MTSC-Net: A Semi-Supervised Counting Network for Estimating the Number of Slash pine New Shoots.

The new shoot density of slash pine serves as a vital indicator for assessing its growth and photosynthetic capacity, while the number of new shoots offers an intuitive reflection of this density. With deep learning methods becoming increasingly popular, automated counting of new shoots has greatly improved in recent years but is still limited by tedious and expensive data collection and labeling. To resolve these issues, this paper proposes a semi-supervised counting network (MTSC-Net) for estimating the number of slash pine new shoots. First, based on the mean-teacher framework, we introduce the improved VGG19 to extract multiscale new shoot features. Second, to connect local new shoot feature information with global channel features, attention feature fusion module is introduced to achieve effective feature fusion. Finally, the new shoot density map and density probability distribution are processed in a fine-grained manner through multiscale dilated convolution of the regression head and classification head. In addition, a masked image modeling strategy is introduced to encourage the contextual understanding of global new shoot features and improve the counting performance. The experimental results show that MTSC-Net outperforms other semi-supervised counting models with labeled percentages ranging from 5% to 50%. When the labeled percentage is 5%, the mean absolute error and root mean square error are 17.71 and 25.49, respectively. These findings demonstrate that our work can be used as an efficient semi-supervised counting method to provide automated support for tree breeding and genetic utilization.

A case report of AQP4-IgG-seropositive refractory neuromyelitis optica spectrum disorder patient with Sjögren's syndrome and pancytopenia treated with inebilizumab.

Patients with neuromyelitis optica spectrum disorder (NMOSD) coexisting with both Sjögren's syndrome (SS) and pancytopenia are exceptionally rare. There is no study on the treatment of such patients. We presented a case of AQP4-IgG seropositive refractory NMOSD patient combined with SS and pancytopenia with significant response to inebilizumab. In 2017 the 49-year-old female patient was diagnosed with SS and pancytopenia without any treatment. In August 2022, she had a sudden onset of lower limbs weakness, manifested as inability to walk, accompanied by urinary incontinence. After receiving methylprednisolone and cyclophosphamide, she regained the ability to walk. In February 2023, she suffered from weakness of both lower limbs again and paralyzed in bed, accompanied by retention of urine and stool, and loss of vision in both eyes. After receiving methylprednisolone and three plasmapheresis, the condition did not further worsen, but there was no remission. In March 2023, the patient was admitted to our hospital and was formally diagnosed with AQP4-IgG seropositive NMOSD combined with SS and pancytopenia. After receiving two 300 mg injections of inebilizumab, not only the symptoms of NMOSD improved significantly, but also the symptoms of concurrent SS and pancytopenia. In the cases of AQP4-IgG seropositive NMOSD who have recurrent episodes and are comorbid with other autoimmune disorders, inebilizumab may be a good choice.

Normalized circulating Tfh and Th17 associates with improvement in myasthenia gravis treated with ofatumumab.

Objective: To assess the effect of B cell depletion therapy (BCDT) on circulating T follicular helper (cTfh) and circulating T helper 17 (cTh17) cells and its relation to clinical improvement in patients with myasthenia gravis (MG). Methods: 28 anti-AchR positive MG patients treated with ofatumumab and 28 healthy controls (HCs) were included. Frequencies of cTfh and cTh17 cells were monitored by flow cytometry at baseline and 4, and 12 weeks after the initial dose ofatumumab. Serum cytokines associated with cTfh and cTh17, including IL-6, IL-21, and IL-17, were also analyzed. Results: The frequency of cTfh and cTh17 significantly increased in MG patients compared with HCs. Additionally, elevated levels of both T-cell subsets correlated with MG severity. During the follow-up, cTfh and cTh17 return to normal after BCDT. Furthermore, the decrease in cTfh and cTh17 was associated with MG scores improvement over time. Notably, cTfh- and cTh17-related cytokines, including IL-6, IL-21, and IL-17, exhibited a marked decrease following ofatumumab therapy. Conclusions: Abnormal expansion of cTfh and cTh17 cells may be key features in the immunopathology of MG. Their levels returned to normal after BCDT, which was closely correlated with clinical amelioration. This result suggests that these two T-cell subsets may be targets for BCDT treatment of MG.

Therapeutic effect of ofatumumab in patients with myasthenia gravis: immunoregulation of follicular T helper cells and T helper type 17 cells.

Introduction: This study aimed to study the therapeutic effects of ofatumumab in patients with myasthenia gravis (MG) in addition to the immunomodulatory effects on peripheral follicular T helper (Tfh) cells and T helper type 17 (Th17) cells. Methods: Thirty-one patients with anti-acetylcholine receptor (AChR) antibody-positive MG were included in this study. At weeks 0, 1, 2, and 4, an initial dose of 20 mg of ofatumumab was injected subcutaneously, with a 2-month follow-up after completing this first cycle. At baseline, 1 month, and 3 months, we assessed the Quantitative MG (QMG), 15-item MG-Quality of Life (MG-QOL15), and MG-Activities of Daily Living (MG-ADL) scales and measured the frequencies of Tfh, Th17, and B cells and the levels of anti-AChR antibody, IL-6, IL-21, and IL-17 in the peripheral blood. Results: At 1 month and 3 months, the QMG, MG-QOL15, and MG-ADL scores were all significantly reduced. At 3 months, doses of prednisone were reduced by an average of 37%. Decreased frequencies of Tfh and Th17 cells, depletion of B cells, and reduced levels of IL-6, IL-21, and IL-17 were all observed at 1 month or 3 months. Discussion: Therefore, the therapeutic effect of ofatumumab could be detected after one cycle of treatment, which was maintained for 2 months. The immunomodulatory effect of ofatumumab during the observation period may involve depletion of B cells, reduction of Tfh and Th17 cells frequencies, and reduced levels of IL-6, IL-21, and IL-17. The findings provide novel data for the potential application of ofatumumab in MG.

Glycemic variability correlates with medial temporal lobe atrophy and decreased cognitive performance in patients with memory deficits.

Background: In the past, researchers have observed a significant link between glycemia and dementia. Medial temporal atrophy (MTA) is regarded as a common marker of dementia. The correlation between glycemic variability and MTA is unclear, and it has not been determined whether glycemic variability can be utilized as a biomarker of MTA and cognitive performance. Methods: The patients in a memory clinic who underwent brain MRI scans and cognitive assessments within the first week of their hospital visit, were enrolled. All participants underwent three fasting blood glucose and one HBA1c assessments on three self-selected days within 1 week of their first visit. The variability independent of the mean (VIM) was employed. Validated visual scales were used to rate the MTA results. The mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales were employed to assess the cognitive functions of the participants. Spearman's correlation and regression models were used to examine the relationship between the MMSE and MoCA scales, and also determine the link between the MRI characteristics and cognitive status, where vascular risk factors, educational status, age, gender, and mean glucose parameters served as covariates. Results: Four hundred sixty-one subjects completed the MMSE scale, while 447 participants completed the MoCA scale. Data analysis revealed that 47.72% of the participants were men (220/461), and the median age of the patients was 69.87 ± 5.37 years. The findings of Spearman's correlation analysis exhibited a strong negative relationship between the VIM and MMSE score (r = -0.729, P < 0.01), and the MoCA score (r = -0.710, P < 0.01). The VIM was regarded as an independent risk factor for determining cognitive impairment in both the MMSE and MoCA assessments. The results were unaffected by sensitivity analysis. In addition, a non-linear relationship was observed between the VIM and MTA scores. Conclusion: The variability in the blood glucose levels, which was presented as VIM, was related to the reduced cognitive function, which was reflected by MMSE and MoCA scales. The relationship between the VIM and the MTA score was non-linear. The VIM was positively related to the MTA score when the VIM was less than 2.42.

Epstein-Barr virus: To be a trigger of autoimmune glial fibrillary acidic protein astrocytopathy?

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease of central nervous system (CNS). It is unclear whether Epstein-Barr virus (EBV) is related to autoimmune GFAP astrocytopathy. OBJECTIVE: To describe the clinical, laboratory, and imaging characteristics of patients with autoimmune GFAP astrocytopathy. METHODS: The clinical, laboratory, and imaging findings of patients are presented. The levels of GFAP in CSF were detected by ELISA. T and B cell subsets in CSF were detected by flow cytometry. GFAP-IgG in serum and cerebrospinal fluid (CSF) were tested by cell-based assay (CBA) and tissue-based assay (TBA). RESULTS: All three patients had fever, cognitive dysfunction, limb weakness, and positive GFAP-IgG with EBV infection in CSF. Enteric glia cells may involve in this disease. Typical imaging findings include the gadolinium enhancement of linear perivascular radial perpendicular to the ventricle, meningeal enhancement (especially in midbrain interpeduncal fossa), longitudinally extensive lesions involving spindle cords, and more T2/Flair-hyperintense lesions in the periventricular white matter at late stage. The patients had poor response to antiviral treatment and strong response to steroid pulse therapy. CONCLUSION: EBV could induce CNS autoimmune response in autoimmune GFAP astrocytopathy. The detection of GFAP-IgG and EBV may facilitate the early diagnosis in these patients.

Ischemic Stroke Shifts the Protein and Metabolite Profiles of Colon in Mice.

Over half of all stroke patients present gastrointestinal complications. It has been speculated that there is an intriguing brain-gut connection. However, molecular mechanisms of the connection remain poorly illuminated. Thus, this study is aimed to investigate molecular alternations regarding proteins and metabolites in the colon upon ischemic stroke using multi-omics analyses. Here, stroke mouse model was induced by means of transient middle cerebral artery occlusion. After the confirmation of successful model evaluated as evidenced by neurological deficit and cerebral blood flow decrease, the proteins and metabolites of colon and brain were respectively measured using multiple omics. Functional analysis of differentially expressed proteins (DEPs) and differential metabolites was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation. There were 434 common DEPs in the colon and brain after stroke. The DEPs in the two tissues displayed common enrichment in several pathways upon GO/KEGG analyses. The common KEGG pathways of DEPs were mainly linked to the inflammation and immune network. Although there was no common differential metabolite and its corresponding pathway in the two tissues, several metabolism pathways in the colon were also changed after stroke. In conclusion, we have demonstrated that the proteins and metabolites in the colon are significantly changed after ischemic stroke, which provides molecular-level evidence regarding the brain-gut connection. In this light, several common enriched pathways of DEPs may become potential therapeutic targets for stroke upon the brain-gut axis. Notably, we have discovered a promising colon-derived metabolite enterolactone possibly beneficial for tackling stroke.

Inhibiting leukocyte-endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no-reflow after arterial recanalization in ischemic stroke.

AIMS: Despite successful vascular recanalization in stroke, one-fourth of patients have an unfavorable outcome due to no-reflow. The pathogenesis of no-reflow is fully unclear, and therapeutic strategies are lacking. Upon traditional Chinese medicine, Tongxinluo capsule (TXL) is a potential therapeutic agent for no-reflow. Thus, this study is aimed to investigate the pathogenesis of no-reflow in stroke, and whether TXL could alleviate no-reflow as well as its potential mechanisms of action. METHODS: Mice were orally administered with TXL (3.0 g/kg/d) after transient middle cerebral artery occlusion. We examined the following parameters: neurological function, no-reflow, leukocyte-endothelial cell interactions, HE staining, leukocyte subtypes, adhesion molecules, and chemokines. RESULTS: Our results showed stroke caused neurological deficits, neuron death, and no-reflow. Adherent and aggregated leukocytes obstructed microvessels as well as leukocyte infiltration in ischemic brain. Leukocyte subtypes changed after stroke mainly including neutrophils, lymphocytes, regulatory T cells, suppressor T cells, helper T type 1 (Th1) cells, Th2 cells, B cells, macrophages, natural killer cells, and dendritic cells. Stroke resulted in upregulated expression of adhesion molecules (P-selectin, E-selectin, and ICAM-1) and chemokines (CC-chemokine ligand (CCL)-2, CCL-3, CCL-4, CCL-5, and chemokine C-X-C ligand 1 (CXCL-1)). Notably, TXL improved neurological deficits, protected neurons, alleviated no-reflow and leukocyte-endothelial cell interactions, regulated multiple leukocyte subtypes, and inhibited the expression of various inflammatory mediators. CONCLUSION: Leukocyte-endothelial cell interactions mediated by multiple inflammatory factors are an important cause of no-reflow in stroke. Accordingly, TXL could alleviate no-reflow via suppressing the interactions through modulating various leukocyte subtypes and inhibiting the expression of multiple inflammatory mediators.

CountShoots: Automatic Detection and Counting of Slash Pine New Shoots Using UAV Imagery.

The density of new shoots on pine trees is an important indicator of their growth and photosynthetic capacity. However, traditional methods to monitor new shoot density rely on manual and destructive measurements, which are labor-intensive and have led to fewer studies on new shoot density. Therefore, in this study, we present user-friendly software called CountShoots, which extracts new shoot density in an easy and convenient way using unmanned aerial vehicles based on the YOLOX and Slash Pine Shoot Counting Network (SPSC-net) models. This software mainly consists of 2 steps. Firstly, we deployed a modified YOLOX model to identify the tree species and location from complex RGB background images, which yielded a high recognition accuracy of 99.15% and 95.47%. These results showed that our model produced higher detection accuracy compared to YOLOv5, Efficientnet, and Faster-RCNN models. Secondly, we constructed an SPSC-net. This methodology is based on the CCTrans network, which outperformed DM-Count, CSR-net, and MCNN models, with the lowest mean squared error and mean absolute error results among other models (i.e., 2.18 and 1.47, respectively). To our best knowledge, our work is the first research contribution to identify tree crowns and count new shoots automatically in slash pine. Our research outcome provides a highly efficient and rapid user-interactive pine tree new shoot detection and counting system for tree breeding and genetic use purposes.

Meta-analysis of risk factors associated with suicidal ideation after stroke.

BACKGROUND: Over the past decade, increasing attention has been paid on post stroke suicide (PSS), which is one of complications of stroke. The rates of stroke and suicide are relatively high, especially in Asian populations. Thus, a deeper understanding of the prevalence and epidemiological impact of suicide after stroke is urgently needed. Clinical diagnosis and prevention of PSS are at the incipient stage, but the risk factors responsible for the occurrence of PSS in different regions and stages of the disease remain largely unknown. The present meta-analysis aimed to determine the incidence of PSS at different stages and time courses, and to identify the underlying risk factors for PSS. METHODS: We systematically searched the Cochrane library, Embase, PubMed, CNKI and Web of Science databases from their inception until April 2019.The research articles reporting on the risk factor for PSS were screened and included in the meta-analysis. The data from the included studies were extracted according to the predefined criteria. RESULTS: A total of 12 studies (n = 2,693,036) were included for meta-analyses. Of these studies, 7 reporting suicide prevalence were meta-analyzed. The pooled estimate of suicidal ideation rates after stroke was 12%, which could be influenced by multiple risk factors, including sex, smoking, depression, sleep disorders, previous stroke and low household income. Studies conducted in Asia demonstrated higher suicide prevalence (approximately 15%) compared to other regions. Smoking, low family income, depression, heart disease and sleep disorders were important risk factors for PSS. When compared to PSS of more than 1 year, the incidence of suicide within 1 year after stroke was more likely to be statistically significant. It was found that 4 out of every 1000 stroke survivors tended to commit suicide. The results of this meta-analysis showed that depression (OR = 2.32; p < 0.01) was significantly associated with suicidal ideation, regardless of stroke duration. CONCLUSION: PSS is one of the common complications of stroke. Despite some limitations, we successfully identified the risk factors associated with suicidal ideation after stroke. Notably, depression was significantly associated with suicidal ideation, regardless of stroke duration. Targeting this risk factor may be helpful to improve stroke patient care and prevent suicidal ideation after stroke. Future research will be carried out to assess whether suicidal ideation or thoughts and actual suicide attempts are strongly predictive of suicide deaths after stroke (Registration No. CRD42019128813).

Total Cerebral Small Vessel Disease Burden on MRI Correlates With Cognitive Impairment in Outpatients With Amnestic Disorders.

Objectives: The main markers of cerebral small vessel disease (cSVD) on MRI may be entered into a scoring system, with the total score representing the overall burden of cSVD. An association between total cSVD score and cognitive dysfunction has been reported in several cohorts. The present study aimed to investigate this association in outpatients with amnestic disorders. Materials and Methods: Outpatients with amnestic complaints in a memory clinic (n = 289) were recruited retrospectively. All the patients had undergone clinical and cognitive evaluation at first presentation. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scale. The total cSVD score was based on the following markers on MRI: lacune; white matter hyperintensities, microbleed, and enlarged perivascular spaces. The association between total cSVD score and MoCA score was tested via Spearman's analysis and a linear regression model. Results: Among the 289 patients, rates for 0-4 cSVD markers respectively ranged from 30.4 to 2.8%. A multiple linear regression model revealed an inverse correlation between the total cSVD score and MoCA score. The association remained significant after adjusting for gender, age, education, levels of medial temporal lobe atrophy, and classical vascular risk factors [ß = -0.729, 95% CI (-1.244, -0.213); P = 0.006]. When individual markers were individually analyzed after adjusting for the same factors, only microbleed associated with MoCA score [ß = -3.007, 95% CI (-4.533, -1.480), P < 0.001]. Conclusions: A significant association was demonstrated between total cSVD score and cognitive performance in the outpatients with amnestic disorders.

Fire Acupuncture versus conventional acupuncture to treat spasticity after stroke: A systematic review and meta-analysis.

BACKGROUND: Post-stroke spasm is currently a complex clinical problem that remains to be resolved. Due to its excellent efficacy and few side effects, clinicians have used fire acupuncture to treat post-stroke spasticity in China. OBJECTIVES: The purpose of this study was to evaluate the clinical efficacy of fire acupuncture compared with conventional acupuncture to treat post-stroke spasms and provide a detailed summary of the commonly used acupoints. METHODS: Eight databases (MEDLINE/PubMed, Web of Science, the Cochrane database, EMBASE, CBM, CNKI, WanFang, and VIP) were searched for randomized controlled trials (RCTs) published from database inception through August 30, 2020. RCTs that compared fire acupuncture with conventional acupuncture as a treatment intervention for patients with spasticity after stroke were included. Revman 5.3 software was used to calculate risk ratios (RR) and standard mean differences (SMD) with 95% confidence intervals (CI). Methodological evaluation or critical appraisal of the included articles was assessed using RoB-2. RESULTS: Sixteen studies with a total of 1,118 patients were included. Although according to the standards of the Rob 2.0 tool, most studies are considered to have some problems. Comprehensive analysis of the results revealed a consistent trend indicating several advantages of using fire needles compared to conventional acupuncture in treating post-stroke spasms, including the effective rate, recovery rate, and improvement of multiple scales represented by MAS. Concerning secondary outcomes, using the scales of FMA, BI, or NDS in this random model meta-analysis, fire acupuncture exhibited better performance compared to acupuncture [SMD = 2.27, 95%CI [1.40,3.13 (random-effects model) ], [SMD = 1.46,95% CI [1.03,1.90 (random-effects model)], and [SMD = 0.90, 95%CI [0.44,1.35 (random-effects model)], respectively, with moderately high heterogeneity. When the effective rate was used as an outcome in the subgroup analysis, fire needles performed better than conventional acupuncture with respect to damage to the upper or lower limbs, and the thickness and depth of acupuncture. When the modified Ashworth scale (MAS) was used as the outcome, and the damage occurred in the lower extremity, the acupuncture depth exceeded 15mm, or the duration of stroke was longer than six months, the fire needles did not perform better than conventional acupuncture, [SMD = 0.01, 95%CI [-0.47,0.48 (fix-effects model)], [SMD = 0.21 [-0.51,0.93(random-effects model)], and [SMD = 0.76, 95%CI [-0.08,1.60 (random-effects model)], respectively. The acupoints identified with the highest frequencies in this study were Yang-meridian, including LI11-Quchi (nine times), LI4-Hegu (seven times), and ST36-Zusanli (five times). Moreover, no serious adverse effects were reported in any of the studies included in this analysis. CONCLUSIONS: Despite several limitations, this was the first meta-analysis to focus on the treatment of post-stroke spasticity using fire needle acupuncture compared with conventional acupuncture. Our results confirmed that fire needles could provide a better clinical effect than conventional acupuncture, which will help standardize fire needle treatment strategies for post-stroke spasms.

Related risk factors associated with post-stroke fatigue: a systematic review and meta-analysis.

BACKGROUND: Post-stroke fatigue (PSF) is one of the most common complications of stroke and has a negative impact on quality of life over time. Although several therapeutic approaches have been explored in the last decade, the risk factors responsible for the occurrence of PSF are still largely unknown. OBJECTIVE: The aim of this meta-analysis was to identify the risk factors contributing to PSF, especially clinical and social risk factors, which may help to prevent PSF. METHODS: A systematic literature search was performed with PubMed, EMBASE, Cochrane Library, and Web of Science databases from inception until April 2019. Only original studies measuring the association between potential risk factors and PSF were included. All relevant data the included studies were extracted by two independent reviewers using predefined data fields. RESULTS: Fourteen studies (n = 3933) were included in this meta-analysis. Female (OR = 1.39; p < 0.01), thalamus (OR = 1.76; p = 0.02), leucoaraiosis (OR = 1.73; p < 0.01), NIHSS score (OR = 1.16; p < 0.01), modified Rankin Scale (OR = 1.63; p < 0.01), depression (OR = 1.75; p < 0.01), and sleeping disturbances (OR = 2.01; p < 0.01) were all significantly associated with PSF. In the subgroup analysis, depression (OR = 2.75; p < 0.01) tended to be associated with Asian patients with PSF. For patients who had a stroke survive for more than half a year, PSF was more likely to occur in stroke survivors with depression (OR = 1.46; p < 0.01), anxiety (OR = 1.13; p < 0.01), or sleeping disturbances (OR = 1.98; p < 0.01). CONCLUSION: Despite some limitations, this study first identified that female and depression conferred an increased susceptibility to PSF, regardless of whether in European or Asian populations. Risk factors associated with PSF included female, thalamic, leucoaraiosis, depression, sleeping disturbances, diabetes mellitus, and anxiety. This meta-analysis shows that chronic PSF appears to be largely attributable to patients with multiple comorbidities. It is necessary to strengthen the treatment for stroke-related complications and improve stroke patient care, which could help to reduce the incidence of PSF. TRIAL REGISTRATION: CRD42019128751.

RCC2 Expression Stimulates ER-Positive Breast Tumorigenesis.

OBJECTIVE: Regulator of chromosome condensation 2 (RCC2) has been reported to be involved in the regulation of cell cleavage. This study investigated the effect of RCC2 expression on breast tumorigenesis. METHODS: MCF-7 cells originating from estrogen receptor-positive (ER+) breast cancer were transfected with anti-RCC2 siRNA or RCC2-expressing plasmids. Cell proliferation, apoptosis, migration, and cytokine production in the transfected cells were examined using the CCK-8 assay, wound healing assay, and flow cytometry, respectively. PCR array was used to investigate the tumorigenic pathway of RCC2 in MCF-7 cells transfected with the anti-RCC2 siRNA. MCF-7 cells were also transfected with lentivirus-containing anti-RCC2 short hairpin RNA and were injected into BALB/c nude mice to generate tumor-bearing mice. Tumor growth in the mouse model was examined using magnetic resonance imaging by diffusion-weighted imaging analysis. RESULTS: Western blotting and immunohistochemistry detected significantly increased expression of RCC2 in ER + breast tumor tissues compared with breast fibroadenoma samples. Inhibiting RCC2 expression decreased cell migration and stimulated apoptosis in MCF-7 cells, while overexpressing RCC2 stimulated cell migration and inhibited apoptosis. The inhibition of RCC2 expression significantly decreased breast tumor growth and IL-6 levels in the tumor-bearing mice. PCR array demonstrated that inhibiting RCC2 expression significantly decreased the expression of IGF1 and TWIST1, two well-known tumor-enhancing genes, in MCF-7 cells; conversely, overexpressing RCC2 increased the expression levels of these two genes in the transfected cells. This result was verified in the mouse model following inhibition of RCC2 expression in MCF-7 cells. Additionally, estradiol-17ß suppressed MCF-7 cell apoptosis, stimulated cell proliferation and cell migration, and increased RCC2, IGF1, and TWIST1 expression. The siRNA-mediated inhibition of RCC2 expression alleviated the inhibitory effects of estrogen on apoptosis in MCF-7 cells, while overexpressing RCC2 enhanced the estrogen-driven inhibition of apoptosis. Modifying RCC2 expression had no impact on MCF-7 cell proliferation in the presence or absence of estradiol-17ß. CONCLUSIONS: Our results suggest that estrogen-induced RCC2 expression prompts IGF1, TWIST1, and IL-6 expression, stimulates cell migration, and inhibits apoptosis to contribute to ER + breast tumorigenesis.

Epigallocatechin Gallate Attenuates ß-Amyloid Generation and Oxidative Stress Involvement of PPARγ in N2a/APP695 Cells.

The accumulation of ß-amyloid (Aß) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aß is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aß generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aß production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aß generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.

Fuzhisan ameliorates Aß production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

Accumulation of amyloid-ß (Aß) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3ß (GSK3ß) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3ß. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aß production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3ß signaling which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Roles of genetic variants in the PI3K/PTEN pathways in susceptibility to colorectal carcinoma and clinical outcomes treated with FOLFOX regimen.

The genetic or abnormal activation of PI3K/PTEN signaling pathway play an important role with regard to disease progression in variety of human malignancies. Experimental and epidemiologic studies indicated that the genetic polymorphisms in the PTEN, PI3K genes are associated with cancer risk, yet little evidence exists for those 2 genes and colorectal cancer (CRC) risk. To address this, we evaluated whether PTEN rs701848, PIK3CA rs2699887 variants are associated with CRC susceptibility, clinicopathological parameters and clinical outcomes in CRC patients treated with FOLFOX (Oxaliplatin, Leucovorin, 5-Fluorouracil) regimen. A case-control study was performed in 780 CRC patients and 764 healthy controls using the TaqMan assay method. A significant increased risk of CRC was observed in patients carrying PTEN rs701848 TC or CC genotype (adjusted OR=1.306, 95% CI=1.030-1.655, P=0.027; adjusted OR=1.543, 95% CI=1.148-2.075, P=0.004, respectively), TC/CC genotype (adjusted OR=1.367, 95% CI=1.090-1.714, P=0.043) in the dominant model, and C allele (adjusted OR=1.229, 95% CI=1.067-1.416, P=0.004). However, no association was detected between rs2699887 in the PIK3CA gene and CRC risk. A significant association was found between pathological grade (Dukes A and B vs. Dukes C and D) and PIK3CA rs2699887 genotypes. Furthermore, Kaplan-Meier analysis revealed that PTEN rs701848 genotypes were significantly associated with the overall survival (OS) of CRC patients treated with FOLFOX regimen (n=780). Individuals carrying PTEN rs701848 TC or TC/CC genotypes showed significantly longer median survival time (MST) than TT genotype and significant hazard ratio (TC: adjusted HR=0.523, 95% CI=0.325-0.840, P=0.007; TC/CC: adjusted HR=0.545, 95% CI=0.351-0.845, P=0.007). Therefore, rs701848 polymorphism in the PTEN gene is associated with susceptibility to CRC, and C allele of rs701848 showed significant independent better prognosis of CRC patients treated with FOLFOX regimen. These results indicate that rs701848 in the PTEN gene might be a candidate pharmacogenomic factor to assess the susceptibility and prognosis in CRC patients.

Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan.

The aim of this study was to investigate the effects of fuzhisan (FZS, 10mg/day), a Chinese herbal medicine, on cerebral glucose metabolism and neuropsychological metrics in patients with mild-to-moderate Alzheimer's disease (AD). This was a 12-week, randomized, double-blind, placebo-controlled pilot study. Twenty-two subjects were randomly assigned to groups that received FZS (n=12) or placebo (n=10). Positron emission tomography (PET) was used to study the regional cerebral metabolic rate of glucose consumption (rCMRglc) at baseline and week 12. We evaluated the clinical efficacy of FZS on cognition and behavioral functions using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Neuropsychiatric Index (NPI), respectively. Compared with placebo, FZS significantly improved ADAS-Cog scores and NPI scores at week 12. Moreover, FZS treatment favorably improved rCMRglc in the bilateral temporal and parietal cortices, hippocampus, and posterior cingulate gyrus. These results suggest that FZS treatment may have a positive effect on cognition, behavioral functions, and rCMRglc in mild-to-moderate AD patients.

Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons.

It has been shown that ß-amyloid (Aß) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aß(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aß(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aß(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aß(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.