymatic cross-coupling. The reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which peptidyl carrier protein (PCP)-tethering so far was shown crucial both in vivo and in vitro.

Treatment emergent central sleep apnea (TECSA) can occur with positive airway pressure (PAP) therapy, mandibular advancement devices, and now recent cases with hypoglossal nerve stimulator (HNS) therapy during treatment for obstructive sleep apnea (OSA). There have been few published reports of Cheyne-Stokes breathing (CSB) emerging after implantation of an HNS. We present a case of a 76-year-old male with chronic atrial fibrillation and OSA who developed significant CSB after implantation of an HNS device. As popularity increases for alternative treatments of OSA, there should be close monitoring for emergence of CSB, especially in those who may have a propensity for high loop gain abnormalities contributing to central sleep apneas, such as patients with chronic atrial fibrillation. Further research is needed on CSA in patients with HNS implantation and atrial fibrillation, the prevalence of TECSA in the growing HNS therapy population, and the development of future management strategies. CITATION: Hong H, Oster J, Grover A, Ismail K. A case of Cheyne-Stokes breathing emerging in a patient with atrial fibrillation and an implanted hypoglossal nerve stimulator. J Clin Sleep Med. 2021;17(8):1731–1735.

The functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly, and its application in the chemo-enzymatic synthesis of arylomycin A2 is described. AryC efficiently converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. The resulting reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which PCP-tethering so far was crucial both in vivo and in vitro. Our work thus provides a basis for the development of general biocatalytic platforms for the efficient biocatalytic synthesis of biaryl peptide antibiotics.

Objective: Management of obstructive sleep apnea in infants with Robin sequence (RS) includes prone positioning during sleep, which conflicts with safe infant sleep data. We examined changes in polysomnography (PSG) parameters for prone versus nonprone body positions in these infants. Design: Pre–post interventional, nonblinded study. Participants: Infants with RS referred for PSG were recruited from craniofacial clinic and inpatient units at Children’s Hospital Los Angeles, a tertiary pediatric center. Fourteen infants were recruited, and 12 studies were completed on both body positions; 11 studies were used in the analysis. Interventions: The PSG was divided into nonprone and prone sleep, moving from their usual sleep position to the other position midway in the study. Main Outcome Measures: Data was collected in each position for obstructive apnea–hypopnea index (oAHI), central apnea index (CAI), sleep efficiency (SE), and arousal index (AI). Signed rank test was used to evaluate the change in body position. Results: All infants were term except 1, age 7 to 218 days (mean: 55 days; standard deviation: 58 days), and 8 (57%) of 14 were female. From nonprone to prone sleep position, the median oAHI (16.0-14.0), CAI (2.9-1.0), and AI (28.0-19.9) decreased ( P = .065); SE increased (67.4-85.2; P = .227). Conclusions: Prone positioning may benefit some infants with RS. However, even those with significant improvement in obstructive sleep apnea did not completely resolve their obstruction. The decision to use prone positioning as a therapy should be objectively evaluated in individual infants.

Objective Tobacco control policies have decreased tobacco use among youth and young adults. We aimed to identify whether specific local tobacco retail licensing ordinances were associated with reasons for e-cigarette use, in order to examine whether strong local policies may reduce e-cigarette initiation rates by influencing the appeal of these products. Methods Online questionnaires were completed by Southern California Children's Health Study participants in 2015–2016 (mean age = 18.9 years). Those who had ever used an e-cigarette (N = 614) were asked about reasons for use; additional data were collected on local jurisdiction tobacco sales policy, friends' attitudes toward e-cigarette use, e-cigarette characteristics (level of nicotine, flavorings), and history of tobacco use. Multivariate logistic regression models evaluated associations of each factor with reasons for e-cigarette use, adjusting for gender, ethnicity, highest parental education, tobacco use history and with a random effect of jurisdiction. Results The top reason for e-cigarette use was “They come in flavors I like” (56.6%). Using e-cigarettes to quit smoking was uncommon (12.8%). Participants in jurisdictions with weaker tobacco retail licensing ordinances were more likely to report use of e-cigarettes because they are less harmful than cigarettes (50.1% vs. 36.2%), more acceptable to non-tobacco users (38% vs. 25%), and because they can use e-cigarettes in places where smoking is prohibited (30.7% vs. 18.3%; all p Conclusion Targeted policy to enforce a strong regulatory environment that denormalizes e-cigarette use, conveys the adverse impact of e-cigarettes, and restricts use in public places may reduce e-cigarette use among adolescents and young adults.

Cellular metabolism and signaling pathways are key regulators to determine conventional T cell fate and function, but little is understood about the role of cell metabolism for natural killer T (NKT) cell survival, proliferation, and function. We found that NKT cells operate distinct metabolic programming from CD4 T cells. NKT cells are less efficient in glucose uptake than CD4 T cells with or without activation. Gene-expression data revealed that, in NKT cells, glucose is preferentially metabolized by the pentose phosphate pathway and mitochondria, as opposed to being converted into lactate. In fact, glucose is essential for the effector functions of NKT cells and a high lactate environment is detrimental for NKT cell survival and proliferation. Increased glucose uptake and IFN-γ expression in NKT cells is inversely correlated with bacterial loads in response to bacterial infection, further supporting the significance of glucose metabolism for NKT cell function. We also found that promyelocytic leukemia zinc finger seemed to play a role in regulating NKT cells' glucose metabolism. Overall, our study reveals that NKT cells use distinct arms of glucose metabolism for their survival and function.

BACKGROUND We investigated preferences between the transcervical and transoral thyroidectomy approach in the United States and Israel. METHODS An online survey assessing scar attitudes and surgical preferences, in English and Hebrew, was distributed on ThyCa.com and other platforms. RESULTS 928 and 339 responses from the United States and Israel cohorts, respectively, were analyzed. In both countries, individuals without prior thyroidectomy preferred a scarless approach when hypothetical risks equaled those of traditional thyroidectomy (77% United States, 76% Israel, p = 0.61). U.S. respondents without thyroidectomy had greater preference to avoid a scar and would pay more to do so than those with thyroidectomy (both p

There have been no published reports of central respiratory control abnormalities in pediatric patients with UNC80 or KCNJ11 mutations which cause neurologic channelopathies. We describe an 8-year-...

Cellular metabolism is essential in dictating T cell development and function, but its role in natural killer T (NKT) cells has not been well studied. Activated CD4 T cells undergo a metabolic switch from oxidative to glycolytic metabolism to fuel their proliferation and effector function. We have previously shown that NKT cells operate distinctly different metabolic programming from CD4 T cells. We found that, unlike CD4 T cells, NKT cells rely more on glutamine for their homeostasis. In fact, we observed that resting NKT cells have higher levels of glutamine-derived metabolites than conventional CD4 T cells. However, the precise mechanisms by which NKT cells use glutamine for their proliferation and cytokine production remain unknown. Glutamine is metabolized into glutamate and then into alpha-ketoglutarate (α-KG) and glutathione (GSH). Using the pathway specific inhibitors revealed that NKT cells rely on both pathways for cell homeostasis, but cytokine production is associated with α-KG production. These glutamine oxidation processes control optimal mTORC1 activity and mitochondrial functions. Importantly, we observed a novel role of 5′ AMP-activated protein kinase (AMPK) in regulating glutamine metabolism in NKT cells. Taken together, glutamine metabolism is essential for NKT cell homeostasis and cytokine production.

BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) is a uniformly fatal pediatric brainstem tumor and the leading cause of brain-tumor related deaths in children. It is therefore imperative to identify novel treatment strategies for this aggressive and devastating disease. Metabolic reprogramming in tumors and in the tumor microenvironment contribute to evasion of therapy and tumor recurrence. The goal of this study was to identify and therapeutically target metabolic vulnerabilities in DIPG that mediate aggressiveness and treatment resistance. METHODS DIPG tumors are marked by cellular heterogeneity and are driven by a population of cells with stem cell properties. We took a comprehensive metabolomics and transcriptomic screening approach to determine the operative pathways in the tumor driving stem cell compartment. To demonstrate efficacy and potential therapeutic window of activity, we treated DIPG tumors with clinically available and brain-penetrant inhibitors of the identified dysregulated metabolic pathways. RESULTS Our multi-omics analyses revealed that tumorigenic patient-derived DIPG cells significantly upregulate metabolic programs including cholesterol biosynthesis and mitochondrial oxidative phosphorylation (OXPHOS) compared to DIPG cells that were induced to undergo differentiation (events associated with a loss of tumorigenic capabilities). The therapeutic targeting of DIPG tumors with clinically available and brain penetrant inhibitors of OXPHOS and cholesterol biosynthesis resulted in tumor cell killing and growth inhibition both in vitro and in vivo. Moreover, there was a therapeutic window of activity in tumorigenic DIPG cells compared with differentiated gliomas and non-malignant cells. CONCLUSION Our findings demonstrate that DIPG harbor perturbations in metabolic programs that can be exploited for therapeutic benefits. The results from this study defined the metabolic pathways operative in the tumor-driving population in DIPG and demonstrated efficacy of targeting these pathways.

There have been no published reports of central respiratory control abnormalities in pediatric patients with UNC80 or KCNJ11 mutations which cause neurologic channelopathies. We describe an 8-year-old male with a pathogenic UNC80 mutation, intellectual disability, hypotonia and epilepsy with severe central sleep apnea (213.5 events/h) on polysomnography (PSG). We also describe a 20-month-old female with a KCNJ11 mutation, neonatal diabetes and developmental delay who had severe central sleep apnea (131.1 events/h). Both patients had irregular respiratory patterns during sleep and wakefulness and were placed on empiric bilevel positive airway pressure therapy, which was well tolerated with resolution of abnormal respiratory control and hypercapnia. Patients with UNC80 and KCNJ11 gene mutations may have abnormal respiratory rhythm during sleep and wakefulness, mirroring animal models. We recommend routine PSG tests and further investigation into the respiratory control of patients with pediatric channelopathies involved in chemoreceptor function or central integration of respiratory control.

Mutated Isocitrate dehydrogenase 1 (IDH1R132H; mIDH1) is found in 50% of all adult gliomas and in 80% of lower-grade gliomas. IDH1R132H promotes 2-hydroxyglutarate production which inhibits histone and DNA demethylases, inducing epigenetic reprogramming of the tumor transcriptome. We recently demonstrated that epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 glioma, harboring p53 and ATRX loss. Furthermore, several studies indicate that IDH1R132H triggers cellular metabolism reprogramming. In this study, RNA-seq data revealed that mIDH1 glioma neurospheres (mIDH1-NS) have downregulated gene ontologies related to mitochondrial metabolism. Analysis of mitochondrial and glycolytic activity, using a Seahorse Analyzer, showed that mIDH1-NS have decreased levels of oxygen consumption and extracellular acidification rates, characteristic of quiescent state. Nevertheless, mIDH1 glioma cells can grow and generate tumors, suggesting that they might maintain self-renewal via autophagy. To investigate this hypothesis, we studied autophagy in wild-type and mIDH1 glioma cells analyzing LC3 conversion, p62 expression, and ULK1 protein phosphorylation. Mouse and human mIDH1 glioma cells exhibited increased expression of pULK1-S555, enhanced conversion of LC3I to LC3II, and decreased expression of p62, indicating that mIDH1 cells have an augmented autophagy. Also, key proteins involved in autophagy, including MST4 and UVRAG, are upregulated in mIDH1-NS. We also studied autophagy flux using LC3-mCherry-GFP reporter to identify LC3 recruitment at the autophagosome membranes and the autolysosome activity. Our results showed that mIDH1 cells have increased LC3 recruitment and enhanced autolysosome activity. Interestingly, autophagy has been related with glioma radioresistance. In our study, mouse and human mIDH1 glioma cells are sensitive to autophagy inhibition. In addition, autophagy inhibition restored radiosensitivity in mouse and human mIDH1 glioma cells, and in our mIDH1 glioma model, enhancing median survival compared with radiation alone. In conclusion, our results indicate that mIDH1 glioma cells maintain self-renewal via activation of autophagy, which represents a novel therapeutic target.

Pancreatic ductal adenocarcinoma (PDA) remains a leading cause of cancer related death, contrasting a relatively low incidence rate. A principle barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma, rich with immune cell infiltration including macrophages. Macrophages are polarized by environmental cues which dictate their function. In PDA, macrophages within the tumor (tumor associated macrophages, or TAMs) are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T-cells. Additionally, TAMs have been shown to drive resistance to chemotherapy, though the mechanism for which remains unclear. Several pathways have been described by which PDA cells recruit and polarize macrophages into TAMs, and the effects that TAMs have on the tumor microenvironment. These pathways have largely focused on signaling proteins, however, metabolic byproducts also influence the behavior of immune cells within the tumor microenvironment. To explore potential metabolic crosstalk, we have profiled the metabolic factors exchanged between PDA cells and TAMs. Among these, we have found that TAMs release metabolites which can regulate the response of PDA cells to chemotherapy. Importantly, this response is consistent across several murine and patient-derived pancreatic cancer cell lines, and this metabolite release appears to be a general property of anti-inflammatory macrophage metabolism. We further validated these findings in vivo, using a combination of pharmacological and genetic models to modulate myeloid cells within the tumor microenvironment. Taken together, these data suggest that further development of interventions which target either PDA-mediated polarization of TAMs or TAM-mediated inhibition of chemotherapy represent opportunities to improve the efficacy of currently available treatment options. Citation Format: Christopher J. Halbrook, Corbin Pontious, Ilya Kovalenko, Laura Lapienyte, Stephan Dreyer, Yaqing Zhang, Barbara Nelson, Hanna Hong, Daivid Chang, Jennifer P. Morton, Marina Pasca di Magliano, Costas A. Lyssiotis. Macrophage-epithelial metabolic crosstalk impairs chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4549.

Rates of adolescent electronic (e-) cigarette use are increasing, but there has been little study of the chronic effects of use. Components of e-cigarette aerosol have known pulmonary toxicity.To investigate the associations of e-cigarette use with chronic bronchitis symptoms and wheeze in an adolescent population.Associations of self-reported use of e-cigarettes with chronic bronchitic symptoms (chronic cough, phlegm, or bronchitis) and of wheeze in the previous 12 months were examined in 2,086 Southern California Children's Health Study participants completing questionnaires in 11th and 12th grade in 2014.Ever e-cigarette use was reported by 502 (24.0%), of whom 201 (9.6%) used e-cigarettes during the last 30 days (current users). Risk of bronchitic symptoms was increased by almost twofold among past users (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.37-2.49), compared with never-users, and by 2.02-fold (95% CI, 1.42-2.88) among current users. Risk increased with frequency of current use (OR, 1.66; 95% CI, 1.02-2.68) for 1-2 days and 2.52 (95% CI, 1.56-4.08) for 3 or more days in past 30 days compared with never-users. Associations were attenuated by adjustment for lifetime number of cigarettes smoked and secondhand smoke exposure. However, risk of bronchitic symptoms among past e-cigarette users remained elevated after adjustment for relevant potential confounders and was also observed among never-cigarette users (OR, 1.70; 95% CI, 1.11-2.59). There were no statistically significant associations of e-cigarette use with wheeze after adjustment for cigarette use.Adolescent e-cigarette users had increased rates of chronic bronchitic symptoms. Further investigation is needed to determine the long-term effects of e-cigarettes on respiratory health.

The marine-derived filamentous fungus Asteromyces cruciatus 763, obtained off the coast of La Jolla, San Diego, USA, yielded the new pentapeptide lajollamide A (1), along with the known compounds regiolone (2), hyalodendrin (3), gliovictin (4), 1N-norgliovicitin (5), and bis-N-norgliovictin (6). The planar structure of lajollamide A (1) was determined by Nuclear Magnetic Resonance (NMR) spectroscopy in combination with mass spectrometry. The absolute configuration of lajollamide A (1) was unambiguously solved by total synthesis which provided three additional diastereomers of 1 and also revealed that an unexpected acid-mediated partial racemization (2:1) of the l-leucine and l-N-Me-leucine residues occurred during the chemical degradation process. The biological activities of the isolated metabolites, in particular their antimicrobial properties, were investigated in a series of assay systems.