JMJD2A contributes to breast cancer progression through transcriptional repression of the tumor suppressor ARHI.

INTRODUCTION: Breast cancer is a worldwide health problem and the leading cause of cancer death among females. We previously identified Jumonji domain containing 2A (JMJD2A) as a critical mediator of breast cancer proliferation, migration and invasion. We now report that JMJD2A could promote breast cancer progression through transcriptional repression of the tumor suppressor aplasia Ras homolog member I (ARHI). METHODS: Immunohistochemistry was performed to examine protein expressions in 155 cases of breast cancer and 30 non-neoplastic tissues. Spearman correlation analysis was used to analyze the correlation between JMJD2A expression and clinical parameters as well as several tumor regulators in 155 cases of breast cancer. Gene and protein expressions were monitored by quantitative polymerase chain reaction (qPCR) and Western blot. Results from knockdown of JMJD2A, overexpression of JMJD2A, Co-immunoprecipitation (Co-IP) assay, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) elucidated molecular mechanisms of JMJD2A action in breast cancer progression. Furthermore, the effects of ARHI overexpression on JMJD2A-mediated tumor progression were investigated in vitro and in vivo. For in vitro experiments, cell proliferation, wound-healing, migration and invasion were monitored by cell counting, scratch and Boyden Chamber assays. For in vivo experiments, control cells and cells stably expressing JMJD2A alone or together with ARHI were inoculated into mammary fat pads of mice. Tumor volume, tumor weight and metastatic nodules were measured by caliper, electronic balance and nodule counting, respectively. RESULTS: JMJD2A was highly expressed in human breast cancers and positively correlated with tumor progression. Knockdown of JMJD2A increased ARHI expression whereas overexpression of JMJD2A decreased ARHI expression at both protein and mRNA levels. Furthermore, E2Fs and histone deacetylases were involved in the transcriptional repression of ARHI expression by JMJD2A. And the aggressive behavior of JMJD2A in breast cancers could be reversed by re-expression of ARHI in vitro and in vivo. CONCLUSION: We demonstrated a cancer-promoting effect of JMJD2A and defined a novel molecular pathway contributing to JMJD2A-mediated breast cancer progression.

Anaphylactic deaths: A retrospective study of forensic autopsy cases from 2009 to 2019 in Shanghai, China.

Anaphylaxis is a rare but well-known cause of sudden unexpected death, although data from forensic autopsies in anaphylactic deaths are limited. Herein, a retrospective study of a series of allergic deaths from 2009 through 2019 in Shanghai, China, was conducted to investigate the demographic, medical, and forensic pathological characteristics of fatal anaphylaxis to improve medicolegal understanding on anaphylactic death. Sixty-two autopsy cases of anaphylactic death were registered in this study. Males dominated the cases (74.2%) against females (25.8%), with an average age of 38.8 years. Medications (98.4%), particularly antibiotics (72.6%), were the most frequent cause of anaphylaxis, and 44 cases (71.0%) occurred in clinics administered illegally by unlicensed clinicians. The anaphylactic symptoms began within a few minutes to less than 1 h in 53 cases, with dyspnea (56.5%) and sudden shock (46.8%) being the most common clinical signs. Thirty cases (48.4%) of anaphylaxis resulted in death within 1 h. Laryngeal edema and multiple tissue eosinophil infiltration (85.5%) were the most prevalent autopsy findings, followed by pulmonary edema and congestion (24.2%), which were considered to be non-specific but suggestive. The comorbidities were mainly cardiovascular disease (33.9%), pneumonia (8.1%) and asthma (8.1%). Serum IgE were measured in 11 of 62 cases, ranging from 43.3 to 591 IU/ml, severed as a helpful marker. Therefore, we suggested a thorough analysis of allergen exposure, clinical history and autopsy findings is required for the diagnosis of anaphylactic death currently.

Expression of JMJD2A in infiltrating duct carcinoma was markedly higher than fibroadenoma, and associated with expression of ARHI, p53 and ER in infiltrating duct carcinoma.

Jumonji Domain Containing 2A (JMJD2A) may be a cancer-associated gene involved in human breast cancer. With a view to investigating expression of JMJD2A in human breast cancer and benign lesion tissues as well as relationship between JMJD2A and tumor related proteins, histological and immunohistochemical analysis, Western blot and quantitative real-time PCR in infiltrating duct carcinoma and fibroadenoma for JMJD2A and immunohistochemical analysis and quantitative real-time PCR in infiltrating duct carcinoma for tumor related proteins (ARHI, p53, ER, PR and CerbB-2) were performed. Histological examination validated the clinical diagnosis. The JMJD2A positive rate of infiltrating duct carcinoma was significantly higher than fibroadenoma by immunohistochemical analysis. The mean optical density of JMJD2A in infiltrating duct carcinoma was higher than fibroadenoma by western blot. JMJD2A mRNA level in infiltrating duct carcinoma was higher than fibroadenoma by quantitative real-time PCR. Spearman correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from immunohistochemical results respectively. Pearson correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from quantitative real-time PCR results respectively. Expression of JMJD2A in infiltrating duct carcinoma was higher, and associated with ARHI, p53 and ER. The results may take JMJD2A as a potential diagnostic and therapeutic target in human breast cancer.

The selection of endogenous genes in human postmortem tissues.

Precisely determining the postmortem interval (PMI), which is crucial to criminal and forensic cases, is a research in which quantitative RT-PCR (also known as qRT-PCR or real-time RT-PCR) has been used to analyse gene expression levels and data normalisation should be required to eliminate the differences among the samples. Therefore, it is quite necessary to find stable molecular biological markers in PMI determination research. In this study, we compared nine commonly used endogenous markers (containing ACTB, GAPDH, B2M, U6, 18S rRNA, hsa-mir-1, hsa-mir-9, hsa-mir-194-1 and hsa-mir-203) in the 109 human tissue samples obtained from autopsy at the aim of finding stable markers in human tissues with consideration of the impact of parameters (PMI and cause of death). After RNA was extracted from four tissues (heart, brain, kidney, skin), the Ct values of nine endogenous markers were obtained by qRT-PCR and assessed by geNorm software. The results showed that U6, GAPDH and 18S rRNA were the suitable markers in our set of samples in various corpse conditions, that B2M and ACTB were reliable internal controls in heart tissue only, and that microRNAs had such high M values that they should not be chosen for endogenous control genes.

[The role and significance of microRNA in human cardiovascular disease and forensic science].

microRNA (miRNA or miR) is a small single stranded non-coding RNA (21-25nt) that regulates gene expression in almost creatures. Currently, plenty of researches on how miRNA affects human cardiovascular disease have been reported. This review highlights recent findings about the role of miRNA in heart tissue and circulation correlated with human cardiovascular disease and explores the application of miRNA in sudden cardiac death in forensic science.

Effects of kinesio taping on static balance performance and muscle activity in children with developmental coordination disorder: a single-group pretest-posttest study.

OBJECTIVE: To compare the effects of various kinesio tape applications on static balance and muscle activity in children with developmental coordination disorder.  Methods: Four taping conditions were applied to 48 children with developmental coordination disorder: no taping, gastrocnemius taping, tibialis anterior taping; and peroneus longus taping. Postural sway and electromyographic data were assessed, with eyes closed (30 s), standing still in 2-leg stance, dominant-leg stance, and non-dominant-leg stance. RESULTS: Kinesio taping significantly reduced postural sway in both anteroposterior and mediolateral directions for dominant-leg stance and non-dominant-leg stance, but not 2-leg stance. During single-leg stances, anteroposterior sway was significantly lower for the gastrocnemius taping condition than for the no taping, tibialis anterior and peroneus longus taping conditions, and significantly lower in the tibialis anterior and peroneus longus taping conditions than in the no taping condition (gastrocnemius < tibialis anterior = peroneus longus < no taping). In addition, mediolateral sway was significantly lower in the tibialis anterior and peroneus longus taping conditions than in the no taping and gastrocnemius taping conditions, and significantly lower in the gastrocnemius taping condition than in the no taping condition (tibialis anterior = peroneus longus < gastrocnemius < no taping). Electromyographic data showed that muscle activity was significantly greater only for muscles where kinesio tape was applied. CONCLUSION: Various kinesio tape applications can differentially reduce postural sway and increase muscle activity during single-leg stances in children with developmental coordination disorder.

Cardiotoxicity of current antipsychotics: Newer antipsychotics or adjunct therapy?

Use of newer antipsychotics for substitution of current antipsychotics might be one way awaiting to be clinically verified to address antipsychotic cardiotoxic effects. Alternatively, the combination of existing antipsychotics with cardioprotective agents is also beneficial for patients with mental disorders for avoiding cardiotoxicity to the maximum.

Antipsychotics cardiotoxicity: What's known and what's next.

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns. These cardiotoxic effects range from arrhythmia to heart failure in the clinic, with myocarditis/cardiomyopathy, ischemic injuries, and unexplained cardiac lesions as the pathological bases. Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity. This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level. We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity. We propose that third-generation antipsychotics or drug adjuvant therapy, such as cannabinoid receptor modulators that confer dual benefits - i.e., alleviating cardiotoxicity and improving metabolic disorders - deserve further clinical evaluation and marketing.

Finger soaking enhances effects of light touch on reducing body sway in children with developmental coordination disorder.

OBJECTIVES: To compare sensitivity to light touch in children with developmental coordination disorder and those with typical development. Also, to investigate how changes/increases in sensitivity to light touch influence the effects of light fingertip touch on reducing body sway in both groups, while controlling for the confounding effects of arm configuration. METHODS: Twenty-six children with developmental coordination disorder and 26 typically developing children were enrolled in the study. To change/increase sensitivity to light touch, participants immersed their dominant index finger in a surfactant-water solution. Sensitivity to light touch was measured before and after soaking. Participants performed all conditions (no fingertip touch, light fingertip touch, and light fingertip touch after soaking) with the same arm configuration, while body sway was measured. RESULTS: Analysis of variance (ANOVA) revealed that the children with developmental coordination disorder were less sensitive to light touch than typically developing children (p <0.05). For both groups, immersing a fingertip in surfactant-water solution increased sensitivity to light touch (p < 0.05). Finger soaking enhanced the effects of light fingertip touch on reducing body sway only in those children with developmental coordination disorder (p < 0.05). CONCLUSION: Finger soaking can be used as a rehabilitation strategy for promoting sensitivity to light touch, as well as for enhancing the effects of light fingertip touch in reducing body sway in children with developmental coordination disorder.

External focus of attention concurrently elicits optimal performance of suprapostural pole-holding task and postural stability in children with developmental coordination disorder.

The aim of this study was to determine the effects of different attentional focus conditions (external focus (EF) vs. internal focus (IF) vs. no focus (NF)) on the performance of a pole-holding task and postural stability in children with developmental coordination disorder (DCD) and typically developing children (TDC), while addressing previous study limitations. A total of 186 participants were enrolled in the analysis comprising 91 children with DCD (28 in the EF, 32 in the IF, and 31 in the NF condition) and 95 TDC (31 in the EF, 33 in the IF, and 31 in the NF condition). Participants were required to hold a pole with their hands still and parallel to the floor while focusing on pole movement (EF), focusing on hands (IF), or without focus instructions (NF), while pole movements and postural sway were recorded. Results showed that pole movements were significantly smaller during the EF condition (p < 0.05) compared with IF and NF conditions for both the DCD and TDC groups. In addition, postural sway was significantly lower during the EF condition compared with IF and NF conditions (p < 0.05). This study verified that the EF condition can not only facilitate better performance in holding a pole horizontal and immobile, but also concurrently promote greater postural stability than both IF and NF conditions for children with DCD and TDC.

Lipoxin A4 attenuates brain damage and downregulates the production of pro-inflammatory cytokines and phosphorylated mitogen-activated protein kinases in a mouse model of traumatic brain injury.

The present study was designed to investigate the effects of lipoxin A4 (LXA4) on traumatic brain injury (TBI) and to analyze the possible mechanism. Outcome parameters consist of blood-brain barrier (BBB) breakdown, brain edema and lesion volume. Using western blot and quantitative real-time PCR, we examined the levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) and activation of mitogen-activated protein kinases (MAPKs) (including ERK, JNK, p38) following TBI. To investigate the cell types in which the LXA4 receptor (ALXR) staining was localized, brain sections pulsed with ALXR were subjected to immunofluorescence staining with antibodies against cell type-specific antigens. Our findings show that LXA4 decreases BBB permeability, attenuates brain edema, and reduces TBI-induced lesion volume. In addition, LXA4 inhibits TBI-induced elevation of mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). In the injured cortex at 24h post-TBI, the phosphorylated-ERK (p-ERK) and -JNK (p-JNK), but not -p38 (p-p38) levels were increased. The p-ERK and p-JNK production were attenuated by their respective inhibitors (PD98059 and SP600125), as well as LXA4. Moreover, ALXR was found to label more GFAP positive cells, whereas few CD11b-positive cells were labeled by ALXR within the layers of the injured cortex at 24h post-TBI. The activation of ALXR in astrocytes was partially enhanced by LXA4 treatment. Taken together, these data indicate that TBI activates pro-inflammatory cytokines, the MAPK pathways together with ALXR in astrocytes, and these mechanisms may be exploited by pharmacological interventions.

Poloxamer 188 attenuates in vitro traumatic brain injury-induced mitochondrial and lysosomal membrane permeabilization damage in cultured primary neurons.

Acute membrane damage due to traumatic brain injury (TBI) is a critical precipitating event. However, the subsequent effects of the mechanical trauma, including mitochondrial and lysosomal membrane permeability (MOMP and LMP) remain elusive. The main objective of the current study was to assess the role of a putative membrane-resealing agent poloxamer 188 (P188) in MOMP and LMP in response to a well-defined mechanical insult. Using an in vitro cell shearing device (VCSD), mechanical injury resulted in immediate disruption of membrane integrity in cultured primary neurons, and neurons were treated with P188 or a cathepsin B inhibitor (CBI) after VCSD 10 min. The protective effect of P188 on cultured primary neurons was first detected visually with a light microscope, and measured by MTT assay and LDH assay. The validity of monitoring changes in mitochondrial membrane potential (ΔΨm) was measured by JC-1 staining, and Western blot for cytochrome c and truncated Bid (tBid) in purified mitochondria was also performed. In addition, lysosomal integrity was detected by blotting for cathepsin B and tBid in purified lysosomes. Our results showed post-injury P188 treatment moderated the dissipation of ΔΨm in mitochondria, and inhibited VCSD-induced cytochrome c release from mitochondria as well as cathepsin B from lysosomes. Cathepsin B inhibition (CBI) could also increase cell viability, maintain mitochondrial membrane potential, and repress VCSD-induced release of cytochrome c from mitochondria to cytosol. Both P188 and CBI treatment decreased the cytosolic accumulation of tBid in supernatant of purified lysosomes, and the amount of mitochondrial localized tBid. These data indicate injured neurons have undergone mitochondrial and lysosomal membrane permeability damage, and the mechanism can be exploited with pharmacological interventions. P188's neuroprotection appears to involve a relationship between cathepsin B and tBid-mediated mitochondrial initiation of cell death.