Diet-induced obesity induces transcriptomic changes in neuroimmunometabolic-related genes in the striatum and olfactory bulb

The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions of the brain associated with olfaction and hedonic food-seeking, respectively, in high-fat-diet (HFD)-fed obese mice. To isolate the dietary effects from obesity, we also examined transcriptomic changes in normal-chow-fed and limited-HFD-fed groups, with the latter being pair-fed with an HFD isocaloric to the consumption of the normal-chow-fed mice. Using RNA sequencing, we identified 274 differentially expressed genes (DEGs) in the striatum and 11 in the olfactory bulb of ad libitum HFD-fed mice compared to the chow-fed group, and thirty-eight DEGs in the striatum between the ad libitum HFD and limited-HFD-fed groups. The DEGs in both tissues were associated with inflammation and immune-related pathways, including oxidative stress and immune function, and with mitochondrial dysfunction and reward pathways in the striatum. These results shed light on potential obesity-associated genes in these regions of the brain

Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in Resectable Lung Cancer: The Phase II NeoCOAST Platform Trial

Neoadjuvant chemoimmunotherapy improves pathologic complete response rate and event-free survival in patients with resectable non-small cell lung cancer (NSCLC) versus chemotherapy alone. NeoCOAST was the first randomized, multidrug platform trial to examine novel neoadjuvant immuno-oncology combinations for patients with resectable NSCLC, using major pathologic response (MPR) rate as the primary endpoint. Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). MPR rates were higher for patients in the combination arms versus durvalumab alone. Safety profiles for the combinations were similar to those of durvalumab alone. Multiplatform immune profiling suggested that improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune cell activation. Significance: A neoadjuvant platform trial can rapidly generate clinical and translational data using candidate surrogate endpoints like MPR. In NeoCOAST, patients with resectable NSCLC had improved MPR rates after durvalumab plus oleclumab or monalizumab versus durvalumab alone and tumoral transcriptomic signatures indicative of augmented immune cell activation and function. See related commentary by Cooper and Yu, p. 2306. This article is featured in Selected Articles from This Issue, p. 2293

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Olanzapine as a Novel Treatment for Chemotherapy Induced Nausea and Vomiting

Background: Chemotherapy-Induced Nausea and Vomiting (CINV) is a prevalent adverse effect of chemotherapy, reducing quality of life and resulting in considerable healthcare resource utilization costs. Olanzapine, historically used as an antipsychotic, is now added to cancer antiemetic guidelines due to its effectiveness in preventing and managing CINV. While therapeutic options have improved CINV treatment, the literature highlights a substantial gap in knowledge regarding the pathophysiology of CINV and the biological basis of olanzapine’s effect on CINV. The primary objective of this dissertation was to better understand how olanzapine alleviates CINV. These data can increase knowledge of the pathophysiology of CINV and help identify potential biological mediators to target for therapeutic interventions. Methods/Results: To address our objective, we conducted a literature review of CINV with a focus on olanzapine and identified potential biological mediators of olanzapine’s effects on CINV: ghrelin and serotonin g. Subsequently, we conducted a series of behavioral experiments in rats to study the antiemetic effects of olanzapine. Olanzapine in rats (as in humans) decreased chemotherapy-induced malaise/nausea, anorexia, and body weight loss. To test the effect of olanzapine on potential biological mediators of these chemotherapy-induced adverse effects, we assessed the effects of olanzapine on ghrelin and serotonin. We found that olanzapine decreases the number of cisplatin (a chemotherapeutic agent known to induce CINV in almost 100% of people and animals in the absence of antiemetic prophylaxis) activated neurons in the hindbrain and determined olanzapine’s effect on chemotherapy-induced malaise is at least in part mediated by the hindbrain. Additionally, we found olanzapine counteracts cisplatin-induced decreases in circulating ghrelin and central ghrelin receptor [GHSR] gene expression six hours post chemotherapy. Lastly, we report olanzapine decreased serotonin 2C receptor [5-HT2C] gene expression in the hindbrain and the hypothalamus. Conclusion: These findings suggest that olanzapine may alleviate CINV by counteracting the effects of cisplatin on the hindbrain, circulating ghrelin, ghrelin receptor expression, and 5-HT2C receptor gene expression in the hindbrain and hypothalamus. Future research should further define the role of these potential biological mediators in CINV and determine whether counteracting cisplatin-induced alterations of ghrelin and 5-HT2C signaling are sufficient to help control CINV

A qualitative metasynthesis of the experience of fatigue across five chronic conditions

Context Fatigue is a symptom reported by patients with a variety of chronic conditions. However, it is unclear whether fatigue is similar across conditions. Better understanding its nature could provide important clues regarding the mechanisms underlying fatigue and aid in developing more effective therapeutic interventions to decrease fatigue and improve quality of life. Objectives To better understand the nature of fatigue, we performed a qualitative metasynthesis exploring patients' experiences of fatigue across five chronic noninfectious conditions: heart failure, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, and chronic obstructive pulmonary disease. Methods We identified 34 qualitative studies written in the last 10 years describing fatigue in patients with one of the aforementioned conditions using three databases (Embase, PubMed, and CINAHL). Studies with patient quotes describing fatigue were synthesized, integrated, and interpreted. Results Across conditions, patients consistently described fatigue as persistent overwhelming tiredness, severe lack of energy, and physical weakness that worsened over time. Four common themes emerged: running out of batteries, a bad life, associated symptoms (e.g., sleep disturbance, impaired cognition, and depression), and feeling misunderstood by others, with a fear of not being believed or being perceived negatively. Conclusion In adults with heart failure, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, and chronic obstructive pulmonary disease, we found that fatigue was characterized by severe energy depletion, which had negative impacts on patients' lives and caused associated symptoms that exacerbated fatigue. Yet, fatigue is commonly misunderstood and inadequately acknowledged

No significant salt or sweet taste preference or sensitivity differences following ad libitum consumption of ultra-processed and unprocessed diets : A randomized controlled pilot study

Ultra-processed food consumption has increased worldwide, yet little is known about the potential links with taste preference and sensitivity.This exploratory study aimed to (i) compare sweet and salty taste detection thresholds and preferences following consumption of ultra-processed and unprocessed diets, (ii) investigate whether sweet and salty taste sensitivity and preference were associated with taste substrates (i.e. sodium and sugar) and ad libitum nutrient intake, and (iii) examine associations of taste detection thresholds and preferences with blood pressure (BP) and anthropometric measures following consumption of ultra-processed and unprocessed diets. In a randomized crossover study, participants (N = 20) received ultra-processed or unprocessed foods for 2 weeks, followed by the alternate diet. Baseline food intake data were collected prior to admission. Taste detection thresholds and preferences were measured at the end of each diet arm. Taste-substrate/nutrient intake, body mass index (BMI), and body weight (BW) were measured daily. No significant differences were observed in participant salt and sweet detection thresholds or preferences after 2 weeks on ultra-processed or unprocessed diets.There was no significant association between salt and sweet taste detection thresholds, preferences, and nutrient intakes on either diet arm. A positive correlation was observed between salt taste preference and systolic BP (r = 0.59; P = 0.01), BW (r = 0.47, P = 0.04), and BMI (r = 0.50; P = 0.03) following consumption of the ultra-processed diet. Thus, a 2-week consumption of an ultra-processed diet does not appear to acutely impact sweet or salty taste sensitivity or preference. Trial Registration: ClinicalTrials.gov Identifier NCT03407053