18F- or 177Lu-labeled bivalent ligand of fibroblast activation protein with high tumor uptake and retention.

PURPOSE: Fibroblast activation protein (FAP) has become a promising cancer-related target for diagnosis and therapy. The aim of this study was to develop a bivalent FAP ligand for both diagnostic PET imaging and endoradiotherapy. METHODS: We synthesized a bivalent FAP ligand (ND-bisFAP) and labeled it with 18F or 177Lu. FAP-positive A549-FAP cells were used to study competitive binding to FAP, cellular internalization, and efflux properties in vitro. Micro-PET imaging with [18F]AlF-ND-bisFAPI was conducted in mice bearing A549-FAP or U87MG tumors. Biodistribution and therapeutic efficacy of [177Lu]Lu-ND-bisFAPI were conducted in mice bearing A549-FAP tumors. RESULTS: The FAP binding affinity of ND-bisFAPI is 0.25 ± 0.05 nM, eightfold higher in potency than the monomeric DOTA-FAPI-04 (IC50 = 2.0 ± 0.18 nM). In A549-FAP cells, ND-bisFAPI showed specific uptake, a high internalized fraction, and slow cellular efflux. Compared to the monomeric [18F]AlF-FAPI-42, micro-PET imaging with [18F]AlF-ND-bisFAPI showed higher specific tumor uptake and retention for at least 6 h. Biodistribution studies showed that [177Lu]Lu-ND-bisFAPI had higher tumor uptake than [177Lu]Lu-FAPI-04 at the 24, 72, 120, and 168 h time points (all P < 0.01). [177Lu]Lu-ND-bisFAPI delivered fourfold higher radiation than [177Lu]Lu-FAPI-04 to A549-FAP tumors. For the endoradiotherapy study, 37 MBq of [177Lu]Lu-ND-bisFAPI significantly reduced tumor growth compared to the same dose of [177Lu]Lu-FAPI-04. Half of the dose of [177Lu]Lu-ND-bisFAPI (18.5 MBq) has comparable median survival as 37 MBq of [177Lu]Lu-FAPI-04 (37 vs 36 days). CONCLUSION: The novel bivalent FAP ligand was developed as a theranostic radiopharmaceutical and showed promising properties including higher tumor uptake and retention compared to the established radioligands [18F]AlF-FAPI-42 and [177Lu]Lu-FAPI-04. Preliminary experiments with 18F- or 177Lu-labeled ND-bisFAPI showed promising imaging properties and favorable anti-tumor responses.

A home-made sampling system coupled to hectowatt-MPT mass spectrometry in positive ion mode to confirm target ions of copper and zinc from Poyang Lake, China.

A novel home-made H2SO4-Nafion (HN) tube sampling system coupled to a line ion trap mass spectrometer (LTQ-MS) with a versatile ambient ionization source, hectowatt microwave plasma torch (HMPT), has manifested unique advantages for picking directly metal elements in aqueous samples and acquiring the fully characteristic MPT mass spectra of copper and zinc composite ions. Here, we report the development of a novel HN-HMPT-LTQ-MS for metal elements assay based on environmental water to analyze samples of Poyang Lake, China. Detailed multi-stage tandem mass spectra show that the general structural form of target ions is [M(NO3)x(H2O)y(OH)z]+ for the positive ion mode. Under the optimized conditions, the proposed method provided low limits of detection (LODs) of 0.23 µg.L-1 for 63Cu+ and 1.1 µg.L-1 for 66Zn+, with relative standard deviations (RSDs) of less than 12.7% by MPT-LTQ-MS. This new result has met the requirements of national standards (GB 5750.6-2006) and is only about one magnitude order larger than the LOD of ICP-MS method. A wide linear response range of about 4 orders of magnitude for the method with linear coefficients (R2) of 0.99709 - 0.99962 for copper and zinc tested was in accordance with that of ICP-MS. Except for the recovery of 79% for the third sample and 123.8% for the seventh sample, the present method also provided good recoveries (84 - 119.3%) in spiked 10 batches of drinking water samples. Furthermore, it is envisioned that the developed approach might build a powerful hectowatt-MPT-MS platform for food security detection, drug analysis, and origin traceability.

Repetitive transcranial magnetic stimulation improves consciousness in some patients with disorders of consciousness.

OBJECTIVE: To investigate the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with disorders of consciousness. DESIGN AND SETTING: We performed a randomized, double-blinded, sham-controlled trial. PARTICIPANTS: Patients (N = 40) with disorders of consciousness. INTERVENTIONS: Forty patients with disorders of consciousness (time since onset of the disorder 49.0 ± 24.6 days) were enrolled and randomized to groups receiving either active-rTMS or sham-rTMS. The active-TMS protocol had a frequency of 20 Hz, was delivered over the left dorsolateral prefrontal cortex and had a 100% rest motor threshold. The sham-rTMS protocol was the same as the active protocol without magnetic stimulation over the cortex. MAIN OUTCOME MEASURES: Consciousness was evaluated by the Coma Recovery Scale-Revised (CRS-R) before and after the four-week intervention. The ratio of patients that awakened from disorders of consciousness was followed up at discharge. RESULTS: Before rTMS sessions, there were no significant differences in consciousness scores between groups. Compared to sham-rTMS (6.25 ± 1.29), patients with disorders of consciousness treated by active rTMS showed strikingly improved consciousness (8.45 ± 3.55). In-depth analysis revealed that only some patients showed obvious increases in consciousness scores induced by active rTMS. Furthermore, rTMS did not significantly enhance the awakening ratio. CONCLUSIONS: rTMS showed therapeutic efficacy for improving consciousness in some, but not all, patients with disorders of consciousness. It is essential to discern the potential patients whose consciousness can be improved by rTMS.

Novel 18F-Labeled Isonicotinamide-Based Radioligands for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3ß.

Glycogen synthase kinase-3ß (GSK-3ß), a cytoplasmic serine/threonine protein kinase, is involved in several human pathologies including Alzheimer's disease, bipolar disorder, diabetes, and cancer. Positron emission tomography (PET) imaging of GSK-3ß could aid in investigating GSK-3ß levels under normal and pathological conditions. In this study, we designed and synthesized fluorinated PET radioligands starting with recently identified isonicotinamide derivatives that showed potent affinity to GSK-3ß. After extensive in vitro inhibitory activity assays and analyzing U87 cell uptake, we identified [18F]10a-d as potential tracers with good specificity and high affinity. They were then subjected to further in vivo evaluation in rodent brain comprising PET imaging and metabolism studies. The radioligands [18F]10b-d penetrated the blood-brain barrier and accumulated in GSK-3ß-rich regions, including amygdala, cerebellum, and hippocampus. Also, it could be specifically blocked using the corresponding standard compounds. With these results, this work sets the basis for further development of novel 18F-labeled GSK-3ß PET probes.

Antioxidant status of uric acid, bilirubin, albumin and creatinine during the acute phase after traumatic brain injury: sex-specific features.

BACKGROUND: It is known that the alteration of antioxidants can been seen in early phase after traumatic brain injury (TBI) in order to block oxidative damage, but little is known about the influence of sex on antioxidant system in patients with TBI. This study investigates whether there are sex differences in these endogenous antioxidant agents during the acute phase after TBI and their association with the disease. METHODS: Serum levels of uric acid (UA), bilirubin, albumin and creatinine were measured in 421 individuals included 157 female TBI patients, 156 male TBI patients and 108 age- and sex-matched controls. RESULTS: The statistically significant changes were found in UA, bilirubin, albumin and creatinine for both sexes with TBI, but the trend of changes in bilirubin and creatinine was opposite for gender groups. Serum levels of UA, bilirubin, albumin and creatinine were associated with the severity of TBI patients for both sexes. Male patient subgroups with elevated UA, albumin and creatinine had higher frequency of regaining consciousness in a month. Moreover, addition of UA and creatinine to the established clinical model had significantly improved the predictive performance over using clinical model alone in male patients with TBI. However, no similar findings were observed on female TBI patients. CONCLUSION: Our results suggest sex-based differences in the serum endogenous antioxidant response to TBI. Use of serum UA and creatinine could help in the outcome prediction of male patients with TBI in combination with other prognostic factors.

TGF-ß1 activates the canonical NF-κB signaling to promote cell survival and proliferation in dystrophic muscle fibroblasts in vitro.

Activated fibroblasts continue to proliferate at injury sites, leading to progressive muscular fibrosis in Duchenne muscular dystrophy (DMD). TGF-ß1 is a dominant profibrotic mediator thought to play a critical role in muscle fibrosis; however, the implicated mechanisms are not fully understood. Here we showed that TGF-ß1 increased the resistance to apoptosis and stimulated cell cycle progression in dystrophic muscle fibroblasts under serum deprivation conditions in vitro. TGF-ß1 treatment activated the canonical NF-κB pathway; and we found that pharmacological inhibition of IKKß with IMD-0354 and RelA gene knockdown with siRNA attenuated these effects of TGF-ß1 on dystrophic muscle fibroblasts. Collectively, our data suggest that TGF-ß1 prevents apoptosis and cell cycle arrest in dystrophic muscle fibroblasts through the canonical NF-κB signaling pathway.

Association of vitamin D receptor gene polymorphism with the risk of lung cancer: a meta-analysis.

Relationship between vitamin D receptor (VDR) gene polymorphism and the risk of lung cancer from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR TaqI (rs731236), BsmI (rs1544410) and ApaI (rs7975232) gene polymorphism and the risk of lung cancer using meta-analysis method. The association studies were identified from PubMed and Cochrane Library on 1 December 2013, and eligible investigations were included and synthesized using meta-analysis method. Six reports were recruited into this meta-analysis for the association of VDR gene polymorphism with lung cancer susceptibility. In the meta-analysis for ApaI gene polymorphism, AA genotype was associated with the risk of lung cancer in Asians. In the meta-analysis for BsmI gene polymorphism, B allele, BB genotype and bb genotype were associated with lung cancer in Asians, and B allele bb genotype were associated with lung cancer risk in overall populations; furthermore, bb genotype was associated with lung cancer risk in Caucasians. In the meta-analysis for TaqI gene polymorphism, t allele and TT genotype were associated with lung cancer in overall populations and in Caucasians. In conclusion, B allele bb genotype t allele and TT genotype were associated with lung cancer risk in overall populations. AA genotype, B allele, BB genotype and bb genotype were associated with the risk of lung cancer in Asians. Furthermore, bb genotype t allele and TT genotype was associated with lung cancer risk in Caucasians. However, more studies should be conducted to confirm it.

Cerebral [18F]AIF-FAPI-42-Based PET Imaging of Fibroblast Activation Protein for Non-invasive Quantification of Fibrosis After Ischemic Stroke.

The development of fibrosis after injury to the brain or spinal cord limits the regeneration of the central nervous system in adult mammals. However, the extent of fibrosis in the injured brain has not been systematically investigated in mammals in vivo. This study aimed to assess whether [18F]AlF-FAPI-42-based cerebral positron emission tomography (PET) can be utilized to assess the extent of fibrosis in ischemic regions of the brain in vivo. Sprague-Dawley rats underwent permanent occlusion of the right middle cerebral artery (MCAO). On days 3, 7, 14, and 21 after MCAO, the uptake of [18F]AlF-FAPI-42 in the ischemic region of the brain in the MCAO groups surpassed that in the control group (day 0). The specific expression of fibroblast activation protein-α (FAP) in ischemic regions of the brain was also confirmed in immunohistofluorescence experiments in vitro. [18F]AlF-FAPI-42 intensity correlated with the density of collagen deposition in the ischemic hemisphere (p < 0.001). [18F]AlF-FAPI-42 PET/CT imaging demonstrated a specific uptake of radioactivity in the infarcted area in an ischemic stroke patient. PET imaging by using [18F]AlF-FAPI-42 offers a promising non-invasive method for monitoring the progression of cerebral fibrosis caused by ischemic stroke and may facilitate the clinical management of stroke patients. Trial registration: chictr.org.cn ChiCTR2200059004. Registered April 22, 2022.

[18F]AlF-ND-bisFAPI PET imaging of fibroblast activation protein as a biomarker to monitor the progression of liver fibrosis.

BACKGROUND: Hepatic fibrosis is a progressive disease, which is reversible in the early stages. The current monitoring methods have notable limitations that pose a challenge to early detection. In this study, we evaluated the utility of [18F]AlF-ND-bisFAPI positron emission tomography imaging of fibroblast activation protein (FAP) to monitor the progression of liver fibrosis. METHODS: Two mouse models of liver fibrosis were established by bile duct ligation and carbon tetrachloride administration, respectively. Positron emission tomography imaging was performed with the FAP-specific radiotracer [18F]AlF-ND-bisFAPI for the evaluation of rat HSCs and mouse models of fibrosis and combined with histopathology, immunohistochemical staining, and immunoblotting to elucidate the relationships among radioactivity uptake, FAP levels, and liver fibrosis progression. Furthermore, [18F]AlF-ND-bisFAPI autoradiography was performed to assess tracer binding in liver sections from patients with varying degrees of liver fibrosis. RESULTS: Cell experiments demonstrated that [18F]AlF-ND-bisFAPI uptake was specific in activated HSCs. Compared with control mice, [18F]AlF-ND-bisFAPI uptake in livers increased in the early stages of fibrosis and increased significantly further with disease progression. Immunohistochemistry and western blot analyses demonstrated that FAP expression increased with fibrosis severity. In accordance with the findings in animal models, ex vivo autoradiography on human fibrotic liver sections showed that radioactivity increased as fibrosis progressed from mild to severe. CONCLUSIONS: [18F]AlF-ND-bisFAPI positron emission tomography imaging is a promising noninvasive method for monitoring the progression of liver fibrosis.

Effect of Physical Activity on the Association Between Diet and Constipation: Evidence From the National Health and Nutrition Examination Survey 2007-2010.

Background/Aims: Previous studies have shown that diet and physical activity can influence constipation. However, the combined effect of diet and physical activity on constipation remains unclear. Methods: Constipation was defined based on stool consistency and frequency, while overall diet quality was assessed using Healthy Eating Index (HEI)-2015 scores. Participants were categorized into low (metabolic equivalent [MET]-min/wk < 500) and high physical activity groups (MET-min/wk ≥ 500). The association between diet and constipation across physical activity groups was analyzed using survey logistic regression and restricted cubic splines. Results: Higher HEI-2015 scores were associated with reduced constipation risk in the high physical activity group when constipation was defined by stool consistency (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99). However, in the low physical activity group, increased HEI-2015 scores did not significantly affect constipation risk (OR, 1.01; 95% CI, 0.97-1.05). Similar results were found when constipation was defined based on stool frequency. In the high physical activity group, increased HEI-2015 scores were significantly associated with a reduced constipation risk (OR, 0.96; 95% CI, 0.94-0.98). Conversely, in the low physical activity group, increased HEI-2015 scores did not affect the risk of constipation (OR, 0.96; 95% CI, 0.90-1.03). Conclusions: Our findings suggest that a higher HEI-2015 score is negatively associated with constipation among individuals with high physical activity levels but not among those with low physical activity levels. This association was consistent when different definitions of constipation were used. These results highlight the importance of combining healthy diet with regular physical activity to alleviate constipation.

Distinct serum apolipoprotein A-I levels in neuromyelitis optica and acute transverse myelitis.

OBJECTIVE: NMO and ATM are intertwined both clinically and pathologically. Apolipoprotein (apo) A-I, the main apolipoprotein of HDL, plays an important role in lipid metabolism in the cerebrospinal fluid and is known to suppress pro-inflammatory cytokines generated by activated T cells in some autoimmune diseases as an immune regulator. However, the differences in the levels of serum apoA-I between NMO and ATM patients are unclear. METHODS: In the present study, serum apo A-I levels were measured in 53 NMO patients, 45 ATM patients and 49 healthy subjects. We tested serum apoA-I levels in all participants and investigated EDSS scores of patients with NMO and ATM. Statistical analyses were performed by using SPSS statistical software. RESULT: We found that serum apoA-I levels in patients with NMO were significantly lower in comparison to those with ATM. We also found that serum levels of apoA-I was lower in male subjects in comparison to the female subjects in all groups although these differences were not statistically significant in patients with NMO or ATM. It is also shown in our study that serum apoA-I levels in patients with NMO were significantly elevated after receiving a high dosage of intravenous corticosteroids over a period of one week. However, we did not find any correlation between the apoA-I levels and disease disability. CONCLUSION: From this study, we concluded that serum levels of apoA-I were lower in NMO patients compared to patients with ATM. Serum apoA-I studies might provide some useful clues to differentiate NMO cases from ATM cases.

Synthesis and preclinical evaluation of a heterodimeric radioligand targeting fibroblast activation protein and integrin-αvß3.

Tumor progression is accompanied by intrinsic heterogeneity and different phenotypes, which implies a different expression of cell surface receptors. Fibroblast activation protein (FAP) and integrin αvß3 are highly expressed in the cell surface of cancer-associated cells or cancer cells compared with normal cells. Therefore, a FAP/integrin αvß3 bispecific heterodimer was developed for positron emission tomography (PET) diagnostic imaging and radiotherapy. The heterodimer DOTA-FAPI-RGD was labeled with the diagnostic radionuclide gallium-68 or the therapeutic radionuclide lutetium-177, with yields >80%, and high stability. The competitive displacement binding assay showed an IC50 = 6.8 ± 0.6 nM for DOTA-FAPI-RGD towards FAP and IC50 = 2.1 ± 0.4 nM towards integrin αvß3. Radionuclide labeled DOTA-FAPI-RGD showed high specificity and rapid internalization into U87MG cells (FAP/αvß3-positive) in vitro. Micro-PET and biodistribution studies of [68Ga]Ga-DOTA-FAPI-RGD in tumor-bearing mice demonstrated that a high and specific tumor uptake of the tracer and a fast body clearance, resulting in high contrast images. In addition to the imaging applications demonstrated in this study, the labeling of the heterodimeric ligand with the radionuclide lutetium-177 used in cancer treatment might allow the therapeutic application of this ligand.

Self-assembly of Ni2P/γ-Ga2O3 nanosheets for efficient photocatalytic water splitting hydrogen production.

The development of photocatalysts enabling stable and highly efficient water splitting hydrogen production remains an open challenge in the field of energy photocatalysis. Herein, Ni2P/γ-Ga2O3 nanosheets have been reported as excellent water splitting photocatalysts. Ni2P particles and γ-Ga2O3 nanosheets were synthesized by a facile hydrothermal process. The Ni2P/γ-Ga2O3 samples were prepared by an electrostatic self-assembly method with Ni2P particles and γ-Ga2O3 nanosheets as precursors. The 0.5 wt% Ni2P/γ-Ga2O3 sample shows a photocatalytic H2-production activity as high as 2.7 mmol g-1 h-1 in pure water and 12 mmol g-1 h-1 in an aqueous methanol solution under a 125 W high pressure mercury lamp, respectively, which are much higher than those of pure γ-Ga2O3 and Pt/γ-Ga2O3 nanosheets modified with a comparable Pt content. The Ni2P component plays a role as an electron collector that promotes efficient separation of photogenerated electrons and holes, and thereby improves the efficiency of photocatalytic hydrogen production. The effects of inorganic and organic sacrificial reagents on the reaction efficiency and stability were observed and discussed. This work shows that Ni2P as a cocatalyst substituting noble metals can greatly improve the photocatalytic hydrogen production efficiency of γ-Ga2O3 compared to that in pure water and a methanol-water solution.

Radiosynthesis and Preclinical Evaluation of Bispecific PSMA/FAP Heterodimers for Tumor Imaging.

Due to tumor heterogeneity and complex tumor-stromal interactions in multicellular systems, the efficiency of monospecific tracers for tumor diagnosis and therapy is currently limited. In light of the evidence of prostate-specific membrane antigen (PSMA) overexpression in tumor cells and fibroblast activation protein (FAP) upregulation in the tumor stroma, heterodimer dual targeting PSMA and FAP may have the potential to improve tumor diagnosis. Herein, we described the radiosynthesis, in vitro characterization, and micro-PET/CT imaging of two novel 18F-labeled bispecific PSMA/FAP heterodimers. 18F-labeled heterodimers showed high specificity and affinity targeting to PSMA and FAP in vitro and in vivo. Compared with the monospecific tracers [18F]AlF-PSMA-BCH and [18F]FAPI-42, both 18F-labeled heterodimers exhibited better tumor uptake in tumor-bearing mice. Their favorable characterizations such as convenient synthesis, high tumor uptake, and favorable pharmacokinetic profile could lead to their future applications as bispecific radiotracers for clinical cancer imaging.

Simultaneously stimulating both brain hemispheres by rTMS in patients with unilateral brain lesions decreases interhemispheric asymmetry.

BACKGROUND: Interhemispheric asymmetry caused by brain lesions is an adverse factor in the recovery of patients with neurological deficits. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate cortical oscillation and proposed as an approach to rebalance the symmetry, which has not been documented well. OBJECTIVE: In this study, we investigated the influence of repetitive transcranial magnetic stimulation (rTMS) on EEG power in patients with unilateral brain lesions by simultaneously stimulating both brain hemispheres and to elucidate asymmetrical changes in rTMS-induced neurophysiological activity. METHODS: Fourteen patients with unilateral brain lesions were treated with one active and one sham session of 10 Hz rTMS over the vertex (Cz position). Resting-state EEGs were recorded before and immediately after rTMS. The brain symmetry index (BSI), calculated from a fast Fourier transform, was employed to quantify the power asymmetry in both hemispheres and paired channels over the entire range and five frequency bands (delta, theta, alpha, beta and gamma bands). RESULTS: Comparison between active and sham sessions demonstrated rTMS-induced EEG after-effects. rTMS in the active session significantly reduced the BSI in patients with unilateral brain lesions over the entire frequency range (t = 2.767, P = 0.016). Among the five frequency bands, rTMS only induced a noticeable decrease in the BSI in the delta band (t = 2.254, P = 0.042). Furthermore, analysis of different brain regions showed that significant changes in the BSI of the alpha band were only demonstrated in the posterior parietal lobe. In addition, EEG topographic mapping showed a decreased power of delta oscillations in the ipsilesional hemisphere, whereas distinct cortical oscillations were observed in the alpha band around the parietal-occipital lobe in the contralesional hemisphere. CONCLUSIONS: When both brain hemispheres were simultaneously activated, rTMS decreased interhemispheric asymmetry primarily via reducing the delta band in the lesioned hemisphere.

Effectiveness of motor control exercise on non-specific chronic low back pain, disability and core muscle morphological characteristics: a meta-analysis of randomized controlled trials.

INTRODUCTION: Chronic low back pain (CLBP) has been recognized as the leading cause of disability. Up to 90% of patients with CLBP are classified as having non-specific CLBP (NSCLBP). Motor control exercise (MCE) is one of the most popular and widespread treatment options, and has many advantages in alleviating pain and disability. This meta-analysis is aimed to investigate the effectiveness of MCE on NSCLBP, disability, and core muscles reported in randomized controlled trials (RCTs). EVIDENCE ACQUISITION: PubMed, Web of Science, and EMBASE were searched from inception to August 2020. Articles were eligible if they were RCTs that evaluated MCE against sham or other treatments in isolation and measured outcomes including pain intensity and disability or core muscles morphologic characteristics. EVIDENCE SYNTHESIS: Two authors independently extracted the data. Eighteen studies of 894 studies with a total of 1333 individuals with NSCLBP were retained for the meta-analysis. Compared with other conservative treatments, MCE was better in reducing pain and disability posttreatment and was better in reducing pain at the 6-month follow-up period. However, it had comparable effects on pain reduction at 12-month and 24-month follow-up period, and on disability at the 6-month, 12-month and 24-month follow-up period. MCE resulted in comparable effects to other treatments in improving the core muscle thickness posttreatment. CONCLUSIONS: Low to very low quality of evidence supported that MCE resulted in a greater reduction of pain and disability posttreatment, and a greater reduction of pain at the 6-month follow-up than other treatments for NSCBLP. The findings in this review further support that MCE may be more effective than other treatments at short-term follow-ups, and at least has equivalent long-term effects to other forms of treatments in NSCLBP.

Assessment of biomarkers for clinical diagnosis of papillary thyroid carcinoma with distant metastasis.

Early diagnosis and treatment of thyroid cancers are critical for better prognosis and better survival rates. The purpose of this study was to identify potential diagnostic markers for papillary thyroid carcinomas with distant metastasis. Fifty-eight papillary thyroid tumor specimens (27 papillary thyroid carcinomas with distant metastasis and 31 without metastasis) were examined, and protein expression of pituitary tumor-transforming gene (PTTG), E-cadherin, p27kip1, vascular endothelial growth factor (VEGF)-C, metalloproteinase (MMP) 2, MMP9, chemokine receptor CXCR4, and basic fibroblast growth factor (bFGF) in these tumors was assessed by immunohistochemistry. The clinicopathological variables with diagnostic significance were determined by multivariate analysis, and their diagnostic values were evaluated by ROC curve analysis. PTTG, VEGF-C, MMP2, MMP9, CXCR4, and bFGF were overexpressed in metastatic papillary thyroid carcinomas, whereas p27kip1 expression was elevated only in carcinomas lacking metastasis. Multiple-factor binary ordinal logistic regression analysis revealed that PTTG, VEGF-C, MMP2, and bFGF were independently related to biological metastatic behavior in thyroid tumors, suggesting their potential use as biomarkers. ROC curve analysis showed that among these four proteins, VEGF-C and bFGF were the best diagnostic biomarkers. A VEGF-C and bFGF cluster was the most useful factor for the differential diagnosis between metastatic and non-metastatic papillary thyroid cancers. Thus, the combined use of VEGF-C and bFGF as biomarkers may improve the diagnostic accuracy of papillary thyroid carcinoma and may be useful in multimodal screening programs for the clinical diagnosis of papillary thyroid carcinoma and early detection of papillary thyroid carcinoma with distant metastasis.

Differentiating Responders and Non-responders to rTMS Treatment for Disorder of Consciousness Using EEG After-Effects.

Background: It is controversial whether repetitive transcranial magnetic stimulation (rTMS) has potential benefits in improving the awareness of patients with disorder of consciousness (DOC). We hypothesized that rTMS could improve consciousness only in DOC patients who have measurable brain responses to rTMS. Objective: In this study, we aimed to investigate the EEG after-effects induced by rTMS in DOC patients and attempted to propose a prediction algorithm to discriminate between DOC patients who would respond to rTMS treatment from those who would not. Methods: Twenty-five DOC patients were enrolled in this study. Over 4 weeks, each patient received 20 sessions of 20 Hz rTMS that was applied over the left dorsolateral prefrontal cortex (DLPFC). For each patient, resting-state EEG was recorded before and immediately after one session of rTMS to assess the neurophysiologic modification induced by rTMS. The coma recovery scale revised (CRS-R) was used to define responders with improved consciousness. Results: Of the 25 DOC patients, 10 patients regained improved consciousness and were classified as responders. The responders were characterized by more preserved alpha power and a significant reduction of delta power induced by rTMS. The analysis of receiver operating characteristic (ROC) curves showed that the algorithm calculated from the relative alpha power and the relative delta power had a high accuracy in identifying DOC patients who were responders. Conclusions: DOC patients who had more preserved alpha power and a significant reduction in the delta band that was induced by rTMS are likely to regain improved consciousness, which provides a tool to identify DOC patients who may benefit in terms of therapeutic consciousness.

Upregulation of microRNA-205 is a potential biomarker for intracranial aneurysms.

Inhibition of microRNA-205 is considered to be a therapeutic target for abdominal aortic aneurysm in animal model. Hepatocyte growth factor also plays pivotal roles in the pathogenesis of intracranial aneurysms, and its expression can be regulated by different miRNAs in different processes. We investigated the involvement of microRNA-205 in intracranial aneurysms and explored is potential interaction with hepatocyte growth factor. We found that blood levels of microRNA-205 were significantly higher in patients with intracranial aneurysms than in healthy controls. High blood levels of microRNA-205 showed diagnostic values for intracranial aneurysms. MicroRNA-205 and hepatocyte growth factor were negatively correlated in patients with intracranial aneurysms. MicroRNA-205 overexpression inhibited hepatocyte growth factor expression and reduced cell viability. Therefore, microRNA-205 may participate in intracranial aneurysms and may serve as a diagnostic marker for this disease.

Gelsemium elegans Poisoning: A Case with 8 Months of Follow-up and Review of the Literature.

BACKGROUND: Gelsemium elegans (G. elegans) is a toxic plant indigenous to Southeast Asia. It is highly poisonous due to its strong respiratory depressive effect. However, G. elegans poisoning cases have not been summarized comprehensively and are rarely reported in English journals. Furthermore, none of the present reports present prognosis in detail. CASE PRESENTATION: A 26-year-old female was found comatose at home and brought to the hospital with deep coma, hypoxia, and acidosis. After mechanical ventilation for hours, the patient recovered from coma with sequelae of impaired short-term memory, disorientation, and childish behaviors. Brain magnetic resonance imaging (MRI) showed bilateral hippocampus and basal ganglia damage due to hypoxia. During 8 months of follow-up, both her symptoms and brain MRI scan improved significantly. CONCLUSION: G. elegans is highly toxic. Although patients may die within 30 min due to its strong respiratory depressive effect, they can survive with timely respiratory support and enjoy gradual improvement without delayed postanoxic encephalopathy.