Transgenic ferret models define pulmonary ionocyte diversity and function.

Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.

Adipose tissue macrophages (ATM) are key players in the development of obesity and associated metabolic inflammation which contributes to systemic metabolic dysfunction. We here found that fibroblast activation protein α (FAP), a well-known marker of cancer-associated fibroblast, is selectively expressed in murine and human ATM among adipose tissue-infiltrating leukocytes. Macrophage FAP deficiency protects mice against diet-induced obesity and proinflammatory macrophage infiltration in obese adipose tissues, thereby alleviating hepatic steatosis and insulin resistance. Mechanistically, FAP specifically mediates monocyte chemokine protein CCL8 expression by ATM, which is further upregulated upon high-fat-diet (HFD) feeding, contributing to the recruitment of monocyte-derived proinflammatory macrophages with no effect on their classical inflammatory activation. CCL8 overexpression restores HFD-induced metabolic phenotypes in the absence of FAP. Moreover, macrophage FAP deficiency enhances energy expenditure and oxygen consumption preceding differential body weight after HFD feeding. Such enhanced energy expenditure is associated with increased levels of norepinephrine (NE) and lipolysis in white adipose tissues, likely due to decreased expression of monoamine oxidase, a NE degradation enzyme, by Fap-/- ATM. Collectively, our study identifies FAP as a previously unrecognized regulator of ATM function contributing to diet-induced obesity and metabolic inflammation and suggests FAP as a potential immunotherapeutic target against metabolic disorders.

Epithelial chemerin-CMKLR1 signaling restricts microbiota-driven colonic neutrophilia and tumorigenesis by up-regulating lactoperoxidase.

Intestinal barrier immunity is essential for controlling gut microbiota without eliciting harmful immune responses, while its defect contributes to the breakdown of intestinal homeostasis and colitis development. Chemerin, which is abundantly expressed in barrier tissues, has been demonstrated to regulate tissue inflammation via CMKLR1, its functional receptor. Several studies have reported the association between increased expression of chemerin-CMKLR1 and disease severity and immunotherapy resistance in inflammatory bowel disease (IBD) patients. However, the pathophysiological role of endogenous chemerin-CMKLR1 signaling in intestinal homeostasis remains elusive. We herein demonstrated that deficiency of chemerin or intestinal epithelial cell (IEC)-specific CMKLR1 conferred high susceptibility to microbiota-driven neutrophilic colon inflammation and subsequent tumorigenesis in mice following epithelial injury. Unexpectedly, we found that lack of chemerin-CMKLR1 signaling specifically reduced expression of lactoperoxidase (LPO), a peroxidase that is predominantly expressed in colonic ECs and utilizes H2O2 to oxidize thiocyanates to the antibiotic compound, thereby leading to the outgrowth and mucosal invasion of gram-negative bacteria and dysregulated CXCL1/2-mediated neutrophilia. Importantly, decreased LPO expression was causally linked to aggravated microbiota-driven colitis and associated tumorigenesis, as LPO supplementation could completely rescue such phenotypes in mice deficient in epithelial chemerin-CMKLR1 signaling. Moreover, epithelial chemerin-CMKLR1 signaling is necessary for early host defense against bacterial infection in an LPO-dependent manner. Collectively, our study reveals that the chemerin-CMKLR1/LPO axis represents an unrecognized immune mechanism that potentiates epithelial antimicrobial defense and restricts harmful colonic neutrophilia and suggests that LPO supplementation may be beneficial for microbiota dysbiosis in IBD patients with a defective innate antimicrobial mechanism.

GABA signaling enforces intestinal germinal center B cell differentiation.

Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA+ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.

Amide Proton Transfer-Weighted Imaging in Assessing the Aggressive and Proliferative Potential of Bladder Cancer.

BACKGROUND: Ki-67 and human epidermal growth factor receptor 2 (HER2) are known oncogenes involved in bladder cancer (BCa) patient risk stratification. Preoperative assessment of their expression level can assist in clinical treatment decision-making. Recently, amide proton transfer-weighted (APTw) MRI has shown promising potential in the diagnosis of several malignancies. However, few studies reported the value of APTw imaging in evaluating Ki-67 and HER2 status of BCa. PURPOSE: To investigate the feasibility of APTw MRI in assessing the aggressive and proliferative potential regarding the expression levels of Ki-67 and HER2 in BCa. STUDY TYPE: Retrospective. SUBJECTS: 114 patients (mean age, 64.78 ± 11.93 [SD] years; 97 men) were studied. FIELD STRENGTH/SEQUENCE: APTw MRI acquired by a three-dimensional fast-spin-echo sequence at 3.0 T MRI system. ASSESSMENT: Patient pathologic findings, included histologic grade and the expression status of Ki-67 and HER2, were reviewed by one uropathologist. The APTw values of BCa were independently measured by two radiologists and were compared between high-/low-tumor grade group, high-/low-Ki-67 expression group, and high-/low-HER2 expression group. STATISTICAL TESTS: The interclass correlation coefficient, independent sample t-test, Mann-Whitney U test, Spearman's rank correlation, and receiver operating characteristic curve (ROC) analysis were used. P < 0.05 was considered statistically significant. RESULTS: Significantly higher APTw values were found in high-grade BCa patients (7.72% vs. 4.29%, P < 0.001), high-Ki-67 expression BCa patients (8.40% vs. 3.25%, P < 0.001) and HER2 positive BCa patients (8.24% vs. 5.40%, P = 0.001). APTw values were positively correlated with Ki-67 (r = 0.769) and HER2 (r = 0. 356) expression status. The area under the ROC curve of the APTw values for detecting Ki-67 and HER2 expression status were 0.883 (95% CI: 0.790-0.945) and 0.713 (95% CI: 0.592-0.816), respectively. DATA CONCLUSIONS: APTw MRI is a potential method to assess the biological and proliferation potential of BCa. TECHNICAL EFFICACY: Stage 2.

Long-Term Healthcare Resource Utilization and Costs among Patients with Myasthenia Gravis: A Swedish Nationwide Population-Based Study.

INTRODUCTION: Healthcare costs and societal impact of myasthenia gravis (MG), a potentially life-threatening rare, chronic neuromuscular disease, are sparsely studied. We assessed healthcare resource utilization (HCRU) and associated costs among patients with newly diagnosed (ND) and preexisting (PE) MG in Sweden. METHODS: This observational, retrospective cohort study used data from four linkable Swedish nationwide population-based registries. Adult MG patients receiving pharmacological treatment for MG and having ≥24-month follow-up during the period January 1, 2010, to December 31, 2017, were included. RESULTS: A total of 1,275 patients were included in the analysis, of which 554 patients were categorized into the ND MG group and 721 into the PE MG group. Mean (±SD) age was 61.3 (±17.4) years, and 52.3% were female. In the first year post-diagnosis, ND patients had significantly higher utilization of acetylcholinesterase inhibitors (96.0% vs. 83.9%), corticosteroids (59.6% vs. 45.8%), thymectomy (12.1% vs. 0.7%), and plasma exchange (3.8% vs. 0.6%); had higher all-cause (70.9% vs. 35.8%) and MG-related (62.5% vs. 18.4%) hospitalization rates with 11 more hospitalization days (all p < 0.01) and an increased risk of hospitalization (odds ratio [95% CI] = 4.4 [3.43, 5.64]) than PE MG. In year 1 post-diagnosis, ND MG patients incurred EUR 7,302 (p < 0.01) higher total all-cause costs than PE MG, of which 84% were estimated to be MG-related and the majority (86%) were related to inpatient care. These results remained significant also after controlling for baseline demographics and comorbidities (p < 0.01). In year 2 post-diagnosis, the all-cause medical costs decreased by ∼55% for ND MG from year 1 and were comparable with PE MG. CONCLUSION: In this population-based study, MG patients required significantly more healthcare resources in year 1 post-diagnosis than PE MG primarily due to more pharmacological treatments, thymectomies, and associated hospitalizations. These findings highlight the need to better understand potential factors including disease characteristics associated with increased health resource use and costs and need for more efficacious treatments early in the disease course.

A transition-metal-free azide-alkyne cycloaddition/hydroamination cascade reaction for the construction of triazole-fused piperazin-2-ones.

A time-dependent, divergent synthesis of highly functionalized [1,2,3]triazolo[1,5-a]pyrazin-4(5H)-one (reaction time: 12 h) or 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-4(5H)-one (reaction time: 2 h) scaffolds via a cascade azide-alkyne cycloaddition/hydroamination protocol is reported. The transformation features good functional group compatibility, broad substrate scope, high atom economy and avoidance of the use of transition-metal catalysts.

Percutaneous microwave ablation versus sclerotherapy for large hepatic hemangioma: a multi-center cohort study.

OBJECTIVE: The study aimed to compare the effectiveness and safety of ultrasound-guided microwave ablation (MWA) and percutaneous sclerotherapy (PS) for the treatment of large hepatic hemangioma (LHH). METHODS: This retrospective study included 96 patients who underwent MWA (n = 54) and PS (n = 42) as first-line treatment for LHH in three tertiary hospitals from January 2016 to December 2021. Primary outcomes were technique efficacy rate (volume reduction rate [VRR] > 50% at 12 months), symptom relief rate at 12 months and local tumor progression (LTP). Secondary outcomes included procedure time, major complications, treatment sessions, cost and one-, two-, three-year VRR. RESULTS: During a median follow-up of 36 months, the MWA group showed a higher technique efficacy rate (100% vs. 90.4%, p = .018) and symptom relief rate (100% vs. 80%, p = .123) than the PS group. The MWA group had fewer treatment sessions, higher one-, two- and three-year VRR, lower LTP rate (all p < .05), longer procedure time and higher treatment costs than the PS group (both p < .001). MWA shared a comparable major complications rate (1.8% vs. 2.4%, p = .432) with PS. After multivariate analysis, the lesion's heterogeneity and maximum diameter >8.1 cm were independent risk factors for LTP (all p < .05). In the PS group, lesions with a cumulative dose of bleomycin > 0.115 mg/cm3 had a lower risk of LTP (p = .006). CONCLUSIONS: Both MWA and PS treatments for large hepatic hemangioma are safe and effective, with MWA being superior in terms of efficacy.

Parental perceptions and experiences of kangaroo care for preterm infants in neonatal intensive care units in China: a qualitative study.

BACKGROUND: kangaroo care (KC), endorsed by the World Health Organization, is an evidence-based intervention that plays a pivotal role in mitigating preterm infant mortality and morbidity. However, this intervention has not been fully integrated into healthcare systems in China. This study aimed to gain insight into parents' perceptions and experiences of KC for preterm infants to contribute to the KC implementation on a larger scale. METHODS: This study employed a descriptive qualitative design, using face-to-face, semi-structured, in-depth interviews. Fifteen parents participating in KC for preterm infants in the neonatal intensive care units (NICUs) were purposively sampled from four hospitals across four cities in Zhejiang Province, China. Thematic analysis was employed to analyze the data. RESULTS: Four themes and twelve subthemes regarding the parents' perceptions and experiences about KC were identified. The four themes included: (1) Low motivation upon initial engagement with KC, (2) Dynamic fluctuations of emotional states during KC, (3) Unexpected gains, and (4) Barriers to participation. CONCLUSIONS: Parents' perceptions and experiences of KC was a staged process, with parents exhibiting distinct cognitive patterns and unique experiences at each stage. Overall, as KC progresses, parents' experiences tended to become increasingly positive, despite potential obstacles encountered along the way. To enhance the implementation of KC, healthcare providers could utilize prenatal and postnatal education programs. These programs aim to enhance the understanding of KC among parents of preterm infants, fostering sustained engagement in KC practices.

Aconitum coreanum and processed products on its base prevent stroke via the PI3K/Akt and KEAP1/NRF2 in the in vivo study.

Aconitum coreanum (A. coreanum), a traditional Chinese medicine, has been proved to treat ischemic stroke (IS). However, the mechanisms of A. coreanum's anti-stroke is currently unknown. This study aimed to uncover the effect and mechanisms of A. coreanum. And study raw Aconitum coreanum (RA) and steamed Aconitum coreanum (SA) and Aconitum coreanum processed with ginger and Alumen (GA) on the mechanism of the pharmacological action of treating IS. Determining whether the efficacy is affected after processing. The right unilateral ligation of the carotid artery of gerbils was used to mimic IS. The neurological function score, infarct volume, oxidative stress level and inflammatory factor expression were measured in gerbils after IS. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins. Metabolomic analyzes IS-related metabolic pathways in urinary metabolites. RA, SA and GA significantly improved the infarct volume and behavioral score of IS gerbils, increased the expression of brain tissue superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO) and decreased the content of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α). Western blot and immunofluorescence analysis results showed that RA, SA and GA significantly increased the expression of P-Akt, PI3K, HO-1 and KEAP1. Metabolomic studies identified 112 differential metabolites, including L-Proline, Riboflavin, Leukotriene D4, and 7-Methylxanthine, as potential biomarkers of stroke, involving 14 metabolic pathways including riboflavin metabolism, pyrimidine metabolism, and purine metabolism. Our findings indicated that A. coreanum protected against cerebral ischemia injury probably via the PI3K/Akt and KEAP1/NRF2 pathway. A. coreanum before and after processing both had a protective effect against IS brain injury in gerbils. The A. coreanum efficacy was not reduced after processing. Even compared to RA, SA had better efficacy.

A potential mechanism clue to the periodic storm from microglia activation and progressive neuron damage induced by paraquat exposure.

Paraquat (PQ), is characterized by neurotoxicity, which increases the potential risk of Parkinson's disease (PD) exposure in the long-term and low doses. Triggering microglia activation and neuroinflammation is deemed an early event resulting in PD. However, the underlying pathogenesis of PD by PQ is not clear yet. In this article, C57BL/6J mice treated with PQ could successfully act out Parkinson-like. In addition, we observed the fluorescence intensity enhancement of Iba-1 activated microglia with released pro-inflammatory, all ahead of both the damage of dopaminergic neurons in the substantia nigra and corpus striatum of the brain. Surprisingly, the injection of minocycline before PQ for many hours not only can effectively improve the neurobehavioral symptoms of mice but inhibit the activation of microglia and the release of pro-inflammatory substances, even controlling the gradual damage and loss of neurons. A further mechanism of minocycline hampered the expression levels of key signaling proteins PI3K, PDK1, p-AKT, and CD11b (the receptor of microglia membrane recognition), while a large number of inflammatory factors. Our results suggested that the CD11b/PI3K/NOX2 pathway may be a clue that microglia-mediated inflammatory responses and neuronal damage in a PQ-induced abnormal behavior Parkinson-like mouse.

Sonic Hedgehog Signaling Is Essential for Pulmonary Ionocyte Specification in Human and Ferret Airway Epithelia.

Pulmonary ionocytes express high levels of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that is critical for hydration of the airways and mucociliary clearance. However, the cellular mechanisms that govern ionocyte specification and function remain unclear. We observed that increased abundance of ionocytes in cystic fibrosis (CF) airway epithelium was associated with enhanced expression of Sonic Hedgehog (SHH) effectors. In this study, we evaluated whether the SHH pathway directly impacts ionocyte differentiation and CFTR function in airway epithelia. Pharmacological HPI1-mediated inhibition of SHH signaling component GLI1 significantly impaired human basal cell specification of ionocytes and ciliated cells but significantly enhanced specification of secretory cells. By contrast, activation of the SHH pathway effector smoothened (SMO) with the chemical agonist SAG significantly enhanced ionocyte specification. The abundance of CFTR+ BSND+ ionocytes under these conditions had a direct relationship with CFTR-mediated currents in differentiated air-liquid interface (ALI) airway cultures. These findings were corroborated in ferret ALI airway cultures generated from basal cells in which the genes encoding the SHH receptor PTCH1 or its intracellular effector SMO were genetically ablated using CRISPR-Cas9, causing aberrant activation or suppression of SHH signaling, respectively. These findings demonstrate that SHH signaling is directly involved in airway basal cell specification of CFTR-expressing pulmonary ionocytes and is likely responsible for enhanced ionocyte abundance in the CF proximal airways. Pharmacologic approaches to enhance ionocyte and reduce secretory cell specification after CFTR gene editing of basal cells may have utility in the treatment of CF.

Synthesis of Ultrathin Topological Insulator ß-Ag2 Te and Ag2 Te/WSe2 -Based High-Performance Photodetector.

ß-Ag2 Te has attracted considerable attention in the application of electronics and optoelectronics due to its narrow bandgap, high mobility, and topological insulator properties. However, it remains a significant challenge to synthesize 2D Ag2 Te because of the non-layered structure of Ag2 Te. Herein, the synthesis of large-size, ultrathin single crystal topological insulator 2D Ag2 Te via the van der Waals epitaxial method for the first time is reported. The 2D Ag2 Te crystal exhibits p-type conduction behavior with high carrier mobility of 3336 cm2 V-1 s-1 at room temperature. Taking advantage of the high mobility and perfect electron structure of Ag2 Te, the Ag2 Te/WSe2 heterojunctions are fabricated via mechanical stacking and show an ultrahigh rectification ratio of 2 × 105 . Ag2 Te/WSe2 photodetector also exhibits self-driven properties with a fast response speed (40 µs/60 µs) in the near-infrared region. High responsivity (219 mA W-1 ) and light ON/OFF ratio of 6 × 105 are obtained under the photovoltaic mode. The overall performance of the Ag2 Te/WSe2 photodetector is significantly competitive among all reported 2D photodetectors. These results indicate that 2D Ag2 Te is a promising candidate for future electronic and optoelectronic applications.

The Controllable Synthesis of High-Quality Two-Dimensional Iron Sulfide with Specific Phases.

2D Fe-chalcogenides have drawn significant attention due to their unique structural phases and distinct properties in exploring magnetism and superconductivity. However, it remains a significant challenge to synthesize 2D Fe-chalcogenides with specific phases in a controllable manner since Fe-chalcogenides have multiple phases. Herein, a molecular sieve-assisted strategy is reported for synthesizing ultrathin 2D iron sulfide on substrates via the chemical vapor deposition method. Using a molecular sieve and tuning growth temperatures to control the partial pressures of precursor concentrations, hexagonal FeS, tetragonal FeS, and non-stoichiometric Fe7 S8 nanoflakes can be precisely synthesized. The 2D h-FeS, t-FeS, and Fe7 S8 have high conductivities of 5.4 × 105 S m-1 , 5.8 × 105 S m-1 , and 1.9 × 106 S m-1 . 2D tetragonal FeS shows a superconducting transition at 4 K. The spin reorientation at ≈30 K on the non-stoichiometric Fe7 S8 nanoflakes with ferrimagnetism up to room temperature has also been observed. The controllable synthesis of various phases of 2D iron sulfide may provide a route for synthesizing other 2D compounds with various phases.

Real-time detection of laryngopharyngeal cancer using an artificial intelligence-assisted system with multimodal data.

BACKGROUND: Laryngopharyngeal cancer (LPC) includes laryngeal and hypopharyngeal cancer, whose early diagnosis can significantly improve the prognosis and quality of life of patients. Pathological biopsy of suspicious cancerous tissue under the guidance of laryngoscopy is the gold standard for diagnosing LPC. However, this subjective examination largely depends on the skills and experience of laryngologists, which increases the possibility of missed diagnoses and repeated unnecessary biopsies. We aimed to develop and validate a deep convolutional neural network-based Laryngopharyngeal Artificial Intelligence Diagnostic System (LPAIDS) for real-time automatically identifying LPC in both laryngoscopy white-light imaging (WLI) and narrow-band imaging (NBI) images to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists. METHODS: All 31,543 laryngoscopic images from 2382 patients were categorised into training, verification, and test sets to develop, validate, and internal test LPAIDS. Another 25,063 images from five other hospitals were used as external tests. Overall, 551 videos were used to evaluate the real-time performance of the system, and 200 randomly selected videos were used to compare the diagnostic performance of the LPAIDS with that of laryngologists. Two deep-learning models using either WLI (model W) or NBI (model N) images were constructed to compare with LPAIDS. RESULTS: LPAIDS had a higher diagnostic performance than models W and N, with accuracies of 0·956 and 0·949 in the internal image and video tests, respectively. The robustness and stability of LPAIDS were validated in external sets with the area under the receiver operating characteristic curve values of 0·965-0·987. In the laryngologist-machine competition, LPAIDS achieved an accuracy of 0·940, which was comparable to expert laryngologists and outperformed other laryngologists with varying qualifications. CONCLUSIONS: LPAIDS provided high accuracy and stability in detecting LPC in real-time, which showed great potential for using LPAIDS to improve the diagnostic accuracy of LPC by reducing diagnostic variation among on-expert laryngologists.

CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase.

BACKGROUND AND AIMS: We previously demonstrated that cancer-associated fibroblasts (CAFs) promote tumor growth through recruitment of myeloid-derived suppressor cells (MDSCs). 5-lipoxygenase (5-LO) is highly expressed in myeloid cells and is critical for synthesizing leukotriene B4 (LTB4), which is involved in tumor progression by activating its receptor leukotriene B4 receptor type 2 (BLT2). In this study, we investigated whether and how CAFs regulate MDSC function to enhance cancer stemness, the driving force of the cancer aggressiveness and chemotherapy refractoriness, in highly desmoplastic intrahepatic cholangiocarcinoma (ICC). APPROACH AND RESULTS: RNA-sequencing analysis revealed enriched metabolic pathways but decreased inflammatory pathways in cancer MDSCs compared with blood MDSCs from patients with ICC. Co-injection of ICC patient-derived CAFs promoted cancer stemness in an orthotopic ICC model, which was blunted by MDSC depletion. Conditioned media (CM) from CAF-educated MDSCs drastically promoted tumorsphere formation efficiency and stemness marker gene expression in ICC cells. CAF-CM stimulation increased expression and activity of 5-LO in MDSCs, while 5-LO inhibitor impaired the stemness-enhancing capacity of MDSCs in vitro and in vivo. Furthermore, IL-6 and IL-33 primarily expressed by CAFs mediated hyperactivated 5-LO metabolism in MDSCs. We identified the LTB4-BLT2 axis as the critical downstream metabolite signaling of 5-LO in promoting cancer stemness, as treatment with LTB4 was elevated in CAF-educated MDSCs, or blockade of BLT2 (which was preferentially expressed in stem-like ICC cells) significantly reduced stemness-enhancing effects of CAF-educated MDSCs. Finally, BLT2 blockade augmented chemotherapeutic efficacy in ICC patient-derived xenograft models. CONCLUSIONS: Our study reveals a role for CAFs in orchestrating the optimal cancer stemness-enhancing microenvironment by educating MDSCs, and suggests the 5-LO/LTB4-BLT2 axis as promising therapeutic targets for ICC chemoresistance by targeting cancer stemness.

Epidemiology and clinical outcomes of light-chain amyloidosis in Sweden: A nationwide population-based study.

OBJECTIVES: This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. METHODS: Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. RESULTS: 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. CONCLUSION: The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.

Multiparametric MRI-based VI-RADS: can it predict 1- to 5-year recurrence of bladder cancer?

OBJECTIVES: To evaluate whether Vesical Imaging-Reporting And Data System (VI-RADS) scores based on multiparametric MRI (mp-MRI) can predict bladder cancer (BCa) recurrence. METHODS: In this retrospective study, 284 patients with pathologically confirmed bladder neoplasms from November 2011 to October 2020 were included. Two radiologists blindly and independently scored mp-MRI scans according to VI-RADS. Scoring inconsistency was resolved in consensus. The latest follow-up was completed in December 2022. Pearson's correlation analyses, independent-sample t-tests, and receiver operating characteristic analyses were performed to assess the efficacy of VI-RADS score for the 1- to 5-year recurrence prognostication. RESULTS: Based on the latest follow-up, 37 (of 284, 13.0%), 69 (of 284, 24.3%), 70 (of 234, 29.9%), 72 (of 190, 37.9%), and 63 (of 135, 46.7%) patients had cancer recurrence at 1- to 5-year follow-up, respectively. VI-RADS scores showed significantly intergroup differences between recurrent and nonrecurrent cases during 1- to 4-year surveillance (p < 0.05). The recurrence-free survival was significantly higher in patients with VI-RADS scores of 1 or 2, compared to those with scores of 3, 4, or 5 (p < 0.05). Areas under the receiver operating characteristic curves for 1- to 5-year recurrence prediction were 0.744, 0.686, 0.656, 0.595, and 0.536, respectively. VI-RADS score of 3 or more was the threshold for 1-year recurrence assessment, and VI-RADS more than 3 was the cutoff for 2-year recurrence prediction. CONCLUSION: VI-RADS score has potential in preoperative prognostication of BCa recurrence, but its predictive power decreases over time. CLINICAL RELEVANCE STATEMENT: VI-RADS has potential in bladder cancer recurrence assessment, but its prognostic value decreases over time. Patients with VI-RADS ≥ 3 may be more likely to recur in 1 or 2 years postoperatively, thus should be performed with intensive surveillances. KEY POINTS: • VI-RADS scores had significant differences in 1- to 4-year recurrent and nonrecurrent patient groups. • Patients with VI-RADS scores of ≤ 2 showed more favorable recurrence-free survival outcomes. • The prognostic value of VI-RADS score decreased over time for bladder cancer recurrence prediction.

Broad activation of the Parkin pathway induces synaptic mitochondrial deficits in early tauopathy.

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer's disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect-depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer's disease and other tauopathies.

Gasless endoscopic thyroidectomy via the anterior chest approach: the experience with 1500 cases.

BACKGROUND: Conventional thyroidectomy leaves an eye-catching scar in the anterior neck region. Endoscopic thyroidectomy may achieve a better esthetic effect and improve quality of life postoperatively. The aim of this study was to undertake a complete review of a large cohort of the patients undergoing gasless endoscopic thyroidectomy (GET) via anterior chest approach (ACA) with a long-term follow-up period, and evaluate the results and limits of this procedure. METHODS: Between 2003 and 2022, 1413 patients undergoing GET via ACA in our department were included. The demographic, clinicopathological characteristics, oncologic and esthetic outcomes were summarized and analyzed. RESULTS: The indication for surgery was papillary thyroid carcinoma in 686 (48.5%) patients and benign thyroid diseases in 727 (51.5%) patients. Among them, 802 (56.8%) patients took hemithyroidectomy, and 611 (43.2%) patients did sub-total/total thyroidectomy. Meanwhile, 598 (42.3%) ones had central neck dissection, while 88 (6.2%) lateral neck dissection. The most common complication was transient hypoparathyroidism with an incidence of 2.9%. During the follow-up period of 2 to 232 months, three patients were confirmed locoregional recurrence. Most of the patients were satisfied with the cosmetic results. CONCLUSION: Gasless endoscopic thyroidectomy via anterior chest approach is a safe and feasible procedure, which could achieve excellent oncologic and esthetic outcomes.