Positive association between cerebral grey matter metabolism and dopamine D2/D3 receptor availability in healthy and schizophrenia subjects: An 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography study

Abstract

Objectives: Overlapping decreases in extrastriatal dopamine D₂/D₃-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.

Methods: To ascertain this, we used two consecutive ¹⁸F-fluorodeoxyglucose and ¹⁸F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.

Results: ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D₂/D₃-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.

Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.     

针刺调控α7nAchR激活胆碱能抗炎通路的研究现状

胆碱能抗炎通路是一条神经免疫通路,主要依靠乙酰胆碱与巨噬细胞及其他细胞表面上的α7nAchR相结合抑制促炎因子的合成与释放,从而防止组织损伤。α7nAchR是胆碱能递质的主要受体,在胆碱能抗炎通路中起关键作用。针刺治疗有明确的抗炎作用,其作用机制可能与调控α7nAchR激活胆碱能抗炎通路有关。近年来虽然国内外学者对针刺抗炎机制进行了大量研究,然而针刺抗炎的作用机制目前仍不明确。该文从胆碱能抗炎通路概述、α7nAchR结构及功能、α7nAchR的分布、α7nAchR在胆碱能抗炎通路的作用、针刺调控α7nAchR激活胆碱能抗炎通路的机制等方面对针刺调控α7nAchR激活胆碱能抗炎通路进行分析总结,为今后探究针刺抗炎作用机制提供借鉴思路和科学依据。     

浅谈“七损八益”与三阴性乳腺癌雌激素受体、雄激素受体的表达

乳腺癌是我国女性发病率第一的恶性肿瘤[1],其中三阴性乳腺癌较其他类型乳腺癌相比,具有治疗棘手、预后更差的特点。"七损八益"是以阴阳损益之道来谈保身长全的理论思想。文章将结合"七损八益"的观点,从其损益转化的角度来讨论三阴性乳腺癌的治疗方法。其中以七损对应三阴性乳腺癌雌激素受体阴性,八益为应用雄激素受体治疗三阴性乳腺癌的手段。试以《内经》"七损八益"理论来探讨三阴性乳腺癌的关系,为研究治疗乳腺癌提供更多的思路。     

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor–Positive Early Breast Cancer

IntroductionA 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor–positive, lymph node–negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries.Patients and MethodsHormone receptor–positive, lymph node–negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period.ResultsThe median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets.ConclusionA nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.     

Sleep disturbances and restless legs syndrome in postmenopausal women with early breast cancer given adjuvant aromatase inhibitor therapy

IntroductionWhether adjuvant therapy with aromatase inhibitors (AIs) causes sleep disturbances or not in postmenopausal women with early breast cancer (EBC) is still a controversial issue.MethodsBetween March 2014 and November 2017, validated questionnaires for assessing insomnia, anxiety, depression, quality of life (QoL) and restless legs syndrome (RLS) were administered to 160 EBC patients at baseline and after 3, 6, 12, and 24 months of AI therapy.ResultsAI therapy significantly decreased the patients’ QoL, but did not influence insomnia, anxiety or depression. However, it significantly increased the frequency and severity of RLS. Patients with RLS at baseline (19%) or who developed RLS during AI therapy (26.3%) reported statistically lower quality of sleep, higher anxiety and depression, and worse QoL compared to patients who never reported RLS (54.7%).ConclusionAlthough AI therapy does not affect sleep quality, it may increase RLS frequency. The presence of RLS could identify a group of EBC patients who may benefit from psychological support.     

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR

androgen receptor

ATP

adenosine triphosphate

CN

copy number

CPT1

carnitine palmitoyltransferase I

CS

citrate synthase

EMT

epithelial–mesenchymal transition

ET

electron transfer‐state

FABP

fatty acid‐binding protein

LD

lipid droplet

OA

oleic acid

PCa

prostate cancer

PPAR

peroxisome proliferator‐activated receptor

PPRE

peroxisome proliferator‐activated receptor response element

TZD

thiazolidinediones

     

沙库巴曲缬沙坦在心力衰竭治疗中的应用

心力衰竭是一种慢性疾病，是心脏无法泵出足够的血液为其他身体器官提供氧气，从而引发呼吸短促、疲劳和水肿等症状。目前其治疗包括病因治疗、一般治疗、药物治疗及非药物治疗等，其中血管紧张素受体脑啡肽酶抑制剂（ARNI）是当前新研发出的一类抗心衰药物，沙库巴曲缬沙坦是其代表药物，具有阻断肾素-血管紧张-醛固酮系统（RAAS）及抑制脑啡肽酶（NEP）的双重作用，新的欧美指南均推荐用于射血分数降低心力衰竭（HFrEF）的治疗。本文现就沙库巴曲缬沙坦在心力衰竭治疗中的作用机理、临床试验、药物安全性作一综述，旨在为该病的临床治疗提供参考。     

Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism

ObjectiveTo investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants.MethodsA trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes.ResultsWES analysis identified biallelic variants in WARS2, encoding the mitochondrial tryptophanyl tRNA synthetase (mtTrpRS), a gene whose mutations have recently been associated with multiple neurological phenotypes, including childhood-onset, levodopa-responsive or unresponsive parkinsonism in a few patients. A substantial reduction of mtTrpRS levels in mitochondria and reduced OXPHOS function was demonstrated, supporting their pathogenicity. Based on the infantile-onset and severity of the phenotype, additional variants were considered as possible genetic modifiers. Functional assessment of a selected panel of candidates pointed to a de novo missense mutation in CHRNA6, encoding the α6 subunit of neuronal nicotinic receptors, which are involved in the cholinergic modulation of dopamine release in the striatum, as a second event likely contributing to the phenotype. In silico, in vitro (Xenopus oocytes and GH4C1 cells) and in vivo (C. elegans) analyses demonstrated the disruptive effects of the mutation on acetylcholine receptor structure and function.ConclusionOur findings consolidate the association between biallelic WARS2 mutations and movement disorders, and suggest CHRNA6 as a genetic modifier of the phenotype.     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.