HOXB13 facilitates hepatocellular carcinoma progression by activating AKT/mTOR signaling pathway

Introduction and ObjectivesHepatocellular carcinoma (HCC) is one of the sixth most common malignancies worldwide and is accompanied by high mortality. Homeobox B13 (HOXB13) has been shown to be involved in the development of various cancers. This study aimed to investigate the role of HOXB13 in HCC progression.Materials and MethodsThe expression of HOXB13 in HCC tumor tissues was analyzed using qRT-PCR and immunohistochemical staining . After overexpression or downregulation of HOXB13 in HCC cell lines, cell proliferation was detected by CCK8 assay and Ki67 staining and cell invasion ability were tested by transwell assay. Western blot assay was applied to analyze the effect of HOXB13 on related signaling pathways. In addition, the role of HOXB13 on HCC in vivo was explored using a HCC mouse model. IF and WB were performed to detect cell proliferation, apoptosis and related protein expression in mice tumor tissues.ResultsThe results showed that the expression of HOXB13 was significantly increased in HCC tissues compared with adjacent tissues and positively correlated with the tumor stage and survival of HCC patients. Overexpression of HOXB13 promoted the proliferation and invasion of HCC cells and up-regulated the protein expression of AKT, mTOR and MMP2. In contrast, the downregulation of HOXB13 resulted in the opposite results. In vivo experiments, HOXB13 significantly promoted tumor growth in mice bearing HCC by promoting cell proliferation and inhibiting cell apoptosis.ConclusionsThis study suggested that HOXB13 can facilitate HCC progression by activation of the AKT/mTOR signaling pathway. HOXB13 may be a novel target for HCC therapy.     

Atherosclerosis-associated endothelial dysfunction is promoted by miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ

Background and aimsAtherosclerosis (AS) is a chronic inflammatory disease that damages the arterial wall as a result of hyperlipidemia and causes endothelial cell dysfunction, which increases the risk of atherothrombotic events. Multiple pathological conditions have shown ectopic miR-199a-5p levels to cause endothelial injury, but its role in the AS competitive endogenous RNA (CeRNA) network is still unknown.Methods and resultsThe high-fat diet (HFD) apoE−/− mouse model was constructed in vivo, and ECs were cultured under ox-LDL treatment to induce EC injury in vitro. Immunohistochemistry and immunofluorescence staining were used to assess the effect of miR-199a-5p on the macrophage, SMC, collagen content, and endothelial coverage in the artery wall of mouse model. miR-199a-5p level was validated to be overexpression in the aorta tissue of HFD apoE−/− mice and in the ox-LDL-treated ECs, and even in the plasma EVs of the patients with cerebral AS. Silencing of miR-199a-5p significantly attenuated atherosclerotic progress in HFD apoE−/− mice, and the gain/loss-of-function assay indicated that miR-199a-5p overexpression aggravated ox-LDL-induced disabilities of endothelial proliferation, motility, and neovascularization based on cell counting kit-8 assay, transwell assay and matrigel assay. Mechanistically, miR-199a-5p prevented EC activation by activating the FOXO signaling pathway by targeting SIRT1. Additionally, circular RNA (circRNA) circHIF1ɑ was identified as having a low expression in the ox-LDL-treated EC and mediated SIRT1 expression via sponging miR-199a-5p to rescue ox-LDL-induced EC injury.ConclusionsOur study demonstrated the vital role of miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ in AS pathogenesis and provided novel effective targets for AS treatment.     

Nintedanib inhibits epithelial-mesenchymal transition in A549 alveolar epithelial cells through regulation of the TGF-β/Smad pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated.MethodsA549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting.ResultsWe found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3.ConclusionNintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells.     

N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy

Background & AimsAdvanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.MethodsSpontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.ResultsThe conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.ConclusionsTogether, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.     

Grape seed procyanidin suppresses inflammation in cigarette smoke-exposed pulmonary arterial hypertension rats by the PPAR-γ/COX-2 pathway

Background and aimPulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, which is mainly caused by inflammation. Inhibiting inflammation can relieve PAH. Grape seed procyanidin (GSP) possesses remarkable anti-inflammatory property and vascular protective function. In this experiment, we verified the anti-inflammatory property of GSP in cigarette smoke-exposed PAH rats and revealed its molecular mechanism.Methods and resultsIn vivo, 45 Sprague Dawley (SD) rats were divided into 5 groups randomly, treated with normoxia/cigarette smoke (CS)/GSP + CS/CS + solvent/GSP. After GSP + CS administration, a decrease in mPAP, PVR, RVHI, WT%, and WA% was detected in the rats as compared to those treated with CS. In vitro, the proliferation of pulmonary arterial smooth muscle cells (PASMCs) caused by cigarette smoke extract (CSE) was effectively attenuated with GSP + CSE administration. Furthermore, GSP significantly increased the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) together with the lowered expression level of cyclooxygenase 2 (COX-2) in PASMCs co-incubated with CSE.ConclusionThese findings indicate that GSP ameliorates inflammation by the PPAR-γ/COX-2 pathway and finally inhibits the proliferation of PASMCs, which leads to pulmonary vascular remodeling.     

Association Between Changes in Perivascular Adipose Tissue Density and Plaque Progression

BackgroundThe association between the change in vessel inflammation, as quantified by perivascular adipose tissue (PVAT) density, and the progression of coronary atherosclerosis remains to be determined.ObjectivesThe purpose of this study was to explore the association between the change in PVAT density and the progression of total and compositional plaque volume (PV).MethodsPatients were selected from a prospective multinational registry. Patients who underwent serial coronary computed tomography angiography studies with ≥2-year intervals and were scanned with the same tube voltage at baseline and follow-up were included. Total and compositional PV and PVAT density at baseline and follow-up were quantitatively analyzed for every lesion. Multivariate linear regression models using cluster analyses were constructed.ResultsA total of 1,476 lesions were identified from 474 enrolled patients (mean age 61.2 ± 9.3 years; 65.0% men). The mean PVAT density was ?74.1 ± 11.5 HU, and total PV was 48.1 ± 83.5 mm³ (19.2 ± 44.8 mm³ of calcified PV and 28.9 ± 51.0 mm³ of noncalcified PV). On multivariate analysis (adjusted for clinical risk factors, medication use, change in lipid levels, total PV at baseline, luminal HU attenuation, location of lesions, and tube voltage), the increase in PVAT density was positively associated with the progression of total PV (estimate = 0.275 [95% CI: 0.004-0.545]; P = 0.047), driven by the association with fibrous PV (estimate = 0.245 [95% CI: 0.070-0.420]; P = 0.006). Calcified PV progression was not associated with the increase in PVAT density (P > 0.050).ConclusionsIncrease in vessel inflammation represented by PVAT density is independently associated with the progression of the lipid component of coronary atherosclerotic plaques. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)     

Reduction of inflammation in chronic pancreatitis using a soy bread intervention: A feasibility study

IntroductionChronic pancreatitis is a chronic inflammatory disease, which progresses to fibrosis. Currently there are no interventions to delay or stop the progression to irreversible organ damage. In this study, we assessed the tolerability and feasibility of administering soy bread to reduce circulating inflammatory mediators.MethodsSubjects with chronic pancreatitis diagnosed using the American Pancreatic Association diagnostic guidelines were enrolled. During the dose escalation (DE) phase, subjects received one week of soy bread based using a 3 + 3 dose-escalation design, which was then followed by a maximally tolerated dose (MTD) phase with four weeks of intervention. Dose-limiting toxicities (DLTs) were monitored. Plasma cytokine levels were measured using a Meso Scale Discovery multiplex assay kit. Isoflavonoid excretion in 24-h urine collection was used to measure soy bread compliance.ResultsNine subjects completed the DE phase, and one subject completed the MTD phase without any DLTs at a maximum dosage of three slices (99 mg of isoflavones) per day. Reported compliance to soy bread intervention was 98%, and this was confirmed with urinary isoflavones and their metabolites detected in all subjects. There was a significant decline in the TNF-α level during the DE phase (2.667 vs 2.382 pg/mL, p = 0.039); other levels were similar.ConclusionsIn this feasibility study, there was excellent compliance with a short-term intervention using soy bread in chronic pancreatitis. Reduction was seen in at least one pro-inflammatory cytokine with short-term intervention. Larger cohorts and longer interventions with soy are warranted to assess the efficacy of reducing pro-inflammatory mediators of disease.     

Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis

ObjectivesThis study sought to develop an integrative positron emission tomography (PET) with magnetic resonance imaging (MRI) procedure for accurate atherosclerotic plaque phenotyping, facilitated by clinically approved and nanobody radiotracers.BackgroundNoninvasive characterization of atherosclerosis remains a challenge in clinical practice. The limitations of current diagnostic methods demonstrate that, in addition to atherosclerotic plaque morphology and composition, disease activity needs to be evaluated.MethodsWe screened 3 nanobody radiotracers targeted to different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule (VCAM)-1, lectin-like oxidized low-density lipoprotein receptor (LOX)-1, and macrophage mannose receptor (MMR). The nanobodies, initially radiolabeled with copper-64 (⁶⁴Cu), were extensively evaluated in Apoe^–/– mice and atherosclerotic rabbits using a combination of in vivo PET/MRI readouts and ex vivo radioactivity counting, autoradiography, and histological analyses.ResultsThe 3 nanobody radiotracers accumulated in atherosclerotic plaques and displayed short circulation times due to fast renal clearance. The MMR nanobody was selected for labeling with gallium-68 (⁶⁸Ga), a short-lived radioisotope with high clinical relevance, and used in an ensuing atherosclerosis progression PET/MRI study. Macrophage burden was longitudinally studied by ⁶⁸Ga-MMR–PET, plaque burden by T2-weighted MRI, and neovascularization by dynamic contrast-enhanced (DCE) MRI. Additionally, inflammation and microcalcifications were evaluated by fluorine-18 (¹⁸F)-labeled fluorodeoxyglucose (¹⁸F-FDG) and ¹⁸F-sodium fluoride (¹⁸F-NaF) PET, respectively. We observed an increase in all the aforementioned measures as disease progressed, and the imaging signatures correlated with histopathological features.ConclusionsWe have evaluated nanobody-based radiotracers in rabbits and developed an integrative PET/MRI protocol that allows noninvasive assessment of different processes relevant to atherosclerosis progression. This approach allows the multiparametric study of atherosclerosis and can aid in early stage anti-atherosclerosis drug trials.     

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis

BackgroundAtherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood.ObjectivesThis study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk.MethodsThe study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk.ResultsImaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): −1 to 3 plaques] by 2DVUS; 7.6 mm³ [IQR: −32.2 to 57.6 mm³] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk.ConclusionsWith this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318)     

Risk Factors for the Development of Functional Tricuspid Regurgitation and Their Population-Attributable Fractions

ObjectivesThe objective of this study was to determine risk factors for progression to hemodynamically significant tricuspid regurgitation (TR) and the population burden attributable to these risk factors.BackgroundFew data are available with regard to risk factors associated with the development of hemodynamically significant functional TR.MethodsA total of 1,552 subjects were studied beginning with an index echocardiogram demonstrating trivial or mild TR. Risk factors for progression to moderate or severe TR were determined by using logistic regression and classification trees. Population attributable fractions were calculated for each risk factor.ResultsDuring a median follow-up time of 38 (interquartile range [IQR]: 26 to 63) months, 292 patients (18.8%) developed moderate/severe TR. Independent predictors of TR progression were age, female sex, heart failure, pacemaker electrode, atrial fibrillation (AF), and indicators of left heart disease, including left atrial (LA) enlargement, elevated pulmonary artery pressure (PAP), and left-sided valvular disease. Classification and regression tree analysis demonstrated that the strongest predictors of TR progression were PAP of ≥36 mm Hg, LA enlargement, age ≥60 years, and AF. In the absence of these 4 risk factors, progression to moderate or severe TR occurred in ∼3% of patients. Age (28.4%) and PAP (20.5%) carried the highest population-attributable fractions for TR progression. In patients with TR progression, there was a marked concomitant increase of incident cases of elevated PAP (40%); mitral and aortic valve intervention (12%); reductions in left ventricular ejection fraction (19%), and new AF (32%) (all p < 0.01).ConclusionsTR progression is determined mainly by markers of increased left-sided filling pressures (PAP and LA enlargement), AF, and age. At the population level, age and PAP are the most important contributors to the burden of significant TR. TR progression entails a marked parallel increase in the severity of left-sided heart disease.     

Aortic Stenosis Progression: A Systematic Review and Meta-Analysis

BackgroundAortic valve stenosis is a progressive disorder with variable progression rates. The factors affecting aortic stenosis (AS) progression remain largely unknown.ObjectivesThis systematic review and meta-analysis sought to determine AS progression rates and to assess the impact of baseline AS severity and sex on disease progression.MethodsThe authors searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 1, 2020, for prospective studies evaluating the progression of AS with the use of echocardiography (mean gradient [MG], peak velocity [PV], peak gradient [PG], or aortic valve area [AVA]) or computed tomography (calcium score [AVC]). Random-effects meta-analysis was performed to evaluate the rate of AS progression for each parameter stratified by baseline severity, and meta-regression was performed to determine the impact of baseline severity and of sex on AS progression rate.ResultsA total of 24 studies including 5,450 patients (40% female) met inclusion criteria. The pooled annualized progression of MG was +4.10 mm Hg (95% CI: 2.80-5.41 mm Hg), AVA −0.08 cm² (95% CI: 0.06-0.10 cm²), PV +0.19 m/s (95% CI: 0.13-0.24 m/s), PG +7.86 mm Hg (95% CI: 4.98-10.75 mm Hg), and AVC +158.5 AU (95% CI: 55.0-261.9 AU). Increasing baseline severity of AS was predictive of higher rates of progression for MG (P < 0.001), PV (P = 0.001), and AVC (P < 0.001), but not AVA (P = 0.34) or PG (P = 0.21). Only 4 studies reported AS progression stratified by sex, with only PV and AVC having 3 studies to perform a meta-analysis. No difference between sex was observed for PV (P = 0.397) or AVC (P = 0.572), but the level of confidence was low.ConclusionsThis study provides progression rates for both hemodynamic and anatomic parameters of AS and shows that increasing hemodynamic and anatomic baseline severity is associated with faster AS progression. More studies are needed to determine if sex differences affect AS progression. (Aortic Valve Stenosis Progression Rate: A Systematic Review and Meta-Analysis; CRD42021207726)     

The BMSC-derived exosomal lncRNA Mir9-3hg suppresses cardiomyocyte ferroptosis in ischemia-reperfusion mice via the Pum2/PRDX6 axis

Background and aimsThe exosomal long noncoding RNAs (lncRNAs) have been reported to have cardioprotective effects on ischemia-reperfusion (I/R) injury by hindering ferroptosis, but the role of lncRNA Mir9-3 host gene (Mir9-3hg) in cardiac I/R injury remains unclear.Methods and resultsExosomes were extracted from mouse bone marrow mesenchymal stem cells (BMSCs) and identified by detecting the exosome specific marker levels, and the results showed that Mir9-3hg was highly expressed in BMSCs-Exo. Hypoxia/reoxygenation (H/R)-treated HL-1 mouse cardiomyocytes were incubated with exosomes extracted from BMSCs transfected with Mir9-3hg siRNA. BMSCs-Exo incubation observably facilitated cell proliferation, increased glutathione (GSH) content, and reduced iron ion concentration, reactive oxygen species (ROS) level and ferroptosis marker protein levels in H/R-treated cells, while interfering Mir9-3hg reversed these effects. RNA binding protein immunoprecipitation assay was found that Mir9-3hg bound with pumilio RNA binding family member 2 (Pum2) protein and downregulated Pum2 expression. Silence of Pum2 reversed the effects of Mir9-3hg inhibition on cell functions. Chromatin immunoprecipitation assay was revealed that Pum2 bound with peroxiredoxin 6 (PRDX6) promoter and restrained PRDX6 expression. Silence of PRDX6 reversed the improved effects of Pum2 downregulation on cell functions. Additionally, BMSCs-Exo treatment ameliorated cardiac function in I/R-treated mice by inhibiting cardiomyocyte ferroptosis.ConclusionsBMSCs-Exo treatment attenuates I/R-induced cardiac injury by inhibiting cardiomyocyte ferroptosis through modulating the Pum2/PRDX6 axis, thereby ameliorating cardiac function.     

Impact of lncRNA SOX9-AS1 overexpression on the prognosis and progression of intrahepatic cholangiocarcinoma

BackgroundIntrahepatic cholangiocarcinoma (ICC) is a latent and malignant tumor with a dismal prognosis. This study was to evaluate the clinical relevance and therapeutic potential of SOX9-AS1 expression in ICC.MethodsThe cancerous tissues and adjacent normal tissues were collected from ICC patients. Blood samples from ICC, hepatocellular carcinoma (HCC) group, the extrahepatic cholangiocarcinoma (ECC) group and the healthy controls were collected. SOX9-AS1 levels were evaluated in tissues (versus normal tissues) and plasma samples (versus plasma from HCC and ECC by quantitative real-time RT-PCR. The diagnostic value of SOX9-AS1 for ICC was estimated using receiver operating characteristic (ROC) curves. The relevancy between SOX9-AS1 expression and overall survival or recurrence-free survival was assessed by Kaplan-Meier curves multivariate analyses. The overexpression and knockdown of SOX9-AS1 on cell behavior were assessed by CCK-8 and transwell assay.ResultsSOX9-AS1 levels were increased in ICC, both in the tissues and the cell lines. The upregulation of SOX9-AS1 showed a highly discriminative profile, distinguishing ICC patients from healthy subjects or HCC or ECC patients. Upregulation of SOX9-AS1 was related to shorter overall survival and recurrence-free survival. Muli-variate analysis revealed that SOX9-AS1 expression was an independent prognostic purpose factor of worst overall survival and recurrence-free survival.ConclusionsSOX9-AS1 drives tumor growth and metastasis in ICC. SOX9-AS1 may be applied as a new diagnostic and prognostic purposed marker, in addition to a promising therapeutic target in ICC.     

A suggested protocol for the endocrine postoperative management of patients undergoing pituitary surgery

PurposeEndocrine disorders are the most frequent postoperative complications in patients undergoing pituitary surgery. Given the absence of recent guidelines on the postoperative care following pituitary surgery, this article summarizes the available evidence on the topic.MethodWe conducted a systematic search of PubMed up to 2021 and updated the search in December 2022. We retrieved 119 articles and included 53 full-text papers.ResultsThe early postoperative care consists of the assessment for cortisol deficiency and diabetes insipidus (DI). Experts suggest that all patients should receive a glucocorticoid (GC) stress dose followed by a rapid taper. The decision for GC replacement after discharge depends on the morning plasma cortisol level on day 3 after surgery. Experts suggest that patients with a morning plasma cortisol < 10 mcg/dL should receive GC replacement at discharge, and those with 10–18 mcg/dL a morning dose only, with formal assessment of the hypothalamic-pituitary-adrenal axis at week 6 postoperatively. When the cortisol level is > 18 mcg/dL, the patient can be discharged safely without GC, as suggested by observational studies. Postoperative care also includes a close monitoring of water balance. If DI develops, desmopressin is used only in case of uncomfortable polyuria or hypernatremia. The assessment of other hormones is indicated at 3 months postoperatively and beyond.ConclusionThe evaluation and treatment of patients following pituitary surgery are based on expert opinion and a few observational studies. Further research is needed to provide additional evidence on the most appropriate approach.     

New onset diabetes predicts progression of low risk pancreatic mucinous cysts

BackgroundPatients with low-risk lesions require ongoing surveillance since the rate of progression to pancreatic cancer (PC), while small, is much greater than in the general population. Our objective was to study the relationship between new onset diabetes (NODM) and progression in patients with low risk mucinous cysts.MethodsWe evaluated a prospectively maintained cohort of 442 patients with a suspected mucinous cyst without worrisome features (WF) or high-risk stigmata (HRS). Multivariable Cox models were developed for progression to WF and HRS, with diabetes status formulated as both time independent and dependent covariates. The adjusted cumulative risk of progression was calculated using the corrected group prognosis method.ResultsThe 5-year cumulative progression rates to WFs and HRS were 12.8 and 3.6%, respectively. After controlling for other risk factors, the development of NODM was strongly associated with progression to HRS (HR = 11.6; 95%CI, 3.5–57.7%), but not WF. Among patients with the smallest cysts (<10 mm) at baseline, those who developed NODM had a 5-year adjusted cumulative risk of progression to HRS of 8.6% (95%CI, 0.0%–20.2%), compared to only 0.8% (95%CI, 0.0%–2.3%) for patients without NODM. Among patients with the largest cysts (20–29 mm), those who developed NODM during surveillance had a 5-year adjusted cumulative risk of progression of 53.5% (95%CI, 19.6%–89.9%) compared to only 7.5% (95%CI, 1.6%–15.2%) for patients without NODM.ConclusionNew onset diabetes may predict progression in patients with low risk mucinous cysts. Pending validation with large-scale studies, these findings support regular diabetes screening among patients surveilled for suspected IPMNs or MCNs.     

Antibody responses to SARS-CoV-2 nucleocapsid and spike proteins in hospitalized patients with COVID-19: A multicenter,retrospective, cross-sectional study in Japan

BackgroundThere are many commercially available automated assays for assessing coronavirus disease 2019 (COVID-19) immune responses; however, owing to insufficient data, their validities remain unknown. Here, we examined antibody responses during acute-phase COVID-19 using four assays that detect anti-spike protein IgM (S-IgM), anti-nucleocapsid protein IgG (N-IgG), anti-spike protein total Ig (S-total Ig), and anti-spike protein IgG (S-IgG).MethodsWe measured antibody levels in 1154 serum samples collected from 286 hospitalized patients with confirmed COVID-19 by a gene amplification method between February and December 2020 in Japan. Sera from 860 healthcare workers were used as negative controls.ResultsThe antibody positivity rates increased on week 2, peaked, and then started to plateau by the beginning of week 3 after symptom onset. On week 1, there were some significant differences in seropositivity rates between assays (p = 0.032): 14.9% (11.0%–19.4%) for S-IgM and 8.9% (6.0%–12.7%) for N-IgG. The seropositivity for the S-total Ig (10.6% [7.3%–14.6%]) assay was considerably better than that for the S-IgG (6.9% [4.3%–10.4%]) assay, although the difference was not statistically significant (p = 0.150). The levels of S-IgM antibodies and the three others peaked on weeks 3 and 5, respectively. All four assays showed high specificities (>99%).ConclusionsAll four assays had good specificities and were suitable for seropositivity detection after week 3 of symptom onset. Assays of IgM alone or total Ig (containing IgM) were better than those of IgG alone as an adjunct serological test for early-stage COVID-19 diagnosis, albeit the use of a serological assay alone is insufficient.     

Label-Free Visualization and Quantification of Biochemical Markers of Atherosclerotic Plaque Progression Using Intravascular Fluorescence Lifetime

ObjectivesThis study aimed to systematically investigate whether plaque autofluorescence properties assessed with intravascular fluorescence lifetime imaging (FLIm) can provide qualitative and quantitative information about intimal composition and improve the characterization of atherosclerosis lesions.BackgroundDespite advances in cardiovascular diagnostics, the analytic tools and imaging technologies currently available have limited capabilities for evaluating in situ biochemical changes associated with luminal surface features. Earlier studies of small number of samples have shown differences among the autofluorescence lifetime signature of well-defined lesions, but a systematic pixel-level evaluation of fluorescence signatures associated with various histological features is lacking and needed to better understand the origins of fluorescence contrast.MethodsHuman coronary artery segments (n = 32) were analyzed with a bimodal catheter system combining multispectral FLIm with intravascular ultrasonography compatible with in vivo coronary imaging. Various histological components present along the luminal surface (200-μm depth) were systematically tabulated (12 sectors) from each serial histological section (n = 204). Morphological information provided by ultrasonography allowed for the accurate registration of imaging data with histology data. The relationships between histological findings and FLIm parameters obtained from 3 spectral channels at each measurement location (n = 33,980) were characterized.ResultsOur findings indicate that fluorescence lifetime from different spectral bands can be used to quantitatively predict the superficial presence of macrophage foam cells (mFCs) (area under the receiver-operator characteristic curve: 0.94) and extracellular lipid content in advanced lesions (lifetime increase in 540-nm band), detect superficial calcium (lifetime decrease in 450-nm band area under the receiver-operator characteristic curve: 0.90), and possibly detect lesions consistent with active plaque formation such as pathological intimal thickening and healed thrombus regions (lifetime increase in 390-nm band).ConclusionsOur findings indicate that autofluorescence lifetime provides valuable information for characterizing atherosclerotic lesions in coronary arteries. Specifically, FLIm can be used to identify key phenomena linked with plaque progression (e.g., peroxidized-lipid–rich mFC accumulation and recent plaque formation).     

Blood Pressure Variation and Subclinical Brain Disease

BackgroundLarge blood pressure (BP) variability may contribute to stroke and dementia, but the mechanisms are largely unknown.ObjectivesThis study investigated the association of BP variation, considering its magnitude and direction, with the presence and progression of subclinical brain disease in the general population.MethodsThis study included 2,348 participants age ≥55 years from a prospective cohort study. BP was measured at each visit every 3 to 4 years from 1990 onward. Brain magnetic resonance imaging (MRI) was performed at all visits from 2005 onward. The authors primarily assessed variation as the absolute difference in BP divided by the mean over 2 sequential visits for both systolic BP (SBP) and diastolic BP (DBP), and further assessed the direction of the variation. The authors investigated the multivariate-adjusted associations of BP variation with subsequent measurements of MRI markers of cerebral small vessel disease, brain tissue volumes, and white matter microstructural integrity. Longitudinal changes in these markers also were assessed.ResultsA large SBP variation (top vs. bottom tertiles), measured on average 7 years preceding brain MRI, was associated with higher odds of having severe white matter hyperintensities (WMH) (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.21 to 1.43), lacunes (OR: 1.25; 95% CI: 1.04 to 1.48), and microbleeds (OR: 1.16; 95% CI: 1.03 to 1.31). Similarly, this variation was associated with smaller total brain volume and worse white matter microstructural integrity (all p < 0.001). A large SBP variation was also associated with the progression of WMH (rate ratio [RR]: 1.14; 95% CI: 1.02 to 1.27). Higher burdens of these brain imaging markers were observed with both large rises and falls in SBP. Similar findings were observed for DBP variation.ConclusionsElevated BP variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity. These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.