Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

BACKGROUND: The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. METHODS: Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[18F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. RESULTS: MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. CONCLUSION: Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[18F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

Colorimetric and electrochemical dual-mode uric acid determination utilizing peroxidase-mimicking activity of CoCu bimetallic nanoclusters.

We present the preparation of CoCu bimetallic nanoclusters (Co@Cu-BNCs) by a hydrothermal and one-step pyrolysis method to build a colorimetric and electrochemical dual-mode sensing platform for uric acid (UA) detection. In the presence of H2O2, Co@Cu-BNCs with peroxidase-mimicking activity may convert colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue-colored oxidized TMB (oxTMB). However, due to the inhibitory effect of uric acid (UA) on the oxidation process of TMB, the characteristic absorption peak intensity of oxTMB decreased when UA was added into a mixed solution. In this approach, a colorimetric assay platform for the detection of UA was demonstrated, with a linear range of 0.1-195 µM and a low limit of detection of 0.06 µM (S/N ratio of 3). In addition, an even wider detection range is achieved in the electrochemical method, due to the pronounced electrocatalytic activity of Co@Cu-BNCs. The surface of the glassy carbon electrode was modified with Co@Cu-BNCs to build an electrochemical sensor for detecting UA. The sensor achieves a wider linear range from 2 to 1000 µM and a limit of detection of 0.61 µM (S/N ratio of 3). Moreover, the detection of UA in a human serum sample showed satisfactory results. The results proved that the colorimetric and electrochemical dual-mode detection platform was sensitive, convenient and accurate.

Revealing oxidative degradation of lipids and screening potential markers of four vegetable oils during thermal processing by pseudotargeted oxidative lipidomics.

The oxidative degradation of lipids in vegetable oils during thermal processing may present a risk to human health. However, not much is known about the evolution of lipids and their non-volatile derivatives in vegetable oils under different thermal processing conditions. In the present study, a pseudotargeted oxidative lipidomics approach was developed and the evolution of lipids and their non-volatile derivatives in palm oil, rapeseed oil, soybean oil, and flaxseed oil under different thermal processing conditions was investigated. The results showed that thermal processing resulted in the oxidative degradation of TGs in vegetable oils, which generated oxTGs, DGs, and FFAs, as well as TGs with smaller molecular weights. The lower the fatty acid saturation, the more severe the oxidative degradation of vegetable oils and thermal processing at high temperatures should be avoided if possible. From the accumulation of oxTGs concentrations, the hazards during thermal processing at high temperatures were, in descending order, soybean oil, rapeseed oil, flaxseed oil, and palm oil. The non-volatile potential markers were screened in palm oil, rapeseed oil, soybean oil, and flaxseed oil for 1, 7, 5, and 2 markers related to thermal processing time, respectively. The study provided suggestions for the consumption of vegetable oils from multiple perspectives and identified markers for monitored oxidative degradation of vegetable oils.

A recurrence-predictive model based on eight genes and tumor mutational burden/microsatellite instability status in Stage II/III colorectal cancer.

BACKGROUND: Although adjuvant chemotherapy (ACT) is widely used to treat patients with Stage II/III colorectal cancer (CRC), administering ACT to specific patients remains a challenge. The decision to ACT requires an accurate assessment of recurrence risk and absolute treatment benefit. However, the traditional TNM staging system does not accurately assess a patient's individual risk of recurrence. METHODS: To identify recurrence risk-related genetic factors for Stage II/III CRC patients after radical surgery, we conducted an analysis of whole-exome sequencing of 47 patients with Stage II/III CRC who underwent radical surgery at five institutions. Patients were grouped into non-recurrence group (NR, n = 24, recurrence-free survival [RFS] > 5 years) and recurrence group (R, n = 23, RFS <2 years). The TCGA-COAD/READ cohort was employed as the validation dataset. RESULTS: A recurrence-predictive model (G8plus score) based on eight gene (CUL9, PCDHA12, HECTD3, DCX, SMARCA2, FAM193A, AATK, and SORCS2) mutations and tumor mutation burden/microsatellite instability (TMB/MSI) status was constructed, with 97.87% accuracy in our data and 100% negative predictive value in the TCGA-COAD/READ cohort. For the TCGA-COAD/READ cohort, the G8plus-high group had better RFS (HR = 0.22, p = 0.024); the G8plus-high tumors had significantly more infiltrated immune cell types, higher tertiary lymphoid structure signature scores, and higher immunological signature scores. The G8plus score was also a predict biomarker for immunotherapeutic in advanced CRC in the PUCH cohort. CONCLUSIONS: In conclusion, the G8plus score is a powerful biomarker for predicting the risk of recurrence in patients with stage II/III CRC. It can be used to stratify patients who benefit from ACT and immunotherapy.

In situ green synthesis of the nanocomposites of MnO2/graphene as an oxidase mimic for sensitive colorimetric and electrochemical dual-mode biosensing.

Herein we report the colorimetry and an electrochemical for the determination of dopamine (DA) by using MnO2 nanoparticles and graphene nanosheets composite (MnO2@G) that display oxidase mimicking property. MnO2@G could directly oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) into a blue product (oxTMB) without extra oxidants such as H2O2. Nevertheless, the presence of DA will inhibit the TMB oxidation due to the presence of the competitive reaction of MnO2@G and DA, giving a product color change from blue to colorless. A colorimetric assay for detect the concentration of DA was worked out according to this finding. Response is linear in the 0.1 to 15 µM DA concentration range, and the detection limit is 0.14 µM. Wider detection range is achieved in an electrochemical method which is due to the pronounced electrocatalytic activity of MnO2@G. The MnO2@G was modified on the surface of the glassy carbon electrode in order to fabricate one type electrochemical sensor. The sensor achieves a wide detection two linear ranges from 0.4 to 70 µM, with the detection limit of 1.16 µM. The detection of DA in real serum sample proved that the nanozyme based on MnO2@G could be developed into a colorimetry and electrochemical dual-readout sensing platform.

Hyperphosphatemia-Related False-Positive 99m Tc-Pyrophosphate Myocardial Scan: A Case Report With Endomyocardial Biopsy Result.

ABSTRACT: With documented high specificity, 99m Tc-pyrophosphate (PYP) scan enables the diagnosis of transthyretin cardiomyopathy to be made reliably without endomyocardial biopsy in patients who do not have monoclonal gammopathy. We report a case with extensive myocardial uptake of Perugini 3 score in the 3-hour 99m Tc-PYP myocardial SPECT that suggested transthyretin cardiac amyloidosis. However, a followed endomyocardial biopsy revealed no amyloid deposition. In this case, hyperphosphatemia was the most likely and presumptive cause of the false-positive 99m Tc-PYP scan. With this case, our experiences of the potential causes of false-positive results of 99m Tc-PYP are further expanded.

Perineal defect reconstruction after surgery for advanced or locally recurrent rectal cancer involving organ resection: Multiple flaps combined with lining repair.

AIM: The aim of this study was to investigate the efficacy of multiple perineal perforator flaps in repairing deep perineal defects after pelvic exenteration for locally advanced or recurrent rectal cancer. METHOD: We investigated the outcomes of eight patients whose repairs involved a novel method of using an internal pudendal artery perforator (IPAP) flap combined with an inferior gluteal artery perforator (IGAP) flap. RESULTS: There were four male and four female patients with a mean age of 56 years (36-72 years). Bilateral IPAP flaps combined with bilateral IGAP flaps were used in five patients, unilateral IPAP flaps combined with bilateral IGAP flaps were used in two patients and bilateral IPAP flaps were used in one patient. There were no functional limitations in daily activities during the 6-month follow-up period. CONCLUSION: Our study showed that using multiple perineal perforator flaps combined with lining repair is feasible for repairing deep perineal defects in patients who have undergone rectal cancer surgery that includes pelvic exenteration.

E2F3 accelerates the stemness of colon cancer cells by activating the STAT3 pathway.

Introduction: Colon cancer is one of the most prevalent malignancies and causes of cancer-related deaths worldwide. Thus, further research is required to explicate the latent molecular mechanisms and look for novel biomarkers. E2F3 has been confirmed to be an oncogene in a variety of cancers. However, the particular regulation of E2F3 in colon cancer needs further investigation. Methods: The self-renewal ability was detected through a sphere formation assay. The tumorigenic ability was measured through nude mice in vivo assay. The protein expression of genes was examined through a Western blot. The expression of E2F3 in tumor tissues was detected through an IHC assay. The resistance to cisplatin was assessed through the CCK-8 assay. The cell migration and invasion abilities were measured after upregulating or suppressing E2F3 through the Transwell assay. Results: Results uncovered that E2F3 was upregulated in spheroid cells. In addition, E2F3 facilitates stemness in colon cancer. Moreover, E2F3 facilitated colon cancer cell migration and invasion. Finally, it was revealed that E2F3 affected the STAT3 pathway to modulate stemness in colon cancer. E2F3 served as a promoter regulator in colon cancer, aggravating tumorigenesis and stemness in colon cancer progression through the STAT3 pathway. Conclusion: E2F3 may be a useful biomarker for anticancer treatment in colon cancer.

Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

BACKGROUND: This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). METHODS: BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. RESULTS: This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. CONCLUSION: Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Radiation issue in clinical nuclear molecular imaging.

Radiation is ubiquitous in nature, and radiation is also widely used in various fields of medicine, agriculture, and industry. Current biological doses below 100 mSv are called low-dose radiation (LDR). Scientists have no consensus of effects on humans below this dose, so a variety of dose-response curve theories have been derived. This approach makes the public believe that even a small dose of radiation has adverse side effects, and overreact to refuse the related medical procedures for fear of radiation. The linear non-threshold (LNT) model has been used in radiation protection for over 40 years however, adverse effects from low dose, low-dose rate (LDDR) exposures are not detectable. Nuclear molecular imaging is LDR, using different radionuclides or combining with specific ligands (carries) to form "radiopharmaceuticals" for functional or pathological evaluations of diseases. As an integral part of patient care, nuclear medicine is used in the diagnosis, management, treatment, follow-up, and prevention of diseases. Therefore, this paper discusses literature review and provides appropriate scientific data and communication to help the peers and the public understand its advantage and disadvantage.

Measurements of elemental iodine in soy sauces in Taiwan using a modified microplate method.

Background: Soy sauce is widely used in a variety of Asian dishes to enhance flavor. Soybean and most soybean products, including soy sauces, are listed as prohibited foods in a low iodine diet. However, the iodine content in soy sauces is largely unknown. The aim of this study was to determine the iodine content in domestic soy sauces in Taiwan. Methods: Twenty-five different kinds of soy sauces were diluted with distilled water and with a dilution factor of fifty or above. Iodine concentrations of the diluted samples were measured colourimetrically based on the Sandell-Kolthoff reaction by a modified microplate method. All the measurements were repeated twelve times on three different days for determination of mean and standard deviation (SD), and coefficients of variance (CV). Serial dilution and recovery tests were also performed for validation. The results were confirmed by an inductively coupled plasma mass spectrometry (ICP-MS) method. Results: Among the twenty-five surveyed soy sauces, most of them (n=22) were iodine-free (<16 ug/L, and thus un-detectable). The iodine concentrations (mean ± SD) of the three iodine-containing soy sauces were 2.7 ± 0.1, 5.1 ± 0.2, and 10.8 ± 0.6 mg/L, respectively. The inter-assay, intra-assay and total CVs were all <5.3% for the modified microplate method. The results obtained by ICP-MS were consistent with those of the modified microplate method. The recovery rates in the serial dilution test and recovery test ranged from 94.7% to 118.6%. Two of the three iodine-containing soy sauces were supplemented with kelp extract, while the other one without kelp extract had the highest amount of salt among the three iodine-containing soy sauces. Therefore, we postulate that iodized salt instead of kelp extract is the source of higher iodine content in that sauce. Conclusion: The results suggest that most soy sauces are iodine-free and may be allowed during low iodine diets.

Follow-up Tc-99 m pyrophosphate cardiac scan for patients with transthyretin cardiac amyloidosis treated with tafamidis.

BACKGROUND: Tafamidis has been used for treatment of transthyretin cardiac amyloidosis (ATTR-CA). However, Tc-99 m pyrophosphate (PYP) cardiac scan for follow-up after tafamidis therapy has not been reported. METHODS: From May 2017 to March 2022, five patients with or without tafamidis therapy had received two Tc-99 m PYP cardiac scans. Tc-99 m PYP cardiac scan was performed with planar image and single photon emission computed tomography/computed tomography (SPECT/CT) 3 h after administration of Tc-99 m PYP. Perugini grading system was applied to determine positive or negative result of the scan. Heart to contralateral lung (H/CL) ratio as well as the difference of H/CL ratio between first and second Tc-99 m PYP cardiac scans (ΔH/CL ratio) was calculated. RESULTS: In the five patients participated in this study, three received tafamidis therapy and H/CL ratio was significantly decreased (p = 0.02) after tafamidis therapy. Besides, the ΔH/CL ratio was larger in patients with tafamidis therapy than that in those without tafamidis therapy, albeit not reaching statistical significance (p = 0.2). CONCLUSION: A decrease in H/CL ratio was found after tafamidis therapy in patients with ATTR-CA, albeit the magnitude of changes in the H/CL ratio (ΔH/CL ratio) was not significantly different from that of patients without tafamidis therapy. Future study with larger population might be required to further clarify the effect of tafamidis therapy on myocardial uptake of Tc-99 m PYP. CLINICAL TRIAL REGISTRATION: No clinical trial was conducted in our retrospective study.

Development of Nafion/single-walled carbon nanotube integrated arrays for the rapid detection of salbutamol doping.

Salbutamol (SAL), a drug originally intended for the treatment of bronchial and pulmonary diseases, has repeatedly been used for doping in competitive sports. Herein, an integrated array (NFCNT array) that prepared by template-assisted scalable filtration using Nafion-coated single-walled carbon nanotube (SWCNT) is presented for the rapid field detection of SAL. Spectroscopic and microscopic measurements were used to confirm the introduction of Nafion onto the surface of the array and to analyze the resulting morphological changes. The effects of Nafion addition on the resistance and electrochemical properties of the arrays (e.g., the electrochemically active area, charge-transfer resistance, and adsorption charge) are also discussed in depth. With an electrolyte/Nafion/SWCNT interface and moderate resistance, the NFCNT-4 array prepared containing 0.04 wt% Nafion suspension exhibits the greatest voltammetric response to SAL. Subsequently, a possible mechanism for the oxidation of SAL was proposed, and a calibration curve in the range of 0.1-15 µM was established. Finally, the NFCNT-4 arrays were applied to the detection of SAL in human urine samples with satisfactory recoveries.

The Titrated Mannitol Improved Central [99mTc] Tc TRODAT-1 Uptake in an Animal Model-A Clinically Feasible Application.

[99mTc]Tc TRODAT-1 is a widely used single photon emission tomography (SPECT) radiopharmaceutical in Asian practice for early detection of central dopaminergic disorders. However, its imaging quality remains sub-optimal. To overcome this problem, mannitol, an osmotic agent was used to observe its effect on improving striatal [99mTc]Tc TRODAT-1 uptake in rat brain by titrated human dosages to investigate a clinically feasible way to improve human imaging quality. [99mTc]Tc TRODAT-1 synthesis and quality control were performed as described. Sprague-Dawley rats were used for this study. The animal in vivo nanoSPECT/CT and ex vivo autoradiography were employed to observe and verify the striatal [99mTc]Tc TRODAT-1 uptake in rat brains using clinically equivalent doses (i.e., 0, 1 and 2 mL groups, each n = 5) of mannitol (20% w/v, equivalent to 200 mg/mL) by an intravenous administration. Specific binding ratios (SBRs) were calculated to express the central striatal uptake in different experimental groups. In the NanoSPECT/CT imaging, the highest SBRs of striatal [99mTc]Tc TRODAT-1 were reached at 75-90 min post-injection. The averaged striatal SBRs were 0.85 ± 0.13 (2 mL normal saline, the control group), 0.94 ± 0.26 (1 mL mannitol group) and 1.36 ± 0.12 (2 mL mannitol group, p < 0.01 which were significantly different than the control as well as 1 mL mannitol groups (p < 0.05). The SBRs from ex vivo autoradiography also showed a comparable trend of the striatal [99mTc]Tc TRODAT-1 uptake in the 2 mL, 1 mL mannitol and the control groups (1.76 ± 0.52, 0.91 ± 0.29, and 0.21 ± 0.03, respectively, p < 0.05). No remarkable changes of vital signs were found in the mannitol groups and the controls. Pre-treated mannitol revealed a significant increase of the central striatal [99mTc]Tc TRODAT-1 uptake in a rat model which not only enabled us to perform pre-clinical studies of dopaminergic related disorders but also provided a potential way to further optimize image quality in clinical practice.

Sub-differentiation of PI-RADS 3 lesions in TZ by advanced diffusion-weighted imaging to aid the biopsy decision process.

Background: Performing biopsy for intermediate lesions with PI-RADS 3 has always been controversial. Moreover, it is difficult to differentiate prostate cancer (PCa) and benign prostatic hyperplasia (BPH) nodules in PI-RADS 3 lesions by conventional scans, especially for transition zone (TZ) lesions. The purpose of this study is sub-differentiation of transition zone (TZ) PI-RADS 3 lesions using intravoxel incoherent motion (IVIM), stretched exponential model, and diffusion kurtosis imaging (DKI) to aid the biopsy decision process. Methods: A total of 198 TZ PI-RADS 3 lesions were included. 149 lesions were BPH, while 49 lesions were PCa, including 37 non-clinical significant PCa (non-csPCa) lesions and 12 clinical significant PCa (csPCa) lesions. Binary logistic regression analysis was used to examine which parameters could predict PCa in TZ PI-RADS 3 lesions. The ROC curve was used to test diagnostic efficiency in distinguishing PCa from TZ PI-RADS 3 lesions, while one-way ANOVA analysis was used to examine which parameters were statistically significant among BPH, non-csPCa and csPCa. Results: The logistic model was statistically significant (χ2 = 181.410, p<0.001) and could correctly classify 89.39% of the subjects. Parameters of fractional anisotropy (FA) (p=0.004), mean diffusion (MD) (p=0.005), mean kurtosis (MK) (p=0.015), diffusion coefficient (D) (p=0.001), and distribute diffusion coefficient (DDC) (p=0.038) were statistically significant in the model. ROC analysis showed that AUC was 0.9197 (CI 95%: 0.8736-0.9659). Sensitivity, specificity, positive predictive value and negative predictive value were 92.1%, 80.4%, 93.9% and 75.5%, respectively. FA and MK of csPCa were higher than those of non-csPCa (all p<0.05), while MD, ADC, D, and DDC of csPCa were lower than those of non-csPCa (all p<0.05). Conclusion: FA, MD, MK, D, and DDC can predict PCa in TZ PI-RADS 3 lesions and inform the decision-making process of whether or not to perform a biopsy. Moreover, FA, MD, MK, D, DDC, and ADC may have ability to identify csPCa and non-csPCa in TZ PI-RADS 3 lesions.

Development and validation of postoperative circulating tumor DNA combined with clinicopathological risk factors for recurrence prediction in patients with stage I-III colorectal cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) detection following curative-intent surgery could directly reflect the presence of minimal residual disease, the ultimate cause of clinical recurrence. However, ctDNA is not postoperatively detected in ≥ 50% of patients with stage I-III colorectal cancer (CRC) who ultimately recur. Herein we sought to improve recurrence risk prediction by combining ctDNA with clinicopathological risk factors in stage I-III CRC. METHODS: Two independent cohorts, both consisting of early-stage CRC patients who underwent curative surgery, were included: (i) the discovery cohort (N = 124) with tumor tissues and postoperative plasmas for ctDNA determination; and (ii) the external validation cohort (N = 125) with available ctDNA results. In the discovery cohort, somatic variations in tumor tissues and plasmas were determined via a 733-gene and 127-gene next-generation sequencing panel, respectively. RESULTS: In the discovery cohort, 17 of 108 (15.7%) patients had detectable ctDNA. ctDNA-positive patients had a significantly high recurrence rate (76.5% vs. 16.5%, P < 0.001) and short recurrence-free survival (RFS; P < 0.001) versus ctDNA-negative patients. In addition to ctDNA status, the univariate Cox model identified pathologic stage, lymphovascular invasion, nerve invasion, and preoperative carcinoembryonic antigen level associated with RFS. We combined the ctDNA and clinicopathological risk factors (CTCP) to construct a model for recurrence prediction. A significantly higher recurrence rate (64.7% vs. 8.1%, P < 0.001) and worse RFS (P < 0.001) were seen in the high-risk patients classified by the CTCP model versus those in the low-risk patients. Receiver operating characteristic analysis demonstrated that the CTCP model outperformed ctDNA alone at recurrence prediction, which increased the sensitivity of 2 year RFS from 49.6% by ctDNA alone to 87.5%. Harrell's concordance index, calibration curve, and decision curve analysis also suggested that the CTCP model had good discrimination, consistency, and clinical utility. These results were reproduced in the validation cohort. CONCLUSION: Combining postoperative ctDNA and clinical risk may better predict recurrence than ctDNA alone for developing a personalized postoperative management strategy for CRC.

Assessment of the anti-nociceptive effects of fetal ventral mesencephalic tissue allografts in a rat model of hemi-Parkinson's disease using fMRI.

Extensive studies showed increased subjective pain sensitivity in Parkinson's disease (PD), which appeared to be partially reversed by dopaminergic (DA) treatment. Although cell replacement represents an attractive therapeutic strategy, its potential for PD-related hyperalgesia remains unclear. We investigated re-establishment of DA function via allografting exogenic DA cells on pain hypersensitivity in a rat model of PD. We evaluated the anti-nociceptive effects of fetal ventral mesencephalic (rVM) tissue allografts in PD rats after unilateral 6-OHDA-induced toxicity in the medial forebrain bundle. The drug -induced rotation test was used to validate the severity of the nigrostriatal lesion; von Frey and thermal pain tests were employed to evaluate nociceptive function. Nociception-induced cerebral blood volume (CBV) response was measured using a 4.7-T MR system. Finally, the immunohistochemical (IHC) studies were performed and the results were compared with the imaging findings from functional magnetic resonance imaging (fMRI). The grafts significantly improved drug-induced rotation behavior and increased mechanical and thermal nociceptive thresholds in PD rats. The elevation of CBV signals significantly recovered on the grafted striatum, whereas this effect was inhibited by the D2R antagonist eticlopride in each striatum. Quantitative IHC analysis revealed the transplantation markedly increased the numbers of tyrosine hydroxylase immunoreactive cells. Therefore, we concluded transplantation of rVM tissue results in anti-nociceptive effects and improves motor function. Moreover, in vivo CBV response confirmed the key role of D2R-mediated pain modulation. Therefore, we demonstrate fMRI as a reliable imaging index in evaluating the anti-nociceptive therapeutic effects of fetal rVM transplantation in the rat model of PD.

Multi-Modal Synergistic 99mTc-TRODAT-1 SPECT and MRI for Evaluation of the Efficacy of Hyperbaric Oxygen Therapy in CO-Induced Delayed Parkinsonian and Non-Parkinsonian Syndromes.

Background: Delayed neuropsychiatric syndrome (DNS) is characterized by motor dysfunction after acute carbon monoxide (CO) poisoning. We examined the relationship between dopamine transporter (DAT) loss using kit-based Tc-99m-TRODAT-1 (DAT single-photon emission-computed tomography (SPECT) radioligand) and globus pallidus necrosis on MRI, DAT availability before and after hyperbaric oxygen therapy (HBOT), and feasibility of Tc-99m-TRODAT-1 as an index for parkinsonian syndrome in CO poisoning. Methods: Twenty-one CO-intoxicated patients (mean ± SD age, 38.6 ± 11.4; range, 20−68 years) with DNS underwent Tc-99m-TRODAT-1 SPECT and MRI before HBOT and follow-up Tc-99m-TRODAT-1 SPECT to assess DAT recovery. Neurological examinations for Parkinsonism were performed after development of DNS. Results: Over 70% (15/21) of DNS patients showed globus pallidus necrosis on MRI. Significantly lower bilateral striatal DAT availability was associated with globus pallidus necrosis (p < 0.005). Moreover, 68.4% (13/19) of DNS subjects with Parkinsonian syndrome had lower bilateral striatal DAT availability vs. non-parkinsonian subjects pre- or post-HBOT. The SURs for both striata increased by ~11% post-HBOT in the Parkinsonian group; however, the left striatum presented a significantly higher DAT recovery rate than the right (*** p < 0.005). Conclusions: Coupled Tc-99m TRODAT-1 SPECT and MRI could assist evaluation of Parkinsonism risk and indicate DAT availability after HBOT in CO-poisoned patients with DNS.

Dual-tracer positron emission tomography/computed tomography as an imaging probe of de novo lipogenesis in preclinical models of hepatocellular carcinoma.

Background: De novo lipogenesis is upregulated in many cancers, and targeting it represents a metabolic approach to cancer treatment. However, the treatment response is unpredictable because lipogenic activity varies greatly among individual tumors, thereby necessitating the assessment of lipogenic activity before treatment. Here, we proposed an imaging probe, positron emission tomography/computed tomography (PET/CT) with dual tracers combining 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG), to assess the lipogenic activity of hepatocellular carcinoma (HCC) and predict the response to lipogenesis-targeted therapy. Methods: We investigated the association between 11C-acetate/18F-FDG uptake and de novo lipogenesis in three HCC cell lines (from well-differentiated to poorly differentiated: HepG2, Hep3B, and SkHep1) by examining the expression of lipogenic enzymes: acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN), and ATP citrate lyase (ACLY). The glycolysis level was determined through glycolytic enzymes: pyruvate dehydrogenase expression (PDH). On the basis of the findings of dual-tracer PET/CT, we evaluated the treatment response to a lipase inhibitor (orlistat) in cell culture experiments and xenograft mice. Results: Dual-tracer PET/CT revealed the lipogenic activity of various HCC cells, which was positively associated with 11C-acetate uptake and negatively associated with 18F-FDG uptake. This finding represents the negative association between 11C-acetate and 18F-FDG uptake. Because these two tracers revealed the lipogenic and glycolytic activity, respectively, which implies an antagonism between lipogenic metabolism and glucose metabolism in HCC. In addition, dual-tracer PET/CT not only revealed the lipogenic activity but also predicted the treatment response to lipogenesis-targeted therapy. For example, HepG2 xenografts with high 11C-acetate but low 18F-FDG uptake exhibited high lipogenic activity and responded well to orlistat treatment, whereas SkHep1 xenografts with low 11C-acetate but high 18F-FDG uptake exhibited lower lipogenic activity and poor response to orlistat. Conclusion: The proposed non-invasive dual-tracer PET/CT imaging can reveal the lipogenesis and glycolysis status of HCC, thus providing an ideal imaging probe for predicting the therapeutic response of HCC to lipogenesis-targeted therapy.

Targeting PSEN1 by lnc-CYP3A43-2/miR-29b-2-5p to Reduce ß Amyloid Plaque Formation and Improve Cognition Function.

Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates ß-amyloid (Aß) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to reduce Aß levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer's disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aß accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aß reduction.