Transferrin receptor levels and its rare variant are associated with human obesity.

AIM: Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown. METHODS: To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis. RESULTS: TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type. CONCLUSIONS: Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in "cold tumors" with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome.

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes.

Malignant transformation and overall survival of morphological subtypes of intraductal papillary mucinous neoplasms of the pancreas: A network meta-analysis.

BACKGROUND: Emerging evidence suggests the predictive role of morphological subtypes (gastric, intestinal, pancreatobiliary, and oncocytic) of intraductal papillary mucinous neoplasms (IPMNs) in malignant transformation and overall survival. But results of these studies are currently discordant. METHODS: A comprehensive literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) was conducted for eligible studies. Network meta-analysis using the random-effect model was carried out to detect differences in incidences of invasive IPMNs and hazard ratios from survival curves among four morphological subtypes. RESULTS: 19 studies were included in the network comparison. The outcomes showed that pancreatobiliary-type (OR for odds ratio=25.87, 95% CI: 12.11-52.10, compared with gastric-type) and oncocytic-type (OR=18.59, 95% CI: 7.18-42.74) IPMNs had the highest risks of progressing to invasive IPMNs, followed by intestinal-type (OR=5.71, 95% CI: 2.85-10.61) and gastric-type IPMNs. With the gastric type as the baseline, pancreatobiliary-type IPMNs were found to have the worst prognosis (HR for hazard ratio=5.05, 95% CrI: 1.33-13.47) while no significant differences were found for the intestinal type (HR=1.90, 95% CrI: 0.59-4.58) and the oncocytic type (HR=3.29, 95% CrI: 0.75-9.71). CONCLUSION: It is suggested that pancreatobiliary-type IPMNs are the most likely to become invasive and are associated with poor prognosis. In contrast, the other three subtypes have similar overall survivals even though the oncocytic- and intestinal-type IPMNs are predisposed to be more invasive than gastric-type IPMNs.