Background
The bitter taste receptor T2R38 was recently described to play a role in upper airway innate mucosal defense. When activated by bacterial quorum‐sensing molecules, T2R38 stimulates the ...ciliated epithelial cells to produce nitric oxide (NO), resulting in bactericidal activity and an increase in mucociliary clearance (MCC). Polymorphisms within the T2R38 gene (TAS2R38) confer variability in activation of the receptor yielding dramatic differences in upper airway defensive responses (NO production and accelerated MCC) to microbial stimulation based on genotype. Our objective was to determine whether the nonprotective TAS2R38 polymorphisms, which render the receptor inactive, correlate with medically recalcitrant chronic rhinosinusitis (CRS) necessitating surgical intervention in the context of known risk factors, and thus identify whether the TAS2R38 genotype is an independent risk factor for patients undergoing functional endoscopic sinus surgery (FESS).
Methods
CRS patients undergoing primary FESS were prospectively genotyped for TAS2R38. Chi‐square analysis was performed on the genotype distribution with respect to other risk factors, including allergies, asthma, nasal polyposis, aspirin sensitivity, diabetes, and smoking exposure.
Results
Seventy primary FESS patients were genotyped demonstrating a statistically significant skewing from the expected distribution of the general population (p < 0.0383). CRS patients with a particular polymorphism seemed less likely to have allergies, asthma, nasal polyposis, aspirin sensitivity, and diabetes, but this did not demonstrate statistical significance.
Conclusion
Our investigation suggests that TAS2R38 genotype is an independent risk factor for patients failing medical therapy, necessitating surgical intervention.
OBJECTIVE—Platelets are important for the development and progression of atherosclerotic lesions. However, relatively little is known about the contribution of platelet signaling to this pathological ...process. Our recent work identified 2 independent, yet synergistic, signaling pathways that lead to the activation of the small GTPase Rap1; one mediated by the guanine nucleotide exchange factor, CalDAG-GEFI (CDGI), the other by P2Y12, a platelet receptor for adenosine diphosphate and the target of antiplatelet drugs. In this study, we evaluated lesion formation in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr) mice lacking CDGI or P2Y12 in hematopoietic cells.
APPROACH AND RESULTS—Lethally irradiated Ldlr mice were reconstituted with bone marrow from wild-type (WT), Caldaggef1 (cdgI), p2y12, or cdgIp2y12 (double knockout DKO) mice and fed a high-fat diet for 12 weeks. Ldlr chimeras deficient for CDGI or P2Y12 developed significantly smaller atherosclerotic lesions in the aortic sinus and in aortas when compared with the Ldlr/WT controls. We also observed a significant reduction in platelet-leukocyte aggregates in blood from hypercholesterolemic Ldlr/cdgI and Ldlr/p2y12 chimeras. Consistently, fewer macrophages and neutrophils were detected in the aortic sinus of Ldlr/cdgI and Ldlr/ p2y12 chimeras. Compared with controls, the plaque collagen content was significantly higher in Ldlr chimeras lacking CDGI. Interestingly, no statistically significant additive effects were seen in Ldlr/DKO chimeras when compared with chimeras lacking only CDGI.
CONCLUSIONS—Our findings suggest that CDGI is critical for atherosclerotic plaque development in hypercholesterolemic Ldlr mice because of its contribution to platelet-leukocyte aggregate formation and leukocyte recruitment to the lesion area.
Background
Over 550,000 sinus surgeries are performed annually in the United States on patients with chronic rhinosinusitis (CRS). Although the results of sinus surgery vary widely, no known genetic ...factor has been identified to predict surgical outcomes. The bitter taste receptor T2R38 has recently been demonstrated to regulate upper airway innate defense and may affect patient responses to therapy. Our goal was to determine whether TAS2R38 genetics predicts outcomes in CRS patients following sinus surgery.
Methods
A prospective study of patients undergoing sinus surgery evaluating postoperative outcomes through the 22‐item Sino‐Nasal Outcome Test (SNOT‐22). Patients were genotyped for TAS2R38.
Results
A total of 123 patients with CRS were initially analyzed; 82 patients showed nasal polyps (CRSwNP) and 41 patients were without nasal polyps (CRSsNP). Six months after surgery, the overall SNOT‐22 improvement was 25 ± 23 points. The TAS2R38 genotype was found to significantly correlate with surgical outcomes in patients without polyps; homozygotes for the functional receptor had a mean improvement of 38 ± 21, whereas heterozygotes or homozygotes for the nonfunctional receptor had a mean improvement of 12 ± 22 (p = 0.006). This result was confirmed with a multivariate regression that incorporated further patients with 1‐month and 3‐month scores (n = 207).
Conclusion
In patients undergoing sinus surgery for CRS, we have identified a genetic polymorphism that predicts variability in quality of life improvement following surgery at 6 months in nonpolypoid CRS. This is the first genetic polymorphism identified that has demonstrated to predict surgical outcome for a select group of CRS patients.
Structural changes of the arteries in hypertension are determined by the unique genetics of the animals and by various growth promoters and growth inhibitors. Vascular smooth muscle cell growth ...promoting factors include fibroblast growth factor, platelet-derived growth factor, and vasoactive peptides such as norepinephrine, angiotensin II, and endothelin. Endothelial cells secrete three types of growth inhibiting factors. These are heparin--heparan sulfate, transforming growth factor beta, and nitric oxide. The effect of sympathetic innervation on vascular growth is probably dependent on its interaction with the renin-angiotensin system. In the mesenteric vascular bed, the elevated resistance in the arterial system is present in both the macroarteries and in the more distal microarteries and veins. Changes in resistance arteries include hypertrophy and reduction in outer diameter (remodelling). In the resistance arteries from human essential hypertensives, remodelling is the predominant finding. Long-term treatment with an angiotensin I converting enzyme inhibitor but not with a beta-blocker was effective in reversing this type of vascular change. Studies have suggested that in addition to angiotensin II, endothelin may play a role in vascular remodelling of resistance arteries.
Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is up-regulated in several human cancers. MCL-1 is also highly expressed in myocardium, but its function in myocytes has not ...been investigated. We generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that ablation of Mcl-1 in the adult heart led to rapid cardiomyopathy and death. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. Mitochondria isolated from MCL-1-deficient hearts exhibited reduced respiration and limited Ca(2+)-mediated swelling, consistent with opening of the mitochondrial permeability transition pore (mPTP). Double-knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally induced by myocardial stress, but induction of autophagy was impaired in MCL-1-deficient hearts. These data demonstrate that MCL-1 is essential for mitochondrial homeostasis and induction of autophagy in the heart. This study also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1.
Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This ...study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.
TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (
) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (
). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.
Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition,
mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.
These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.
To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC).
Patients had advanced non-clear-cell renal carcinoma ...who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response.
A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included
and
in cohort 1 and
and
in cohort 2. Objective responses were seen in 10/12 patients with either
or
mutations.
Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.
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