Monitoring tumour resistance to the BRAF inhibitor combination regimen in colorectal cancer patients via circulating tumour DNA.

AIMS: This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). METHODS: Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. RESULTS: BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. CONCLUSION: Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.

[Progressive psychomotor regression for 2.5 years in a boy aged 5 years]. / 5岁男童进行性智力运动功能倒退2.5年.

A boy, aged 5 years, attended the hospital due to progressive psychomotor regression for 2.5 years. Motor function regression was the main manifestation in the early stage, and brain MRI and whole-exome sequencing (WES) of the family showed no abnormalities. After the age of 4 years and 9 months, the boy developed cognitive function regression, and brain MRI showed cerebellar atrophy. The reanalysis of WES results revealed a compound heterozygous mutation, [NM_000520, c.784C>T(p.His262Tyr]), c.1412C>T(p.Pro471Leu)], in the HEXA gene. The enzyme activity detection showed a significant reduction in the level of ß-hexosaminidase encoded by this gene. The boy was diagnosed with juvenile Tay-Sachs disease (TSD). TSD has strong clinical heterogeneity, and cerebellar atrophy may be an important clue for the diagnosis of juvenile TSD. The reanalysis of genetic data when appropriate based on disease evolution may improve the positive rate of WES.

Balloon pulmonary angioplasty reverse right ventricular remodelling and dysfunction in patients with inoperable chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis.

OBJECTIVES: Right ventricular (RV) function is considered the major determinant of prognosis in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this meta-analysis was to evaluate RV remodelling and function following balloon pulmonary angioplasty (BPA) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). METHODS: We reviewed all studies evaluating RV function by cardiac magnetic resonance (CMR) and/or echocardiography pre- and post-BPA from PubMed/Medline prior to 15 December 2019. Ten (299 patients) of the 29 studies retrieved met the inclusion criteria: 5 CMR and 5 echocardiography studies. The systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. RESULTS: Pooled data from CMR studies revealed BPA resulted in a significantly decreased RV end-diastolic volume index (weighted mean difference (WMD) - 28.33 ml/m2, p < 0.00001) and RV end-systolic volume index (WMD - 29.06 ml/m2, p < 0.00001) accompanied by an increased RV ejection fraction (RVEF, WMD 8.97%, p < 0.00001). Data from the echocardiography studies showed BPA resulted in decreased RV basal diameter (WMD - 0.37 cm, p = 0.0009) and an increase of RV fractional area change (WMD 5.97 %, p = 0.003), but improvements of tricuspid annular plane systolic excursion (TAPSE) and S' were not significant. CONCLUSIONS: BPA improves RVEF and decreases RV volumes in patients with inoperable CTEPH or persistent/recurrent PH after PEA. KEY POINTS: • Balloon pulmonary angioplasty improves RVEF and decreases RV volumes in patients with inoperable CTEPH or persistent/recurrent PH after PEA.

Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease.

OBJECTIVE: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH. MATERIALS AND METHODS: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays. RESULTS: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/ß-catenin activation. CONCLUSIONS: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.

Intravoxel incoherent motion diffusion-weighted imaging in assessing bladder cancer invasiveness and cell proliferation.

BACKGROUND: Nonmuscle-invasive bladder cancer (NMIBC, Stage T1 or lower) is treated with transurethral resection (TUR), while muscle-invasive bladder cancer (MIBC, Stage T2 or more) requires neoadjuvant chemotherapy before radical cystectomy. Hence, preoperative differentiation is vital. PURPOSE: To investigate whether intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) can differentiate NMIBC from MIBC and to assess whether there were correlations between IVIM parameters and the Ki-67 labeling index (LI). STUDY TYPE: Retrospective. SUBJECTS: Thirty-six patients diagnosed with bladder cancer confirmed by histopathological findings. FIELD STRENGTH/SEQUENCE: 3.0T magnetic resonance imaging (MRI) DWI with eight b-values ranging from 0 to 1000 s/mm2 . ASSESSMENT: Molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADC) were calculated by biexponential and monoexponential models fits, respectively. STATISTICAL TESTS: Comparisons were made between the MIBC and NMIBC group, and differences were analyzed by comparing the areas under the receiver-operating characteristic curves (AUCs). The correlations between these parameters and Ki-67 LI were assessed by Spearman's rank correlation analysis. RESULTS: The ADC and D value were significantly lower in patients with MIBC compared to those with NMIBC (P < 0.01). No significant (P > 0.05) differences were observed in D* and f. The AUC of D value (0.894) was significantly (P < 0.05) larger than the ADC value (0.786), with sensitivities and specificities of 95% and 87.5% (D) and 80% and 68.7% (ADC), respectively. In addition, the D and ADC values were significantly correlated with Ki-67 LI (r = -0.785, r = -0.643, respectively; both P < 0.01). DATA CONCLUSION: The D value obtained from IVIM exhibited better performance than conventional DWI for distinguishing NMIBC from MIBC and may serve as a potential imaging biomarker for bladder cancer invasion. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1054-1060.

Investigation of diffusion kurtosis imaging for discriminating tumors from inflammatory lesions after treatment for bladder cancer.

BACKGROUND: The bladder wall may thicken resulting from chronic inflammation after initial treatment (transurethral resection [TUR] or neoadjuvant chemotherapy), which may mimic the feature of recurrent or residual bladder tumors (RBT). Therefore, it is critical to discriminate RBT from benign lesions after initial treatment. PURPOSE: To investigate whether diffusion kurtosis imaging (DKI) could discriminate RBT from post-therapy bladder inflammatory lesions. STUDY TYPE: Retrospective. SUBJECTS: Fifty patients diagnosed with bladder cancer underwent TUR or received neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0T MRI/conventional T1 -weighted imaging (T1 WI), T2 WI, and diffusion-weighted imaging (DWI) with nine b-values ranging from 0-2000 s/mm2 . ASSESSMENT: Mean diffusion coefficients (MDa , MDb , and MDc ) and mean kurtosis values (MKa , MKb , and MKc ) were obtained from three different measurement methods. The region of interest (ROI) was placed 1) to encompass the entire portion of the thickening bladder wall or to portions that were the most restricted, with a b-value of 2) 2000 s/mm2 or 3) 1000 s/mm2 . STATISTICAL TESTS: The independent-samples t-test was used to compare the differences between RBT and the inflammatory group. Differences in DKI parameters were analyzed by comparing the areas under the receiver-operator characteristic curves (AUCs). RESULTS: In patients with RBT, the MD (MDa , MDb , MDc ) values were significantly lower and the MK (MKa , MKb , MKc ) values were significantly higher than those in patients in the inflammatory lesions group (all P < 0.01). The AUC of MKb (0.934) was significantly larger than those of MDb , MKa , and MKc (0.793, P < 0.05; 0.694, P < 0.01; 0.719, P < 0.01, respectively). DATA CONCLUSION: MK obtained from DKI provided better performance than conventional DWI in distinguishing RBT from inflammatory lesions after bladder cancer treatment. MK calculated with high b-values setting provided better performance in differentiation. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2017.

Impact of Visceral Obesity and Sarcopenia on Short-Term Outcomes After Colorectal Cancer Surgery.

BACKGROUND: With the increased prevalence of obesity and sarcopenia, those patients with both visceral obesity and sarcopenia were at higher risk of adverse outcomes. AIM: The aim of this study was to ascertain the combined impact of visceral obesity and sarcopenia on short-term outcomes in patients undergoing colorectal cancer surgery. METHODS: We conducted a prospective study from July 2014 to February 2017. Patients' demographic, clinical characteristics, physical performance, and postoperative short-term outcomes were collected. Patients were classified into four groups according to the presence of sarcopenia or visceral obesity. Clinical variables were compared. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. RESULTS: A total of 376 patients were included; 50.8 and 24.5% of the patients were identified as having "visceral obesity" and "sarcopenia," respectively. Patients with sarcopenia and visceral obesity had the highest incidence of total, surgical, and medical complications. Patients with sarcopenia or/and visceral obesity all had longer hospital stays and higher hospitalization costs. Age ≥ 65 years, visceral obesity, and sarcopenia were independent risk factors for total complications. Rectal cancer and visceral obesity were independent risk factors for surgical complications. Age ≥ 65 years and sarcopenia were independent risk factors for medical complications. Laparoscopy-assisted operation was a protective factor for total and medical complications. CONCLUSION: Patients with both visceral obesity and sarcopenia had a higher complication rate after colorectal cancer surgery. Age ≥ 65 years, visceral obesity, and sarcopenia were independent risk factors for total complications. Laparoscopy-assisted operation was a protective factor.

Sarcopenia: a new predictor of postoperative complications for elderly gastric cancer patients who underwent radical gastrectomy.

BACKGROUND: A geriatric assessment is needed to identify high-risk elderly patients with gastric cancer. However, the current geriatric assessment has been considered to be either time-consuming or subjective. The present study aimed to investigate the predictive effect of sarcopenia on the postoperative complications for elderly patients who underwent radical gastrectomy. MATERIALS AND METHODS: We conducted a prospective study of patients who underwent radical gastrectomy from August 2014 to December 2015. Computed tomography-assessed lumbar skeletal muscle, handgrip strength, and gait speed were measured to define sarcopenia. RESULTS: Sarcopenia was present in 69 of 240 patients (28.8%) and was associated with lower body mass index, lower serum albumin, lower hemoglobin, and higher nutritional risk screening 2002 scores. Postoperative complications significantly increased in the sarcopenic patients (49.3% versus 24.6%, P < 0.001), compared with nonsarcopenic patients. The multivariate analysis demonstrated that sarcopenia (odds ratio: 2.959, 95% CI: 1.629-5.373, P < 0.001) and the Charlson comorbidity index ≥2 (odds ratio: 3.357, 95% CI: 1.144-9.848, P = 0.027) were independent risk factors for postoperative complications. CONCLUSIONS: Sarcopenia, presented as a new geriatric assessment factor, was a strong and independent risk factor for postoperative complications of elderly patients with gastric cancer.

T2* mapping combined with conventional T2-weighted image for prostate cancer detection at 3.0T MRI: a multi-observer study.

BACKGROUND: T2* relaxation is a primary determinant of image contrast with Gradient echo (GRE) sequences, and it has been widely used across body regions. PURPOSE: To compare the diagnostic performance of T2* mapping in combination with T2-weighted (T2W) imaging to T2W imaging alone for prostate cancer (PCa) detection. MATERIAL AND METHODS: The study included 31 patients (mean age, 62 ± 3 years; age range, 45-78 years) who underwent magnetic resonance imaging (MRI) at 3.0T and histological examination. Three observers with varying experience levels reviewed T2W imaging alone, T2* mapping alone, and T2W imaging combined with T2* mapping. A five-point scale was used to assess the probability of PCa in each segment on MR images. Statistical analysis was performed using Z tests after adjusting for data clustering. RESULTS: The area under the curve (AUC) of T2W imaging and T2* mapping data (observer 1, 0.93; observer 2, 0.90; observer 3, 0.77) was higher than T2W imaging (observer 1, 0.84; observer 2, 0.79; observer 3, 0.69) for all observers (P < 0.01 in all comparisons). The AUC of T2W imaging and T2* mapping data was higher for observers 1 and 2 than for observer 3 (P < 0.01). The sensitivity and specificity of T2W imaging and T2* mapping data (observer 1, 95%, 85%; observer 2, 90%, 83%; and observer 3, 82%, 63%, respectively) was higher than T2W imaging (observer 1, 78%, 79%; observer 2, 76%, 72%; observer 3, 74%, 51%, respectively) for all observers (P < 0.01 for observer 1; P < 0.01 for observers 2 and 3). CONCLUSION: The addition of T2* mapping to T2W imaging improved the diagnostic performance of MRI in PCa detection.

Experimental realization of a 2 × 2 polarization-independent split-ratio-tunable optical beam splitter.

We realized a polarization-independent split-ratio-tunable optical beam splitter supporting two input and output ports through a stable interferometer. By adjusting the angle of a half-wave plate in the interferometer, we can tune the beam splitter reflectivities for both input ports from 0 to 1, regardless of the input light polarization. High-fidelity polarization-preserving transmission from input to output ports was verified by complete quantum process tomography. Nearly optimal interference effects at the beam splitter with various split ratios were observed by two-photon Hong-Ou-Mandel interference for different input polarization states. Such a beam splitter could find a variety of applications in classical and quantum optical technologies.

Imaging of upper urinary tract cancer: using conventional MRI and diffusion-weighted MRI with different b values.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) has been considered to be useful in diagnosing upper urinary tract (UUT) disease; however, the value of DW-MRI with different b values has not been reported. PURPOSE: To evaluate the performance of using conventional MRI alone and in combination with DWI with different b values in diagnosing UUT cancer. MATERIAL AND METHODS: Seventy patients with suspected UUT cancer underwent conventional MRI (T1-weighted and T2-weighted) and DW-MRI (b = 500 and 1500 s/mm(2)) on a 3 T-MRI scanner. The ureteroscopic and histopathologic findings were compared with the imaging findings. The utility of detecting UUT cancer using conventional MRI (set A), combined DW-MRI (b = 500 s/mm(2)) and conventional MRI (set B), and combined DW-MRI (b = 1500 s/mm(2)) and conventional MRI (set C) were independently evaluated by two readers. RESULTS: A total of 32 patients had verified cancer; 23 patients had benign UUT diseases, and 15 had no abnormality. Sets B and C had significantly improved diagnostic accuracy for UUT cancer compared with set A; the specificity in diagnosing UUT cancer was significantly improved when using set C compared with sets A and B. In patients without UUT obstructions, improved sensitivity and accuracy in diagnosis was achieved when using sets B and C compared with set A. CONCLUSION: Using DW-MRI in combination with conventional MRI provides increased diagnostic accuracy and sensitivity in patients without UUT obstruction. The combination of conventional MRI and DW-MRI with a higher b value (1500 s/mm(2)) improved the specificity in diagnosing UUT cancer compared to conventional sequences and DW-MRI with a lower b value (500 s/mm(2)).

[Expression of CD20 in B-cell precursor acute lymphoblastic leukemia and its correlation with clinical outcomes].

OBJECTIVE: To determine whether expression of CD20 is associated with clinical outcomes of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). METHODS: 271 newly diagnosed childhood BCP-ALL during January 2009 to May 2013 were enrolled in this study. The patients were treated in line with the Chinese Childhood Leukemia Group ALL 2008 protocol (CCLG-ALL 2008). The clinical feature, early therapeutic response and clinical outcomes of the patients with a CD20 positive (CD20+ BCP) expression were compared with those with a CD20 negative (CD20- BCP) expression. RESULTS: CD20- BCP accounted for 45.76% (124 cases) of all participants. There were no significant differences between CD20- BCP and CD20- BCP patients in gender distribution, age, WBC counts when diagnosis was made, proportion of prednisone poor responders, and distribution of risk categories (P > 0.05). Patients of 10 years or older comprised 25.81% and 14.29% of CD20+ BCP and CD20- BCP patients, respectively (P = 0.017). Pro-B and pre-B cases accounted for 43.55% and 59.86% of CD20- BCP patients respectively, compared with 56.45 and 40.14% in CD20- BCP patients (P = 0.007). CD20+ BCP patients had 12.20% Philadelphia positive ALL and 6.50% BCP-ALL with TEL-AML1 fusion gene, compared with 4.86% (P = 0.03) and 18.06% (P = 0.005) in those of CD20 BCP. No significant differences were found between the two groups of patients in 15-day (77.50% vs. 74.13%, P = 0.525) and 33-day (95.04% vs. 95.83%, P = 0.757) complete remission rates. No significant differences (P > 0.05) were found in predicted 4-year event-free survival CEFS (78.00% +/- 4.96%) vs. (79.05% +/- 5.40%)) and predicted 4-year overall survival (OS (83.01% +/- 6.13%) vs. (93.64% +/- 2.46%)) between the two groups of patients either. CONCLUSION: CD20 positivity was not found to be associated with worse prognosis of children with BCP-ALL. More studies are needed to validate the correlation between CD20 and unfavorable outcomes in BCP-ALL.

Exposure to 1-nitropyrene after weaning induces anxiety-like behavior partially by inhibiting steroid hormone synthesis in prefrontal cortex.

1-Nitropyrene (1-NP) is a neurodevelopmental toxicant. This study was to evaluate the impact of exposure to 1-NP after weaning on anxiety-like behavior. Five-week-old mice were administered with 1-NP (0.1 or 1 mg/kg) daily for 4 weeks. Anxiety-like behaviour was measured using elevated-plus maze (EPM) and open field test (OFT). In EPM test, time spending in open arm and times entering open arm were reduced in 1-NP-treated mice. In OFT test, time spent in the center region and times entering the center region were diminished in 1-NP-treated mice. Prefrontal dendritic length and number of dendrite branches were decreased in 1-NP-treated mice. Prefrontal PSD95, an excitatory postsynaptic membrane protein, and gephyrin, an inhibitory postsynaptic membrane protein, were downregulated in 1-NP-treated mice. Further analysis showed that peripheral steroid hormones, including serum testosterone (T) and estradiol (E2), testicular T, and ovarian E2, were decreased in 1-NP-treated mice. Interestingly, T and E2 were diminished in 1-NP-treated prefrontal cortex. Prefrontal T and E2 synthases were diminished in 1-NP-treated mice. Mechanistically, GCN2-eIF2α, a critical pathway that regulates ribosomal protein translation, was activated in 1-NP-treated prefrontal cortex. These results indicate that exposure to 1-NP after weaning induces anxiety-like behaviour partially by inhibiting steroid hormone synthesis in prefrontal cortex.

Biventricular intraventricular mechanical and electrical dyssynchrony in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) leads to myocardial remodeling, manifesting as mechanical dyssynchrony (M-dys) and electrical dyssynchrony (E-dys), in both right (RV) and left ventricles (LV). However, the impacts of layer-specific intraventricular M-dys on biventricular functions and its association with E-dys in PAH remain unclear. Methods: Seventy-nine newly diagnosed patients with PAH undergoing cardiac magnetic resonance scanning were consecutively recruited between January 2011 and December 2017. The biventricular volumetric and layer-specific intraventricular M-dys were analyzed. The QRS duration z-scores were calculated after adjusting for age and sex. Results: 77.22 % of patients were female (mean age 30.30 ± 9.79 years; median follow-up 5.53 years). Further, 29 (36.71 %) patients succumbed to all-cause mortality by the end of the study. At the baseline, LV layer-specific intraventricular M-dys had apparent transmural gradients compared with RV in the radial and circumferential directions. However, deceased patients lost the transmural gradients. The LV longitudinal strain rate time to late diastolic peak in the myocardial region (LVmyoLSRTTLDPintra) predicted long-term survival. The Kaplan-Meier curve revealed that patients with PAH with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. Larger right ventricle (RV) intraventricular M-dys resulted in worse RV ejection fraction. However, larger LV intraventricular M-dys in the late diastolic phase indicated remarkable exercise capacity and higher LV stroke volume index. E-dys and intraventricular M-dys had no direct correlations. Conclusions: The layer-specific intraventricular M-dys had varying impacts on biventricular functions in PAH. PAH patients with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. LV intraventricular M-dys in the late diastolic phase needs more attention to precisely evaluate LV function.

Imaging characteristics and prognostic factors of Behcet's disease with arterial involvement: A long-term follow-up study.

PURPOSE: To investigate the imaging characteristics and prognostic factors for the long-term survival of Behcet's disease (BD) with arterial involvement. METHODS: In this retrospective study, BD patients with arterial involvement were identified from January 2003 to January 2020. Arterial lesions were detected by ultrasonography, traditional arteriography, and/or computed tomography angiography (CTA). Cox proportional hazards regression analyses were performed to identify the prognostic factors. RESULTS: Totally, 84 BD patients with arterial involvement were identified (73.8 % males). The mean age at BD diagnosis was 39.1 ± 13.1 years. Arterial involvement was the initial manifestation in 33.3 % of the patients, and the median time from BD diagnosis to arterial involvement was 6 (IQR 1-15.5) years for the rest of patients. Systemic artery involvement and pulmonary artery involvement (PAI) were found in 64 and 27 patients, respectively. Approximately 94.0 % (79/84) of the patients had more than one artery involved concurrently or successively during the course of BD. Aneurysm/dilation was the most prevalent lesion in the aorta (76.0 %), while stenosis/occlusion was the main lesion of the coronary artery (90.9 %) and other aortic branches (74.5 %). Pulmonary hypertension was found in 70.4 % (19/27) of patients with PAI. The 5- and 10-year survival rates of BD patients with arterial involvement were 87.4 % and 84.1 %, respectively. Cardiac involvement (HR: 4.34) and pulmonary artery aneurysm/dilation (HR: 4.89) were independently associated with mortality. CONCLUSIONS: Arterial lesions associated with BD usually involve multiple arteries and manifest differently in different types of arteries. Cardiac involvement and pulmonary artery aneurysm/dilation are independent prognostic factors of BD patients with arterial involvement.

Prenatal 1-Nitropyrene Exposure Causes Autism-Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.

GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis.

BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent TGFß superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH). PROCEDURES: We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children. RESULTS: Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain. CONCLUSIONS: Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux.

[Difference in effect between asthma-based mouse model and Stemona tuberosa extracts].

In this study, OVA-induced asthma mice was taken as the model, and orally administered with different concentration of ethanol extracts of crude and processed Stemona tuberosa, in order to determine the cytokine level released from Th1 and Th2 in splenocytes. RT-PCR was carried out to determine the genetic expression of T-bet/GATA-3 in lung, and compare the differentiation between ethanol extracts of crude and processed S. tuberosa in therapeutic effect on asthma in mice. According to the results, compared with the crude samples, processed samples significantly increased the levels of inflammatory factor INF-gamma (P < 0.05) and decreased IL-5 (P < 0.05) in splenocytes. According to the RT-PCR results, the administration of processed samples could increase the ratio of T-bet/GATA-3 (P < 0.05). The experiment showed that ethanol extracts of both crude and processed S. tuberosa could treat asthma by regulating Th1/Th2 ratio, but processed samples showed more notable effect. This indicated that crude and processed S. tuberosa had significant pharmacological difference. Therefore, it was more rational to apply processed S. tuberosa in clinical treatment of asthma and chronic cough, which layed a foundation for further revealing the processing mechanism of S. tuberosa.

Right heart thrombus in acute pulmonary embolism: A single center experience in China.

Right heart thrombus (RHT) is a rare but life-threatening condition in acute pulmonary embolism (APE) without clear management guidelines. This study aimed to address the clinical characteristics and outcomes of RHT-APE in Chinese patients. In this study, 17 RHT-APE and 329 non-RHT-APE patients, who were diagnosed between September 2015 and August 2019, were retrospectively recruited with the median follow-up was 360 days. The overall prevalence of RHT was 4.91% in APE. Its prevalence increased along the increase of APE risk stratifications. Comparisons showed that with higher proportion of male gender and younger age, RHT-APE patients also had worse hemodynamic instability and heart function, and higher risk stratification levels than non-RHT-APE patients. After adjusting by age and gender, multivariate logistic regression analysis found high/intermediate-high risk stratification, decreased right ventricular (RV) motion, NT-proBNP >600 pg/mL, and RV dysfunction were risk factors for RHT. Kaplan-Meier analysis showed non-RHT had better prognosis than RHT patients (30-day survival: log-rank: p < 0.001; 90-day survival: log-rank: p = 0.002). The multivariate logistic regression analysis showed RHT was an independent risk factor for 30-day mortality in APE. The subgroup analysis showed RHT would result in worse outcomes in patients who already had higher APE early mortality risk. RHT would increase the risk of 30- and 90-day mortality in APE. More attention should be paid to young male APE patients with decreased RV motion, NT-proBNP >600 pg/mL, RV dysfunction, or high level of risk stratification, to exclude the coexistence of RHT.

Gestational 1-nitropyrene exposure causes anxiety-like behavior partially by altering hippocampal epigenetic reprogramming of synaptic plasticity in male adult offspring.

1-Nitropyrene (1-NP), a typical nitro-polycyclic aromatic hydrocarbon, is a developmental toxicant. This study was to evaluate gestational 1-NP-induced anxiety-like behavior in male adult offspring. Pregnant mice were orally administered to 1-NP daily throughout pregnancy. Anxiety-like behaviors, as determined by Elevated Plus-Maze (EPM) and Open-Field Test (OFT), were showed in male adult offspring whose mothers were exposed to 1-NP. Gestational 1-NP exposure reduced dendritic arborization, dendritic length and dendritic spine density in ventral hippocampus of male adult offspring. Additional experiments showed that gephyrin, an inhibitory synaptic marker, was reduced in fetal forebrain and hippocampus in male adult offspring. Nrg1 and Erbb4, two gephyrin-related genes, were reduced in 1-NP-exposed fetuses. Accordingly, 5hmC contents in two CpG sites (32008909 and 32009239) of Nrg1 gene and three CpG sites (69107743, 69107866 and 69107899) of Erbb4 gene were decreased in 1-NP-exposed fetuses. Mechanistically, ten-eleven translocation (TET) activity and alpha-ketoglutarate (α-KG) content were decreased in 1-NP-exposed fetal forebrain. Supplementation with α-KG alleviated 1-NP-induced downregulation of gephyrin-related genes, prevented hippocampal synaptic damage, and improved anxiety-like behavior in male adult offspring. These results indicate that early-life 1-NP exposure causes anxiety-like behavior in male adulthood partially by altering hippocampal epigenetic reprogramming of synaptic plasticity.