SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms.

Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.

Altered perivascular spaces in subcortical white matter in Parkinson's disease patients with levodopa-induced dyskinesia.

Dilated perivascular spaces (PVS) have emerged as a pathological hallmark in various neurological conditions, including Parkinson's disease (PD). Levodopa-induced dyskinesia (LID), an intractable motor complication of PD, remains enigmatic regarding the distribution patterns of PVS. Our objective was to scrutinize the percent PVS (pPVS) changes within PD patients with LID (PD-LID). In total, 132 individuals were enrolled, including PD-LID (n = 42), PD patients without LID (PD-nLID, n = 45), and healthy controls (HCs, n = 45). Employing an automated approach for PVS quantification based on structural magnetic resonance imaging, we comprehensively evaluated total pPVS in subcortical white matter globally and regionally. A significant increase in global pPVS was observed in PD patients versus HCs, particularly evident in PD-LID relative to HCs. Within the PD-LID group, elevated pPVS was discerned in the right inferior frontal gyrus region (rIFG) (pars opercularis), contrasting with PD-nLID and HCs. Moreover, PD patients exhibited increased pPVS in bilateral superior temporal regions compared to HCs. Notably, pPVS in the rIFG positively correlated with dyskinetic symptoms and could well identify LID. Our findings unveiled PVS alternations in subcortical white matter in PD-LID at both global and regional levels, highlighting the increased pPVS in rIFG as a prospective imaging marker for LID.

Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study.

BACKGROUND: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). OBJECTIVE: The aim was to reveal the mechanisms of "OFF-period" FOG (OFF-FOG) and "levodopa-unresponsive" FOG (ONOFF-FOG) in PD. METHODS: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF-FOG, 15 PD patients with OFF-FOG, and 15 PD patients without FOG (Non-FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF-FOG patients. RESULTS: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF-FOG and OFF-FOG) compared to Non-FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF-FOG patients reduced compared to OFF-FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF-FOG patients, and high-frequency repetitive TMS distinctly improved gait in ONOFF-FOG patients, accompanied by enhanced SICI. CONCLUSIONS: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF-FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dynamic functional connectivity reveals hyper-connected pattern and abnormal variability in freezing of gait of Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. METHODS: In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. RESULTS: Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). CONCLUSIONS: Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG.

Purple Yam Polyphenol Extracts Exert Anticolitis and Anticolitis-Associated Colorectal Cancer Effects through Inactivation of NF-κB/p65 and STAT3 Signaling Pathways.

Colorectal cancer is a malignancy with high incidence and mortality worldwide, and ulcerative colitis (UC) is strongly associated with colorectal cancer. Purple yam, also known as Dioscorea alata, has been reported to be rich in plant polyphenols that have possessed anti-inflammatory, antioxidant, and antitumor properties. However, it is not clear whether purple yam polyphenol extracts (PYPE) can improve colitis and inhibit colitis-related colorectal tumorigenesis. Therefore, we used dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer (CAC) models in mice to evaluate the preventive value and possible mechanisms of PYPE. It was found that PYPE effectively alleviated DSS-induced colitis, inhibited macrophage infiltration, and reduced the production of the pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1ß, IL-17A, CXCL1, and MCP-1, and the higher the concentration of PYPE, the better the inhibitory effect. In addition, PYPE dramatically prevented the development of CAC and tumor proliferation in mice. Furthermore, PYPE inactivated NF-κB and STAT3 signaling to exert anti-inflammatory and anticancer effects. Taken together, these findings indicate that PYPE may be used as a promising preventive strategy against UC and CAC.

Transcutaneous auricular vagus nerve stimulation improves gait and cortical activity in Parkinson's disease: A pilot randomized study.

OBJECTIVE: In this randomized, double-blind, sham-controlled trial, we explored the effect of 20 Hz transcutaneous auricular vagus nerve stimulation (taVNS) on gait impairments in Parkinson's disease (PD) patients and investigated the underlying neural mechanism. METHODS: In total, 22 PD patients and 14 healthy controls were enrolled. PD patients were randomized (1:1) to receive active or sham taVNS (same position as active taVNS group but without releasing current) twice a day for 1 week. Meanwhile, all subjects were measured activation in the bilateral frontal and sensorimotor cortex during usual walking by functional near-infrared spectroscopy. RESULTS: PD patients showed instable gait with insufficient range of motion during usual walking. Active taVNS improved gait characteristics including step length, stride velocity, stride length, and step length variability compared with sham taVNS after completion of the 7-day therapy. No difference was found in the Unified Parkinson's Disease Rating Scale III, Timed Up and Go, Tinetti Balance, and Gait scores. Moreover, PD patients had higher relative change of oxyhemoglobin in the left dorsolateral prefrontal cortex, pre-motor area, supplementary motor area, primary motor cortex, and primary somatosensory cortex than HCs group during usual walking. Hemodynamic responses in the left primary somatosensory cortex were significantly decreased after taVNS therapy. CONCLUSION: taVNS can relieve gait impairments and remodel sensorimotor integration in PD patients.

Aberrant voxel-based degree centrality and functional connectivity in Parkinson's disease patients with fatigue.

AIMS: The study aimed to investigate alterations in the inherent connectivity pattern of global functional networks in Parkinson's disease (PD) patients with fatigue. METHODS: Eighteen PD patients with fatigue (PD-F), 20 PD patients without fatigue (PD-NF), and 23 healthy controls (HCs) were recruited and analyzed by the voxel-wise degree centrality (DC) and the seed-based functional connectivity (FC) analysis. Meanwhile, the surface-based morphometry (SBM) analysis was also commanded to explore the structural alternations among groups. RESULTS: PD-F patients displayed reduced DC values in the left postcentral gyrus relative to PD-NF and HCs groups, while increased DC values in the bilateral precuneus compared to HCs. Simultaneously, altered DC value in the left postcentral gyrus negatively corresponded to the mean fatigue severity scale (FSS) in PD-F patients. Additionally, the receiver operating characteristic (ROC) curves uncovered that the reduced DC value of the left postcentral gyrus could discriminate PD-F from PD-NF and HCs groups. Our FC analysis further revealed that altered FC was located predominantly in the sensorimotor network in the PD-F group. Moreover, we discovered no statistically significant differences between the three groups concerning cortical thickness. CONCLUSION: Our findings indicated that the altered functional connectivity in the sensorimotor network centering on the left postcentral gyrus and the bilateral precuneus might be the potential pathogenesis of PD with fatigue.

Cholinergic basal forebrain atrophy in Parkinson's disease with freezing of gait.

BACKGROUND: Mounting research support that cholinergic dysfunction plays a prominent role in freezing of gait (FOG), which commonly occurs in Parkinson's disease (PD). Basal forebrain (BF), especially the cholinergic nuclei 4 (Ch4), provides the primary source of the brain cholinergic input. However, whether the degeneration of BF and its innervated cortex contribute to the pathogenesis of FOG is unknown. OBJECTIVE: To explore the role of structural alterations of BF and its innervated cortical brain regions in the pathogenesis of PD patients with freezing. METHODS: Magnetic resonance imaging assessments and neurological assessments were performed on 20 PD patients with FOG (PD-FOG), 20 without FOG (PD-NFOG), and 21 healthy participants. Subregion volumes of the BF were compared among groups. Local gyrification index (LGI) was computed to reveal the cortical alternations. Relationships among subregional BF volumes, LGI, and the severity of FOG were evaluated by multiple linear regression. RESULTS: Our study discovered that, compared to PD-NFOG, PD-FOG exhibited significant Ch4 atrophy (p = 4.6 × 10-5 ), accompanied by decreased LGI values in the left entorhinal cortex (p = 3.00 × 10-5 ) and parahippocampal gyrus (p = 2.90 × 10-5 ). Based on the regression analysis, Ch4 volume was negatively associated with FOG severity in PD-FOG group (ß = -12.224, T = -2.556, p = 0.031). INTERPRETATION: Our results imply that Ch4 degeneration and microstructural disorganization of its innervated cortical brain regions may play important roles in PD-FOG.

Impaired structural and reserved functional topological organizations of brain networks in Parkinson's disease with freezing of gait.

Background: Freezing of gait (FOG) is a common disabling motor disturbance in Parkinson's disease (PD). Our study aimed to probe the topological organizations of structural and functional brain networks and their coupling in FOG. Methods: In this cross-sectional retrospective study, a total of 30 PD patients with FOG (PD-FOG), 40 patients without FOG, and 25 healthy controls (HCs) underwent clinical assessments and magnetic resonance imaging (MRI) scanning. Large-scale structural and functional brain networks were constructed. Subsequently, global and nodal graph theoretical properties and functional-structural coupling were investigated. Finally, correlations between the altered brain topological properties and freezing severity were analyzed in PD-FOG. Results: For structural networks, at the global level, PD-FOG exhibited increased normalized characteristic path length (P=0.040, Bonferroni-corrected) and decreased global efficiency (P=0.005, Bonferroni-corrected) compared with controls, and showed reduced global (P=0.001, Bonferroni-corrected) and local (P=0.032, Bonferroni-corrected) efficiency relative to patients without FOG. At the nodal level, nodal efficiency of structural networks was reduced in PD-FOG compared with PD patients without FOG, located in the left supplementary motor area (SMA), gyrus rectus, and middle cingulate cortex (MCC) (all P<0.05, Bonferroni-corrected). Notably, altered global and nodal properties of structural networks were significantly correlated with Freezing of Gait Questionnaire scores [all P<0.05, false discovery rate (FDR)-corrected]. However, only an increase in local efficiency (P=0.003, Bonferroni-corrected) of functional networks was identified in PD-FOG compared with those without FOG. No significant structural-functional coupling was detected among the 3 groups. Conclusions: This study demonstrates the extensively impaired structural and relatively reserved functional network topological organizations in PD-FOG. Our results also provide evidence that the pathogenesis of PD-FOG is primarily attributable to network vulnerability established by crucial structural damage, especially in the left SMA, gyrus rectus, and MCC.

Altered dynamic functional network connectivity in levodopa-induced dyskinesia of Parkinson's disease.

AIMS: The aim of this study was to clarify the dynamic neural activity of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). METHODS: Using dynamic functional network connectivity (dFNC) analysis, we evaluated 41 PD patients with LID (LID group) and 34 PD patients without LID (No-LID group). Group spatial independent component analysis and sliding-window approach were employed. Moreover, we applied a k-means clustering algorithm on windowed functional connectivity (FC) matrices to identify reoccurring FC patterns (i.e., states). RESULTS: The optimal number of states was determined to be five, the so-called State 1, 2, 3, 4, and 5. In ON phase, compared with No-LID group, LID group occurred more frequently and dwelled longer in strongly connected State 1, characterized by strong positive connections between visual network (VIS) and sensorimotor network (SMN). When switching from OFF to ON phase, LID group occurred less frequently in State 3 and State 4. Meanwhile, LID group dwelled longer in State 2 and shorter in State 3. No-LID group occurred more frequently in State 5 and less frequently in State 3. Additionally, correlation analysis demonstrated that dyskinesia's severity was associated with frequency of occurrence and dwell time in State 2, dominated by inferior frontal cortex in cognitive executive network (CEN). CONCLUSION: Using dFNC analysis, we found that dyskinesia may be related to the dysfunctional inhibition of CEN on motor loops and excessive excitation of VIS and SMN, which provided evidence of the changes in brain dynamics associated with the occurrence of dyskinesia.

Reduced Short-Latency Afferent Inhibition in Parkinson's Disease Patients with L-dopa-Unresponsive Freezing of Gait.

BACKGROUND: Freezing of gait (FOG) in Parkinson's disease (PD), especially the "L-dopa-unresponsive" subtype, is associated with the dysfunction of non-dopaminergic circuits. OBJECTIVE: We sought to determine whether cortical sensorimotor inhibition evaluated by short-latency afferent inhibition (SAI) related to cholinergic and gamma-aminobutyric acid (GABA)-ergic activities is impaired in PD patients with L-dopa-unresponsive FOG (ONOFF-FOG). METHODS: SAI protocol was performed in 28 PD patients with ONOFF-FOG, 15 PD patients with "off" FOG (OFF-FOG), and 25 PD patients without FOG during medication "on" state. Additionally, 10 ONOFF-FOG patients underwent SAI testing during both "off" and "on" states. Twenty healthy controls participated in this study. Gait was measured objectively using a portable Inertial Measurement Unit system, and participants performed 5-meter Timed Up and Go single- and dual-task conditions. Spatiotemporal gait characteristics and their variability were determined. FOG manifestations and cognition were assessed with clinical scales. RESULTS: Compared to controls, PD patients without FOG and with OFF-FOG, ONOFF-FOG PD patients showed significantly reduced SAI. Further, dopaminergic therapy had no remarkable effect on this SAI alterations in ONOFF-FOG. Meanwhile, OFF-FOG patients presented decreased SAI only relative to controls. PD patients with ONOFF-FOG exhibited decreased gait speed, stride length, and increased gait variability relative to PD patients without FOG and controls under both walking conditions. For ONOFF-FOG patients, significant associations were found between SAI and FOG severity, gait characteristics and variability. CONCLUSION: Reduced SAI was associated with severe FOG manifestations, impaired gait characteristics and variability in PD patients with ONOFF-FOG, suggesting the impaired thalamocortical cholinergic-GABAergic SAI pathways underlying ONOFF-FOG.

Altered functional connectivity of cerebellar dentate nucleus in peak-dose dyskinesia in Parkinson's disease.

The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the z-FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the z-FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.

BDNF rs6265 single-nucleotide polymorphism is involved in levodopa-induced dyskinesia in Parkinson's disease via its regulation of the cortical thickness of the left postcentral gyrus.

Background: Brain-derived neurotrophic factor (BDNF) gene rs6265 single-nucleotide polymorphism (SNP) is thought to be involved in neuroplasticity and influence the development of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). This study aimed to determine how the BDNF rs6265 SNP regulates cortical thickness and to investigate the association between BDNF and the pathological mechanisms of LID in PD. Methods: This cross-sectional study recruited 75 patients with PD, including 37 patients with LID and 38 patients without LID, and 33 healthy controls. All the participants underwent T1-weighted magnetic resonance imaging (MRI) scans, clinical evaluations, and BDNF rs6265 genotyping. Two-way factorial analysis of covariance (ANCOVA) was used to explore the primary effects of disease status, rs6265 genotype, and their interactions on cortical thickness. Associations between cortical thickness in the regions of the brain affected by disease status-genotype interactions and clinical symptoms were detected using Spearman's rank-order correlation. Receiver operating characteristic (ROC) curve analysis was used to test cortical thickness measurements as an indicator of LID. Results: The main effects of disease status were observed in the right pars orbitalis (F=4.229, P=0.017), medial orbitofrontal cortex (F=3.639, P=0.030), and left banks superior temporal sulcus (F=3.172, P=0.046). The left pars orbitalis (F=4.541, P=0.036) and lingual gyrus (F=4.307, P=0.041) were thicker in carriers of the CC genotype than in carriers of the TC/TT genotype. Interaction between disease status and genotype showed that in the LID group, carriers of the CC genotype had a thicker left postcentral gyrus (mean difference =0.103, 95% confidence interval, 0.036 to 0.107, Bonferroni-corrected P<0.005) than did carriers of the TC/TT genotype, whereas no difference was found in the non-LID and healthy control (HC) groups. In carriers of the CC genotype, the cortical thickness of the left postcentral gyrus could identify whether patients with PD had LID, with an area under the receiver operating curve (AUC) of 0.757 (P=0.033, optimal cut-off =2.102). The cortical thickness of the left postcentral gyrus was also positively correlated with the Unified Dyskinesia Rating Scale (UDysRS) score in the LID-CC subgroup (r=0.825, P=0.001). Conclusions: The BDNF rs6265 SNP might be associated with dyskinesia symptoms in patients with PD and LID through its regulation of cortical thickness in the left postcentral gyrus.

Management of Sonographically Suspicious Thyroid Nodules 1 cm or Smaller and Candidacy for Active Surveillance: Experience of a Tertiary Center in China.

OBJECTIVE: Our objective was to investigate the management of patients with asymptomatic suspicious thyroid nodules ≤1 cm. METHODS: We retrospectively reviewed medical records of patients with sonographically suspicious thyroid nodules ≤1 cm and without distant metastases, suspicious lymph node metastasis (LNM), or extrathyroidal extension (ETE). RESULTS: Of the 386 enrolled patients, 174 (45.1%) had immediate surgery (IS), while 212 (54.9%) underwent active surveillance (AS). In the IS group, 166 (95.4%) patients were confirmed as having papillary thyroid microcarcinoma. LNM and ETE were observed in 24.7% and 2.4% cases, respectively. In the AS group, nodule size increased by ≥3 mm in 11 (5.2%) patients and 39 (18.4%) had a >50% increase in nodule volume after a median follow-up of 12 months. Nodules with smaller volume at diagnosis were more likely to increase in volume later. Newly suspicious LNM was detected in 23 (10.8%) patients. Delayed surgery (DS) was performed in 101 patients, with 27 showing disease progression. ETE and LNM were detected in 3% and 36%, respectively, of patients with papillary thyroid microcarcinoma. Compared with IS, tumors in the DS group more frequently showed lateral LNM and capsular invasion (P < .05). No patient had recurrence or died of thyroid cancer during postoperative follow-up (median 26 [4-60] months). CONCLUSIONS: IS or DS of patients with asymptomatic suspicious thyroid nodules ≤1 cm was relatively high in China. The inertia of low-risk nodules and the effectiveness of DS for those that progressed make AS a feasible strategy.

BRAF V600E vs. TIRADS in predicting papillary thyroid cancers in Bethesda system I, III, and V nodules.

OBJECTIVE: Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories I, III, and V account for a significant proportion of fine needle aspiration cytology (FNAC) diagnoses. This study aimed to compare the diagnostic efficacy of BRAF V600E mutation and the Thyroid Imaging Reporting and Data System (TIRADS) classification in differentiating papillary thyroid cancers (PTCs) from benign lesions among BSRTC I, III, and V nodules. METHODS: A total of 472 patients with 479 nodules were enrolled in this prospective study. Ultrasound, BRAF V600E mutation testing, and FNAC were performed in each nodule, followed by surgery or regular ultrasound examination. RESULTS: In the BSRTC I category, BRAF V600E showed similar sensitivity, higher specificity, and lower accuracy when compared with TIRADS. In the BSRTC III/V category, the sensitivity, specificity, and accuracy of BRAF V600E were similar to those of TIRADS. In comparison to BRAF V600E alone, the combination of the two methods significantly improved sensitivity (BSRTC I: 93.6% vs. 67.7%, P < 0.01; BSRTC III: 93.8% vs. 75.0%, P < 0.01; BSRTC V: 96.0% vs. 85.3%, P < 0.001). When compared with TIRADS alone, the combination improved sensitivity in BSRTC I nodules (93.6% vs. 74.2%, P < 0.05), increased sensitivity and decreased accuracy in BSRTC III nodules (93.8% vs. 75.0%, P < 0.01, 91.0% vs. 93.6%, P < 0.01), and improved both sensitivity and accuracy in BSRTC V nodules (96.0% vs. 82.0%, P < 0.001; 94.2% vs. 81.3%, P < 0.001). CONCLUSIONS: BRAF V600E exhibited higher specificity and lower accuracy compared with TIRADS in BSRTC I nodules, while the two methods showed similar diagnostic value in BSRTC III/V nodules. The combination of the two methods distinctly improved sensitivity in the diagnosis of PTCs in BSRTC I, III, and V nodules.

MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport-An anti-atherogenic function of ERK1/2 inhibition.

Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). In this study, we investigated if inhibition of ERK1/2 can activate macrophage ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDL in vitro, and they enhanced reverse cholesterol transport (RCT) in vivo. ApoE deficient (apoE(-/-)) mice receiving U0126 treatment had reduced sinus lesions in the aortic root which was associated with activated macrophage ABCG1 expression in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 expression by MEK1/2 inhibitors was associated with activation of SIRT1, a positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two negative regulators of LXR activity. Taken together, our study suggests that MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell formation and lesion development by multiple mechanisms, supporting the concept that ERK1/2 inhibition is anti-atherogenic.

MEK1/2 inhibitors induce interleukin-5 expression in mouse macrophages and lymphocytes.

Uptake of oxidized low-density lipoprotein (oxLDL) by macrophages facilitates the formation of foam cells, the prominent part of atherosclerotic lesions. Interleukin-5 (IL-5) is a cytokine regulating interactions between immune cells. It also activates the production of T15/EO6 IgM antibodies in B-1 cells, which can bind oxLDL thereby demonstrating anti-atherogenic properties. We previously reported that inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by mitogen-activated protein kinase kinases 1/2 (MEK1/2) inhibitors can reduce atherosclerosis. In this study, we determined the effects of MEK1/2 inhibitors on IL-5 production both in vitro and in vivo. In vitro, MEK1/2 inhibitors (PD98059 and U0126) substantially inhibited phosphorylation of MEK1/2 and ERK1/2. Associated with inhibition of ERK1/2 phosphorylation both in vitro and in vivo, MEK1/2 inhibitors induced IL-5 protein expression in macrophages (RAW macrophages and peritoneal macrophages) and lymphocytes (EL-4 cells). In vivo, administration of mice with MEK1/2 inhibitors increased serum IL-5 levels, and IL-5 protein expression in mouse spleen and liver. At the mechanistic level, we determined that MEK1/2 inhibitors activated IL-5 mRNA expression and IL-5 promoter activity in the liver X receptor (LXR) dependent manner indicating the induction of IL-5 transcription. In addition, we determined that MEK1/2 inhibitors enhanced IL-5 protein stability. Taken together, our study demonstrates that MEK1/2 inhibitors induce IL-5 production which suggests another anti-atherogenic mechanism of MEK1/2 inhibitors.

DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux-an LXR-dependent mechanism.

ATP-binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux and thereby inhibits lipid-laden macrophage/foam cell formation and atherosclerosis. ABCA1 expression is transcriptionally regulated by activation of liver X receptor (LXR). Both etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors and are chemotherapeutic medications used in the treatment of various cancers. Interestingly, etoposide inhibits atherosclerosis in rabbits by unclear mechanisms. Herein, we report the effects of etoposide and teniposide on macrophage ABCA1 expression and cholesterol efflux. Both etoposide and teniposide increased macrophage free cholesterol efflux. This increase was associated with increased ABCA1 mRNA and protein expression. Etoposide and teniposide also increased ABCA1 promoter activity in an LXR-dependent manner and formation of the LXRE-LXR/RXR complex indicating that transcriptional induction had occurred. Expression of ABCG1 and fatty acid synthase (FAS), another two LXR-targeted genes, was also induced by etoposide and teniposide. In vivo, administration of mice with either etoposide or teniposide induced macrophage ABCA1 expression and enhanced reverse cholesterol transport from macrophages to feces. Taken together, our study indicates that etoposide and teniposide increase macrophage ABCA1 expression and cholesterol efflux that may be attributed to the anti-atherogenic properties of etoposide. Our study also describes a new function for Topo II inhibitors in addition to their role in anti-tumorigenesis.