Practical Application of Multivendor MRI-Based R2* Mapping for Liver Iron Quantification at 1.5 T and 3.0 T.

BACKGROUND: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear. PURPOSE: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions. STUDY TYPE: Prospective. SUBJECTS: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers. FIELD STRENGTH/SEQUENCE: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers. ASSESSMENT: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations. STATISTICAL TESTS: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant. RESULTS: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s-1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s-1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals). DATA CONCLUSION: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Total versus proximal gastrectomy for proximal gastric cancer after neoadjuvant chemotherapy: a multicenter retrospective propensity score-matched cohort study.

BACKGROUND: This study aimed to analyze and compare the short-term and long-term outcomes of proximal gastrectomy (PG) and total gastrectomy (TG) in patients with locally advanced proximal gastric cancer (GC) following neoadjuvant chemotherapy (NACT). METHOD: A multicenter retrospective cohort study and propensity score matching (PSM) were employed. The authors examined 367 patients with proximal GC who received NACT followed by PG ( n =164) or TG ( n =203) at two Chinese medical institutions between December 2009 and December 2022. Clinical and pathological parameters, postoperative complications, and 5-year overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups. The dissection status and metastasis rate of each lymph node station were assessed. RESULTS: After PSM, 80 patients were enrolled in both TG and PG group, and baseline characteristics were comparable between the groups (all P >0.05). The TG group had a higher total number of lymph nodes retrieved ( P <0.001) and longer operative time ( P =0.007) compared to the PG group. The incidence of Clavien-Dindo grade II or higher postoperative complications was similar between the TG group (21.3%, 17/80) and the PG group (17.5%, 14/80) ( P =0.689). The 5-year OS rates were 68.4 for the PG group and 66.0% for the TG group ( P =0.881), while the 5-year RFS rates were 64.8 and 61.9%, respectively ( P =0.571), with no statistically significant differences. Metastasis rates at lymph node stations #4d, #5, #6, and #12a were notably low in the TG group, with values of 2.74, 0.67, 1.33, and 1.74%, respectively. CONCLUSION: For proximal GC patients following NACT, PG maintains comparable curative potential and oncological efficacy to TG, making it a safe option.

Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.

pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy.

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

LncRNA CCAT2 promotes malignant progression of metastatic gastric cancer through regulating CD44 alternative splicing.

OBJECTIVE: Gastric cancer (GC) is one of the most malignant tumors worldwide. Thus, it is necessary to explore the underlying mechanisms of GC progression and develop novel therapeutic regimens. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed and regulate the malignant behaviors of cancer cells. Our previous research demonstrated that lncRNA colon cancer-associated transcript 2 (CCAT2) has potential value for GC diagnosis and discrimination. However, the functional mechanisms of lncRNA CCAT2 in GC development remain to be explored. METHODS: GC and normal adjacent tissues were collected to detect the expression of lncRNA CCAT2, ESRP1 and CD44 in clinical specimens and their clinical significance for GC patients. Cell counting kit-8, wound healing and transwell assays were conducted to investigate the malignant behaviors in vitro. The generation of nude mouse xenografts by subcutaneous, intraperitoneal and tail vein injection was performed to examine GC growth and metastasis in vivo. Co-immunoprecipitation, RNA-binding protein pull-down assay and fluorescence in situ hybridization were performed to reveal the binding relationships between ESRP1 and CD44. RESULTS: In the present study, lncRNA CCAT2 was overexpressed in GC tissues compared to adjacent normal tissues and correlated with short survival time of patients. lncRNA CCAT2 promoted the proliferation, migration and invasion of GC cells. Its overexpression modulates alternative splicing of Cluster of differentiation 44 (CD44) variants and facilitates the conversion from the standard form to variable CD44 isoform 6 (CD44v6). Mechanistically, lncRNA CCAT2 upregulated CD44v6 expression by binding to epithelial splicing regulatory protein 1 (ESRP1), which subsequently mediates CD44 alternative splicing. The oncogenic role of the lncRNA CCAT2/ESRP1/CD44 axis in the promotion of malignant behaviors was verified by both in vivo and in vitro experiments. CONCLUSIONS: Our findings identified a novel mechanism by which lncRNA CCAT2, as a type of protein-binding RNA, regulates alternative splicing of CD44 and promotes GC progression. This axis may become an effective target for clinical diagnosis and treatment.

Inhibition of androgen receptor enhanced the anticancer effects of everolimus through targeting glucose transporter 12.

Everolimus was designed as a mammalian target of rapamycin (mTOR) inhibitor. It has been proven as a targeted drug for gastric cancer (GC) therapy. However, long-term treatment with everolimus may cause severe side effects for recipients. Decreasing the dosage and attenuating the associated risks are feasible to promote clinical translation of everolimus. This study aimed to identify the underlying mechanisms of responses to everolimus and develop novel regimens for GC treatment. Our findings proved that there was a significant dose-dependent relationship of everolimus-induced GC cell apoptosis and glycolysis inhibition. Then, we found that a member of glucose transporter (GLUT12) family, GLUT12, was actively upregulated to counteract the anticancer effects of everolimus. GLUT12 might be overexpressed in GC. High expression of GLUT12 might be correlated with tumor progression and short survival time of GC patients. Bioinformatic analysis suggested that GLUT12 might be involved in regulating cancer development and metabolism. The experiments proved that GLUT12 significantly promoted GC growth, glycolysis and impaired the anticancer effects of everolimus. Androgen receptor (AR) is a classical oncogenic factor in many types of cancer. Everolimus elevated GLUT12 expression in an AR-dependent manner. Inhibition of AR activity abrogated the promotive effects on GLUT12 expression. Both in-vitro and in-vivo experiments demonstrated that GLUT12 knockdown augmented anticancer effects of everolimus. Enzalutamide, an AR inhibitor, or AR knockdown was comparable to GLUT12 suppression. This study identified the role of the AR/GLUT12 pathway in the development of poor responses to everolimus. Interference with AR/GLUT12 pathway may serve as a promising approach to promoting the translational application of everolimus in GC therapy.

Multicenter Reproducibility of Liver Iron Quantification with 1.5-T and 3.0-T MRI.

Background MRI is a standard of care tool to measure liver iron concentration (LIC). Compared with regulatory-approved R2 MRI, R2* MRI has superior speed and is available in most MRI scanners; however, the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Purpose To evaluate the reproducibility of LIC via single-breath-hold R2* MRI at both 1.5 T and 3.0 T with use of a multicenter, multivendor study. Materials and Methods Four academic medical centers using MRI scanners from three different vendors (three 1.5-T scanners, one 2.89-T scanner, and two 3.0-T scanners) participated in this prospective cross-sectional study. Participants with known or suspected liver iron overload were recruited to undergo multiecho gradient-echo MRI for R2* mapping at 1.5 T and 3.0 T (2.89 T or 3.0 T) on the same day. R2* maps were reconstructed from the multiecho images and analyzed at a single center. Reference LIC measurements were obtained with a commercial R2 MRI method performed using standardized 1.5-T spin-echo imaging. R2*-versus-LIC calibrations were generated across centers and field strengths using linear regression and compared using F tests. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic performance of R2* MRI in the detection of clinically relevant LIC thresholds. Results A total of 207 participants (mean age, 38 years ± 20 [SD]; 117 male participants) were evaluated between March 2015 and September 2019. A linear relationship was confirmed between R2* and LIC. All calibrations within the same field strength were highly reproducible, showing no evidence of statistically significant center-specific differences (P > .43 across all comparisons). Calibrations for 1.5 T and 3.0 T were generated, as follows: for 1.5 T, LIC (in milligrams per gram [dry weight]) = -0.16 + 2.603 × 10-2 R2* (in seconds-1); for 2.89 T, LIC (in milligrams per gram) = -0.03 + 1.400 × 10-2 R2* (in seconds-1); for 3.0 T, LIC (in milligrams per gram) = -0.03 + 1.349 × 10-2 R2* (in seconds-1). Liver R2* had high diagnostic performance in the detection of clinically relevant LIC thresholds (area under the ROC curve, >0.98). Conclusion R2* MRI enabled accurate and reproducible quantification of liver iron overload over clinically relevant ranges of liver iron concentration (LIC). The data generated in this study provide the necessary calibrations for broad clinical dissemination of R2*-based LIC quantification. ClinicalTrials.gov registration no.: NCT02025543 © RSNA, 2022 Online supplemental material is available for this article.

Comparison of short-term efficacy between totally laparoscopic gastrectomy and laparoscopic assisted gastrectomy for elderly patients with gastric cancer.

BACKGROUND: Totally laparoscopic gastrectomy (TLG) entails both gastrectomy and gastrointestinal reconstruction under laparoscopy. Compared with laparoscopic assisted gastrectomy (LAG), TLG has been demonstrated in many studies to require a smaller surgical incision, result in a faster postoperative recovery and less pain and have comparable long-term efficacy, which has been a research hotspot in recent years. Whether TLG is equally safe and feasible for elderly patients remains unclear. AIM: To compare the short-term efficacy of and quality of life (QOL) associated with TLG and LAG in elderly gastric cancer (GC) patients. METHODS: The clinicopathological data of 462 elderly patients aged ≥ 70 years who underwent LAG or TLG (including distal gastrectomy and total gastrectomy) between January 2017 and January 2022 at the Department of General Surgery, First Medical Center, Chinese PLA General Hospital were retrospectively collected. A total of 232 patients were in the LAG group, and 230 patients were in the TLG group. Basic patient information, clinicopathological characteristics, operation information and QOL data were collected to compare efficacy. RESULTS: Compared with those in the LAG group, intraoperative blood loss in the TLG group was significantly lower (P < 0.001), and the time to first flatus and postoperative hospitalization time were significantly shorter (both P < 0.001). The overall incidence of postoperative complications in the TLG group was significantly lower than that in the LAG group (P = 0.01). Binary logistic regression results indicated that LAG and an operation time > 220 min were independent risk factors for postoperative complications in elderly patients with GC (P < 0.05). In terms of QOL, no statistically significant differences in various preoperative indicators were found between the LAG group and the LTG group (P > 0.05). Compared with the laparoscopic-assisted total gastrectomy group, patients who received totally laparoscopic total gastrectomy had lower nausea and vomiting scores and higher satisfaction with their body image (P < 0.05). Patients who underwent laparoscopic-assisted distal gastrectomy were more satisfied with their body image than patients in the totally laparoscopic distal gastrectomy group (P < 0.05). CONCLUSION: TLG is safe and feasible for elderly patients with GC and has outstanding advantages such as reducing intracorporeal blood loss, promoting postoperative recovery and improving QOL.

Acute ammonia stress-induced oxidative and heat shock responses modulated by transcription factors in Litopenaeus vannamei.

The present study aimed to examine the effects of short-term exposure to ammonia on stress and oxidative responses in shrimp (Litopenaeus vannamei) and to determine whether the antioxidant system related to the regulatory role of transcription factors and stress proteins was activated. Shrimp were exposed ammonia-N at four concentrations: 0 (control), 5, 10, and 15 mg/L, for 48 h. The hepatopancreas was sampled to measure the levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO); the activities of superoxide dismutase (SOD), catalase (CAT), nitric oxide synthase (NOS); and the expression levels of GSH-px (encoding glutathione peroxidase), GST (encoding glutathione-S-transferase), HSP70 (encoding heat shock protein 70), HSP90 (encoding heat shock protein 90), p53, RELISH, and AKIRIN. We observed that exposure to a high ammonia content increased the abundance of oxidative factors (MDA, CAT, SOD, NOS, and NO), reduced the levels of GSH, and upregulated the mRNA expression levels of antioxidant genes (GSH-px and GST), stress-related genes (HSP70 and HSP90), and transcription factor genes (p53, RELISH, and AKIRIN). These results indicated that ammonia induced oxidative stress and inflammation. Both enzymatic and nonenzymatic antioxidant defense systems are involved, which might be regulated by HSPs, as well as certain transcription factors, such as p53 and nuclear factor kappa B (NF-κB), thus mounting an adaptive response to help rebalance redox homoeostasis.

Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury.

BACKGROUND: Traumatic colon injury (TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field. This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield. METHODS: A total of 669 Sprague-Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR. RESULTS: As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis (P < 0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings, we found that oral administration of asparagine (Asn) and 3-indolepropionic acid (IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio (HR) = 0.105, 95% CI 0.031-0.356, P = 0.0003] and restored intestinal homeostasis in TCI rats (P < 0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium (P < 0.05). CONCLUSIONS: Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI-induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.

Short and long-term outcomes between laparoscopic and open total gastrectomy for advanced gastric cancer after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) combined with surgery is regarded as an effective treatment for advanced gastric cancer (AGC). Laparoscopic surgery represents the mainstream of minimally invasive surgery. Currently, surgeons focus more on surgical safety and oncological outcomes of laparoscopic gastrectomy after NACT. Thus, we sought to evaluate short- and long-term outcomes between laparoscopic total gastrectomy (LTG) and open total gastrectomy (OTG) after NACT. AIM: To compare the short and long-term outcomes between LTG and OTG for AGC after NACT. METHODS: We retrospectively collected the clinicopathological data of 136 patients who accepted gastrectomy after NACT from June 2012 to June 2019, including 61 patients who underwent LTG and 75 who underwent OTG. Clinicopathological characteristics between the LTG and OTG groups showed no significant difference. SPSS 26.0, R software, and GraphPad PRISM 8.0 were used to perform statistical analyses. RESULTS: Of the 136 patients included, eight acquired pathological complete response, and the objective response rate was 47.8% (65/136). The LTG group had longer operation time (P = 0.015), less blood loss (P = 0.003), shorter days to first flatus (P < 0.001), and shorter postoperative hospitalization days (P < 0.001). LTG spent more surgical cost than OTG (P < 0.001), while total hospitalized cost of LTG was less than OTG (P < 0.001). 21 (28.0%) patients in the OTG group and 14 (23.0%) in the LTG group had 30-d postoperative complications, but there was no significant difference between the two groups (P = 0.503). The 3-year overall survival (OS) rate was 60.6% and 64.6% in the LTG and OTG groups, respectively [hazard ratio (HR) = 0.859, 95% confidence interval (CI): 0.522-1.412, P = 0.546], while the 3-year disease-free survival (DFS) rate was 54.5% and 51.8% in the LTG and OTG group, respectively (HR = 0.947, 95%CI: 0.582-1.539, P = 0.823). Multivariate cox analysis showed that body mass index and pTNM stage were independent risk factors for OS while vascular invasion and pTNM stage were independent risk factors for DFS (P < 0.05). CONCLUSION: After NACT, LTG shows comparable 30-d postoperative morbidity as well as 3-year OS and DFS rate to OTG. We recommend that experienced surgeons select LTG other than OTG for proper AGC patients after NACT.

The Significance of Neutrophil Extracellular Traps in Colorectal Cancer and Beyond: From Bench to Bedside.

Neutrophil extracellular traps (NETs), products of neutrophil death when exposed to certain stimuli, were first proposed as a type of response to bacterial infection in infectious diseases. Since then, extensive studies have discovered its involvement in other non-infectious inflammatory diseases including thromboembolism, autoimmune diseases, and cancer. Colorectal cancer (CRC) is one of the most common malignancies in the world. NET formation is closely associated with tumorigenesis, progression, and metastasis in CRC. Therefore, the application of NETs in clinical practice as diagnostic biomarkers, therapeutic targets, and prognostic predictors has a promising prospect. In addition, therapeutics targeting NETs are significantly efficient in halting tumor progression in preclinical cancer models, which further indicates its potential clinical utility in cancer treatment. This review focuses on the stimuli of NETosis, its pro-tumorigenic activity, and prospective clinical utility primarily in but not limited to CRC.

circDNMT1 Promotes Malignant Progression of Gastric Cancer Through Targeting miR-576-3p/Hypoxia Inducible Factor-1 Alpha Axis.

Background: Circular RNAs (circRNAs) regulate multiple malignant behaviors of various types of cancer. The role of circDNMT1, a newly identified circRNA, remains unknown in gastric cancer (GC). This study aimed to elucidate the underlying mechanisms of circDNMT1 in regulating GC progression. Methods: microRNA (miRNA) and circRNA expression was detected by quantitative real-time PCR. Western blotting was performed to measure hypoxia inducible factor-1 alpha (HIF-1α) protein expression. Sanger sequencing, gel electrophoresis and fluorescence in situ hybridization were performed to identify the presence of circDNMT1. The clinicopathological features and overall survival of patients were analyzed based on circDNMT1 expression. The proliferation, migration and invasion of GC cells were determined by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing and transwell assays. Glycolysis of GC cells was detected based on the levels of glucose uptake, the lactate acid, ATP and pyruvic acid production and the extracellular acidification and oxygen consumption rates. The binding sites between miR-576-3p and circDNMT1 or HIF-1α were predicted by online bioinformatic tools and were validated using RNA pull-down and luciferase reporter assays. Xenograft models were established to determine the effects of the circDNMT1/miR-576-3p/HIF-1α axis on GC growth and metastasis in vivo. Results: circDNMT1 was successfully identified and shown to be overexpressed in GC tissues and cell lines. The expression levels of circDNMT1 were correlated with pathological T stage, pathological TNM stage and shorter survival time of GC patients. circDNMT1 knockdown inhibited the proliferation, migration, invasion and glycolysis of GC cells. circDNMT1 functioned as an oncogenic factor by sponging miR-576-3p. HIF-1α was negatively regulated by miR-576-3p via binding its mRNA 3' untranslated region. circDNMT1 promoted malignant behaviors and metabolic reprogramming of GC by targeting the miR-576-3p/HIF-1α axis both in vitro and in vivo. Conclusion: These findings demonstrated that circDNMT1 knockdown inhibited GC proliferation, migration, invasion and glycolysis through sponging miR-576-3p/HIF-1α axis. circDNMT1 may be a novel target for GC treatment.

Improved free-breathing liver fat and iron quantification using a 2D chemical shift-encoded MRI with flip angle modulation and motion-corrected averaging.

OBJECTIVES: 3D chemical shift-encoded (CSE) MRI enables accurate and precise quantification of proton density fat fraction (PDFF) and R2*, biomarkers of hepatic fat and iron deposition. Unfortunately, 3D CSE-MRI requires reliable breath-holding. Free-breathing 2D CSE-MRI with sequential radiofrequency excitation is a motion-robust alternative but suffers from low signal-to-noise-ratio (SNR). To overcome this limitation, this work explores the combination of flip angle-modulated (FAM) 2D CSE imaging with a non-local means (NLM) motion-corrected averaging technique. METHODS: In this prospective study, 35 healthy subjects (27 children/8 adults) were imaged on a 3T MRI-system. Multi-echo 3D CSE ("3D") and 2D CSE FAM ("FAM") images were acquired during breath-hold and free-breathing, respectively, to obtain PDFF and R2* maps of the liver. Multi-repetition FAM was postprocessed with direct averaging (DA)- and NLM-based averaging and compared to 3D CSE using Bland-Altmann and regression analysis. Image qualities of PDFF and R2* maps were reviewed by two radiologists using a Likert-like scale (score 1-5, 5 = best). RESULTS: Compared to 3D CSE, multi-repetition FAM-NLM showed excellent agreement (regression slope = 1.0, R2 = 0.996) for PDFF and good agreement (regression slope 1.08-1.15, R2 ≥ 0.899) for R2*. Further, multi-repetition FAM-NLM PDFF and R2* maps had fewer artifacts (score 3.8 vs. 3.2, p < 0.0001 for PDFF; score 3.2 vs. 2.6, p < 0.001 for R2*) and better overall image quality (score 4.0 vs. 3.5, p < 0.0001 for PDFF; score 3.4 vs. 2.7, p < 0.0001 for R2*). CONCLUSIONS: Free-breathing FAM-NLM provides superior image quality of the liver compared to the conventional breath-hold 3D CSE-MRI, while minimizing bias for PDFF and R2* quantification. KEY POINTS: • 2D CSE FAM-NLM is a free-breathing method for liver fat and iron quantification and viable alternative for patients unable to hold their breath. • 2D CSE FAM-NLM is a feasible alternative to breath-hold 3D CSE methods, with low bias in proton density fat fraction (PDFF) and no clinically significant bias in R2*. • Quantitatively, multiple repetitions in 2D CSE FAM-NLM lead to improved SNR.

A pH-/Enzyme-Responsive Nanoparticle Selectively Targets Endosomal Toll-like Receptors to Potentiate Robust Cancer Vaccination.

Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at the receptor site in the endosomal compartments while keeping stable encapsulation and inactive in nontarget environment. Here, we report a pH-/enzyme-responsive TLR7/8 agonist-conjugated nanovaccine (TNV), which responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at the endosomal membrane, stimulates DCs maturation, and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.

A pH-Responsive Nanoparticle Library with Precise pH Tunability by Co-Polymerization with Non-Ionizable Monomers.

Precise monitoring of the subtle pH fluctuation during biological events remains a big challenge. Previously, we reported an ultra-pH-sensitive (UPS) nanoprobe library with a sharp pH response using co-polymerization of two tertiary amine-containing monomers with distinct pKa . Currently, we have generalized the UPS nanoparticle library with tunable pH transitions (pHt ) by copolymerization of a tertiary amine-containing monomer with a series of non-ionizable monomers. The pHt of nanoparticles is fine-tuned by the non-ionizable monomers with different hydrophobicity. Each non-ionizable monomer presents a constant contribution to pH tunability regardless of tertiary amine-containing monomers. Based on this strategy, we produced two libraries of nanoprobes with continuous pHt covering the entire physiological pH range (5.0-7.4) for fluorescent imaging of endosome maturation and cancers. This generalized strategy provides a powerful toolkit for biological studies and cancer theranostics.

Lesion-Based Radiomics Signature in Pretherapy 18F-FDG PET Predicts Treatment Response to Ibrutinib in Lymphoma.

PURPOSE: The aim of this study was to develop a pretherapy PET/CT-based prediction model for treatment response to ibrutinib in lymphoma patients. PATIENTS AND METHODS: One hundred sixty-nine lymphoma patients with 2441 lesions were studied retrospectively. All eligible lymphomas on pretherapy 18F-FDG PET images were contoured and segmented for radiomic analysis. Lesion- and patient-based responsiveness to ibrutinib was determined retrospectively using the Lugano classification. PET radiomic features were extracted. A radiomic model was built to predict ibrutinib response. The prognostic significance of the radiomic model was evaluated independently in a test cohort and compared with conventional PET metrics: SUVmax, metabolic tumor volume, and total lesion glycolysis. RESULTS: The radiomic model had an area under the receiver operating characteristic curve (ROC AUC) of 0.860 (sensitivity, 92.9%, specificity, 81.4%; P < 0.001) for predicting response to ibrutinib, outperforming the SUVmax (ROC AUC, 0.519; P = 0.823), metabolic tumor volume (ROC AUC, 0.579; P = 0.412), total lesion glycolysis (ROC AUC, 0.576; P = 0.199), and a composite model built using all 3 (ROC AUC, 0.562; P = 0.046). The radiomic model increased the probability of accurately predicting ibrutinib-responsive lesions from 84.8% (pretest) to 96.5% (posttest). At the patient level, the model's performance (ROC AUC = 0.811; P = 0.007) was superior to that of conventional PET metrics. Furthermore, the radiomic model showed robustness when validated in treatment subgroups: first (ROC AUC, 0.916; P < 0.001) versus second or greater (ROC AUC, 0.842; P < 0.001) line of defense and single treatment (ROC AUC, 0.931; P < 0.001) versus multiple treatments (ROC AUC, 0.824; P < 0.001). CONCLUSIONS: We developed and validated a pretherapy PET-based radiomic model to predict response to treatment with ibrutinib in a diverse cohort of lymphoma patients.

Spectroscopy-based multi-parametric quantification in subjects with liver iron overload at 1.5T and 3T.

PURPOSE: To evaluate the precision profile (repeatability and reproducibility) of quantitative STEAM-MRS and to determine the relationships between multiple MR biomarkers of chronic liver disease in subjects with iron overload at both 1.5 Tesla (T) and 3T. METHODS: MRS data were acquired in patients with known or suspected liver iron overload. Two STEAM-MRS sequences (multi-TE and multi-TE-TR) were acquired at both 1.5T and 3T (same day), including test-retest acquisition. Each acquisition enabled estimation of R1, R2, and FWHM (each separately for water and fat); and proton density fat fraction. The test-retest repeatability and reproducibility across acquisition modes (multi-TE vs. multi-TE-TR) of the estimates were evaluated using intraclass correlation coefficients, linear regression, and Bland-Altman analyses. Multi-parametric relationships between parameters at each field strength, across field strengths, and with liver iron concentration were also evaluated using linear and nonlinear regression. RESULTS: Fifty-six (n = 56) subjects (10 to 73 years, 37 males/19 females) were successfully recruited. Both STEAM-MRS sequences demonstrated good-to-excellent precision (intraclass correlation coefficient ≥ 0.81) for the quantification of R1water , R2water , FWHMwater , and proton density fat fraction at both 1.5T and 3T. Additionally, several moderate (R2 = 0.50 to 0.69) to high (R2 ≥ 0.70) correlations were observed between biomarkers, across field strengths, and with liver iron concentration. CONCLUSIONS: Over a broad range of liver iron concentration, STEAM-MRS enables rapid and precise measurement of multiple biomarkers of chronic liver disease. By evaluating the multi-parametric relationships between biomarkers, this work may advance the comprehensive MRS-based assessment of chronic liver disease and may help establish biomarkers of chronic liver disease.