Electroacupuncture promotes remyelination and alleviates cognitive deficit via promoting OPC differentiation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating cerebral vascular disease which causes neurological deficits including long-term cognitive deficit. Demyelination of white matter is correlated with cognitive deficit in SAH. Electroacupuncture (EA) is a traditional Chinese medical treatment which protects against cognitive deficit in varies of neurological diseases. However, whether EA exerts protective effect on cognitive function in SAH has not been investigated. The underlying mechanism of remyelination regulated by EA remains unclear. This study aimed to investigate the protective effects of EA on cognitive deficit in a rat model of SAH. SAH was induced in SD rats (n = 72) by endovascular perforation. Rats in EA group received EA treatment (10 min per day) under isoflurane anesthesia after SAH. Rats in SAH and sham groups received the same isoflurane anesthesia with no treatment. The mortality rate, neurological score, cognitive function, cerebral blood flow (CBF), and remyelination in sham, SAH and EA groups were assessed at 21 d after SAH.EA treatment alleviated cognitive deficits and myelin injury of rats compared with that in SAH group. Moreover, EA treatment enhanced remyelination in white matter and promoted the differentiation of OPCs after SAH. EA treatment inhibited the expression of Id2 and promoted the expression of SOX10 in oligodendrocyte cells. Additionally, the cerebral blood flow (CBF) of rats was increased by EA compared with that in SAH group. EA treatment exerts protective effect against cognitive deficit in the late phase of SAH. The underlying mechanisms involve promoting oligodendrocyte progenitor cell (OPC) differentiation and remyelination in white matter via regulating the expression of Id2 and SOX10. The improvement of CBF may also account for the protective effect of EA on cognitive function. EA treatment is a potential therapy for the treatment of cognitive deficit after SAH.

Descending aorta translocation for bronchial stenosis caused by shorter interaortic distance.

BACKGROUND AND AIM OF THE STUDY: Numerous anatomic relationships of arteries could cause extrinsic compression of the trachea or bronchus. We report a rare left bronchial stenosis just caused by shorter inter-aortic distance. METHODS: One patient wih recurrent coughing and wheezing was diagnosed as left emphysema.Cardiac computed tomography (CTA) shows a shorter distance between ascending aorta (AAo) and descending aorta (DAo) caused left bronchial stenosis with extrinsic compression of right pulmonary artery. RESULTS: A translocation of the descending aorta was performed in this patient, and postoperative CTA showed that the DAo was translocated to the AAo and the left main bronchial stenosis was relieved. CONCLUSIONS: Translocation of the DAo was necessary for the rare left bronchial stenosis caused by shorter inter-aortic distance and could bring a good outcome.

Cardiac-specific methylation patterns of circulating DNA for identification of cardiomyocyte death.

BACKGROUND: Correct detection of human cardiomyocyte death is essential for definitive diagnosis and appropriate management of cardiovascular diseases. Although current strategies have proven utility in clinical cardiology, they have some limitations. Our aim was to develop a new approach to monitor myocardial death using methylation patterns of circulating cell-free DNA (cf-DNA). METHODS: We first examined the methylation status of FAM101A in heart tissue and blood of individual donors using quantitative methylation-sensitive PCR (qMS-PCR). The concentrations and kinetics of cardiac cf-DNA in plasma from five congenital heart disease (CHD) children before and after they underwent cardiac surgery at serial time points were then investigated. RESULTS: We identified demethylated FAM101A specifically present in heart tissue. Importantly, our time course experiments demonstrated that the plasma cardiac cf-DNA level increased quickly during the early post-cardiac surgery phase, peaking at 4-6 h, decreased progressively (24 h) and returned to baseline (72 h). Moreover, cardiac cf-DNA concentrations pre- and post-operation were closely correlated with plasma troponin levels. CONCLUSIONS: We proposed a novel strategy for the correct detection of cardiomyocyte death, based on analysis of plasma cf-DNA carrying the cardiac-specific methylation signature. Our pilot study may lead to new tests for human cardiac pathologies.

Long noncoding RNA GAS5 regulates the proliferation, migration, and invasion of glioma cells by negatively regulating miR-18a-5p.

INTENTION: Long noncoding RNAs, transcribed from a recently discovered class of noncoding genes, may play a critical role in regulating cellular processes, such as cell proliferation and apoptosis, as well as in cancer progression and metastasis. We previously detected the induction of growth arrest-specific 5 (GAS5) during glioma cell death. However, the function and underlying mechanism of GAS5 in human gliomas remain to be elucidated. METHODS: Cell proliferation was detected using CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay (MTS) and tumorigenicity assay in nude mice. Wound-healing assay and transwell assay were utilized to examine the effects of GAS5 expression on glioma cells migration and invasion. In situ hybridization (ISH) was performed to evaluate GAS5 and microRNA (miR)-18a-5p levels in tissue microarrays. The relationship between GAS5 and miR-18a-5p was evaluated by quantitative reverse-transcription polymerase chain reaction and RNA precipitation. RESULTS: In this study, we demonstrated that overexpression of GAS5 inhibits malignant phenotypes in glioma cells, including proliferation, migration, and invasion, whereas GAS5 knockdown enhances these phenotypes. We further observed Argonaute 2-dependent reciprocal repression between GAS5 and miR-18a-5p in glioma cells. Downregulation of GAS5 and upregulation of miR-18a-5p were observed in glioma tissue microarrays relative to normal brain tissue by ISH. By deletion analysis, we identified one miR-18a-5p-binding site within exon 2 of GAS5 that is partially responsible for the tumor-suppressor functions of GAS5. CONCLUSION: Taken together, our findings suggest that GAS5 is a tumor suppressor in human gliomas that acts in part by repressing miR-18a-5p.

An applied anatomical study of bronchial artery.

The aim of this study was to reveal the external features of the bronchial artery (BA) system, so as to provide morphological basis for clinic. The BAs in 48 adult cadavers were dissected and analyzed. The number of BAs in 48 cases was 118. The incidence of BA arising from thoracic aorta, right posterior intercostal artery, and right subclavian artery was 69.49, 27.12, and 3.39%, respectively. The origin of BAs in individual specimen might be single, two, or all of them, respectively. According to the different origin and/or origins of BAs, it could be divided into five categories. As for the course of BAs, in this study, all the left BAs arising from thoracic aorta passed forward around the left side of esophagus and then entered left pulmonary hilum; most (n = 15) of the right BAs arising from thoracic aorta passed forward around the left side of esophagus and then entered right pulmonary hilum; a few (n = 8) of the right BAs arising from thoracic passed forward the right side of esophagus and bronchus and then entered right pulmonary hilum. Besides, in our group, the special courses were that right intercostal-bronchial trunk (RICBT) arising from thoracic aorta passed between vertebra and esophagus and gave off BA which curved forward around the right side of esophagus and then entered right pulmonary hilum, common bronchial trunk (CBT) arising from thoracic aorta passed forward around the left side of esophagus laying anterior to bronchus or posterior to bronchus, then dividing into a left and a right BAs entering right and left pulmonary hilum, respectively. In 4 cadavers, the RICBT gave off the radiculomedullary artery and BA in turn, so radiculomedullary artery has the same origin with BA. Of all BAs, the mean diameter of right posterior intercostal artery, CBT, left BA, and right BA was 2.17 ± 0.84, 1.79 ± 0.57, 1.44 ± 0.50, and 1.39 ± 0.38 mm, respectively. The information gained from this study will be of value in clinic application.

[Identification of 22q11.2 microdeletion among patients with congenital heart diseases using droplet digital PCR].

OBJECTIVE To develop a new method for detecting 22q11.2 deletion syndrome (22q11.2 DS) in clinical settings. METHODS Specific primers and fluorescence probes were designed to target the TBX1 gene within the 22q11.2 deletion region and a reference gene RPP30. Multiplexed droplet digital PCR (ddPCR) was run to detect the 22q11.2 microdeletion by calculating the ratio of positive droplet number of TBX1/RPP30. RESULTS Three cases of 22q11.2 microdeletion previously confirmed by array comparative genome hybridization were successfully identified. Subsequently, the ddPCR detected two further cases of 22q11.2 microdeletion among 14 children with congenital heart diseases. CONCLUSION The ddPCR technique has provided a rapid and cost-effective method for detecting 22q11.2 microdeletion in clinical settings.

Both endoplasmic reticulum and mitochondrial pathways are involved in oligodendrocyte apoptosis induced by capsular hemorrhage.

OBJECTIVE: The white matter injury caused by intracerebral hemorrhage (ICH) includes demyelination and axonal injury. Oligodendrocyte apoptosis is reported to be involved in triggering demyelination. Experimental observations indicate that both endoplasmic reticulum and mitochondrial pathways could mediate cell apoptosis. The purpose of this study was to investigate the demyelination and the possible mechanisms in an autologous blood-injected rat model of internal capsule hemorrhage. METHODS: Transmission electron microscope was applied to examine the pathological changes of myelinated nerve fibers in internal capsule. Western blotting was used to detect the myelin basic protein (MBP) which was an important component of myelin sheath. Double immunofluorescence and Western blotting were used to determine the apoptosis and apoptotic pathways. The levels of caspase-12 (a representative protein of endoplasmic reticulum stress) and cytochrome c (an apoptosis factor released from mitochondria) were assessed in this study. RESULTS: Demyelination occurred on day 1, 3, and 7 after ICH onset. Myelin sheaths of internal capsule nerve fibers were swollen and broken down in ICH groups. MBP expression showed a downregulation after ICH with its minimum value occurred on day 7 post-ICH. Besides, neuron and oligodendrocyte apoptosis were observed at different time intervals post-ICH accompanied with an upregulated caspase-12 expression and enhanced cytochrome c release. CONCLUSIONS: These results suggested that oligodendrocyte and neuron apoptosis may contribute to the demyelination induced by internal capsule hemorrhage and oligodendrocyte apoptosis is positively mediated through both endoplasmic reticulum and mitochondrial pathways.

Altered expression of long non-coding RNAs during genotoxic stress-induced cell death in human glioma cells.

Long non-coding RNAs (lncRNAs), a recently discovered class of non-coding genes, are transcribed throughout the genome. Emerging evidence suggests that lncRNAs may be involved in modulating various aspects of tumor biology, including regulating gene activity in response to external stimuli or DNA damage. No data are available regarding the expression of lncRNAs during genotoxic stress-induced apoptosis and/or necrosis in human glioma cells. In this study, we detected a change in the expression of specific candidate lncRNAs (neat1, GAS5, TUG1, BC200, Malat1, MEG3, MIR155HG, PAR5, and ST7OT1) during DNA damage-induced apoptosis in human glioma cell lines (U251 and U87) using doxorubicin (DOX) and resveratrol (RES). We also detected the expression pattern of these lncRNAs in human glioma cell lines under necrosis induced using an increased dose of DOX. Our results reveal that the lncRNA expression patterns are distinct between genotoxic stress-induced apoptosis and necrosis in human glioma cells. The sets of lncRNA expressed during genotoxic stress-induced apoptosis were DNA-damaging agent-specific. Generally, MEG3 and ST7OT1 are up-regulated in both cell lines under apoptosis induced using both agents. The induction of GAS5 is only clearly detected during DOX-induced apoptosis, whereas the up-regulation of neat1 and MIR155HG is only found during RES-induced apoptosis in both cell lines. However, TUG1, BC200 and MIR155HG are down regulated when necrosis is induced using a high dose of DOX in both cell lines. In conclusion, our findings suggest that the distinct regulation of lncRNAs may possibly involve in the process of cellular defense against genotoxic agents.

Changes in lactate content and monocarboxylate transporter 2 expression in Aß25₋35-treated rat model of Alzheimer's disease.

Decreased brain energy metabolism is correlated with cognitive impairment in Alzheimer's disease (AD). Accumulating evidence indicates that lactate and monocarboxylate transporters (MCTs) participate in brain energy metabolism. To date, changes in lactate level and expression of MCTs in AD remain unclear. This study was conducted to detect the changes in lactate content and expression of MCT2 in Aß25-35-treated rat model of AD. Sprague-Dawley rats were randomly divided into control and model groups, which received bilateral intrahippocampal injections of saline and Aß25-35, respectively. Cognitive functions were detected by Morris water-maze test. Lactate content in the cerebral cortex and hippocampus was measured by absorbance assay. The MCT2 level in the brain was examined by immunohistochemistry and Western blot. Morris water-maze test showed that the model group exhibited impaired learning and memory compared with the control group. Lactate content in the cerebral cortex and hippocampus was decreased in the model group compared with that in the control group. Immunohistochemistry and Western blot showed that the expression of MCT2 in the model group significantly decreased compared with that in the control group. Results indicate that decreased lactate content and downregulated MCT2 expression in the cerebral cortex and hippocampus reflected impaired energy metabolism in the brain, which may participate in the pathologic progression of AD.

Expression of aquaporin8 in human astrocytomas: correlation with pathologic grade.

Aquaporin8 (AQP8), a member of the aquaporin (AQP) protein family, is weakly distributed in mammalian brains. Previous studies on AQP8 have focused mainly on the digestive and the reproductive systems. AQP8 has a pivotal role in keeping the fluid and electrolyte balance. In this study, we investigated the expression changes of AQP8 in 75 cases of human brain astrocytic tumors using immunohistochemistry, Western blotting, and reverse transcription polymerase chain reaction. The results demonstrated that AQP8 was mainly distributed in the cytoplasm of astrocytoma cells. The expression levels and immunoreactive score of AQP8 protein and mRNA increased in low-grade astrocytomas, and further increased in high-grade astrocytomas, especially in glioblastoma. Therefore, AQP8 may contribute to the proliferation of astrocytomas, and may be a biomarker and candidate therapy target for patients with astrocytomas.

The V-shaped double-layer patch technique for complete atrioventricular septal defect: A novel surgical technique.

OBJECTIVE: Several surgical techniques for repair of a complete atrioventricular septal defect have been developed. However, the postoperative complications with these methods may lead to reoperation during follow-up. The aim of this report is to share our experience with a modified surgical technique for complete atrioventricular septal defect that has anatomic advantages postoperatively and could reduce the reoperation rate. METHODS: Twenty-nine patients who underwent repair of complete atrioventricular septal defect using a V-shaped double-layer patch between April 2011 and September 2019 were retrospectively investigated. RESULTS: There were no deaths (0%) and only 1 reoperation (3.4%) in the series. The aortic crossclamp and cardiopulmonary bypass times were 62.7 ± 16.0 minutes and 113.9 ± 25.9 minutes, respectively. The median follow-up duration was 5.1 years. To date, no significant residual ventricular septal defects have been detected and no left ventricular outflow tract obstruction has been seen on echocardiography in any patient. During follow-up, the left atrioventricular valve status was assessed as no incompetence in 9 patients (31.0%), trivial in 18 patients (62.1%), and mild in 2 patients (6.9%). CONCLUSIONS: The V-shaped double-layer patch technique is a valuable surgical option for patients with complete atrioventricular septal defects. The midterm results in our series document excellent performance of this technique, which augments the area of the anterior valve of the left atrioventricular valve to make it closer to a normal mitral valve and may also reduce the need for reoperation.

A mid- and long-team follow-up study of the application of single-valved bovine pericardium patches in right ventricular outflow tract reconstruction.

Background: Pulmonary regurgitation following right ventricular outflow tract (RVOT) reconstruction may cause right heart dysfunction and even right heart failure. Installation of a single valve at this time point can effectively reduce pulmonary regurgitation, thereby protecting right heart function. Here, we analyzed the outcomes and mid- and long-term follow-up data of patients undergoing single-valved bovine pericardium patch (svBPP) placement for reconstruction and explored the effectiveness and gaps of svBPP in preventing right heart failure. Methods: A retrospective analysis was performed on patients undergoing RVOT reconstruction using BalMonocTM svBPP from October 2010 to August 2020. The follow up procedures included outpatient visits and collection of outcomes. The cardiac ultrasound-related indicators during the follow-up visits included ejection fraction (EF), right ventricular end-diastolic diameter (EDD), pulmonary regurgitation, and pulmonary artery stenosis. The survival rates and reoperation-free rate were analyzed by Kaplan-Meier method. Results: Patients includes tetralogy of Fallot, pulmonary atresia and other complex congenital heart disease. A total of 5 patients (5.7%) died during the perioperative period. Early complications included pleural effusion, cardiac insufficiency, respiratory insufficiency, chylothorax, and atelectasis, all of which were cured. After discharge, 83 patients (94.3%) were effectively followed up. During follow-up, 1 patient died and 1 patient underwent reoperation. The 1-, 5-, and 10-year survival rates were 98.8%, 98.8%, and 98.8%, respectively, and the reintervention-free rates for the same intervals were 98.8%, 98.8%, and 98.8%, respectively. The last follow-up ultrasound revealed severe pulmonary stenosis in 0 cases, moderate stenosis in 2 cases, mild stenosis in 7 cases, and no stenosis in 73 cases. Pulmonary regurgitation was not found in 12 patients; however, there were 2 cases of severe pulmonary regurgitation, 20 cases of moderate pulmonary regurgitation, and 48 cases of mild pulmonary regurgitation. Conclusions: As shown in the mid- and long-term follow-up studies, BalMonocTM svBPP has good performance in RVOT reconstruction. It can effectively eliminate or reduce pulmonary valve regurgitation and protect right heart function. Both réparation à l'Etage ventriculaire (REV) and the modified Barbero-Marcial procedure can bring growth potential and reduce reoperation rate.

Electroacupuncture alleviates early brain injury via modulating microglia polarization and suppressing neuroinflammation in a rat model of subarachnoid hemorrhage.

Subarachnoid hemorrhage refers to an uncommon but severe subtype of stroke leading to high mortality and disability rates. Electroacupuncture, a traditional Chinese medical therapy combined with modern technology, shows evident curative effects on cerebral vascular diseases. This study attempts to investigate the possible treatment effects and mechanisms of EA on early brain injury after SAH. Data were gathered among sham group, SAH-induced group, and EA-treated group of male SD rats, concerning mortality rates, weight loss, rotarod latencies, cerebral blood flow, cell apoptosis, pro-inflammatory cytokines releasing, apoptotic protein level, microglia activation and related signal pathway. All results were collected 24-72 h after SAH induction. EA treatment demonstrated significant improvement on motor function 24 h after SAH without significant changes in mortality rate, weight loss, and cerebral blood flow. Another important finding was that EA regulated Bax and Bcl-2 imbalance and reduced cleaved casepase-3 caused by SAH. Additionally, levels of TNF-α, IL-1ß, IL-6 were suppressed. The neuron apoptosis was suppressed by EA. The M1 polarization of activated microglia decreased while M2 polarized phenotype increased after EA treatment. Furthermore, pSTAT3-NOX2 signal axis, the M1 phenotype related activation pathway, was depressed after EA treatment. These findings suggested that EA improved motor deficits and ameliorated early brain injury after SAH probably via decreasing neuron apoptosis and anti-inflammation, which may involve modulation of microglia polarization. Taken together, EA may be a potential therapy for SAH treatment.

An applied anatomical study on the recurrent laryngeal nerve and inferior thyroid artery.

PURPOSE: The aim of this study was to provide some important information about the morphology and topography of the recurrent laryngeal nerve (RLN) and inferior thyroid artery (ITA), which significantly helps localize and protect the RLN in neck surgery, especially in thyroid surgery. METHODS: Eighty adult cadavers (160 sides) fixed with formalin were dissected, analyzed and measured. RESULTS: (1) 87.5% of the RLNs gave off multiple branches like a tree; the incidence of the RLN loop, connecting one branch to another was 3.125%; in 9.375%, one branch of RLN combined with cervical sympathetic chain (CSC) or superior laryngeal nerve (SLN). (2) A double RLN appeared in four sides, a non-recurrent inferior laryngeal nerve appeared in two cases. (3) In two cases, the RLN communicated with both of the SLN and the CSC near thyroid gland. (4) Most of the ITAs was derived from thyrocervical trunk, and divided into two or three branches before entering the thyroid gland. (5) Three ITAs gave off esophageal branch, one ITA gave off tracheal branch, one right ITA originated abnormally. (6) On the left side, the RLN was behind the ITA in 86.25% of the cases, in front of the artery in 7.5%, the nerve was between artery branches in 2.5%, the artery was between nerve branches in 1.25%, and was among the combined in 2.5%. On the right side, the RLN was in front of the artery in 75.0%, behind the artery in 10.0%, among the branches of the artery in 5.0%, 10.0% the branches of both nerves and artery were interlaced that the relationship between the branches of the nerve and the artery was uncertain. CONCLUSIONS: Because of the variability of the RLN and ITA and the complicated relationship between them, it is necessary to dissect and recognize the RLN to avoid mistaking, ignoring, and misligating of the nerve before ligating the ITA.

Superior laryngeal nerve loop: patterns and surgical implications.

This study clarifies the patterns of the superior laryngeal nerve loop (SLN loop), connecting the cervical sympathetic chain (CSC) and the SLN and its branches, so as to provide an anatomic basis for decreasing the risk of injury to the external laryngeal nerve (ELN) during neck surgery. Fifty Chinese adult human cadavers fixed with 4 % formalin were dissected, and their SLN loop patterns were analyzed and summarized. In 98 of 100 sides the CSC anastomosed with the SLN and its branches, forming a looped nerve structure which we called the SLN loop. The SLN loops could be divided into five types: e ( n ), t ( n ), i ( n ), t ( n ) e ( n ), and i ( n ) e ( n ) based on morphological variations. The results demonstrated that e ( n ) was most frequently found in the samples (82/100) followed by t ( n ) (9/100), i ( n ) (3/100), t ( n ) e ( n ) (2/100), and i ( n ) e ( n ) (2/100). Comparing with the previous work, we identified additional 18 subtypes of the SLN loop. The relations of the SLN loop to the surrounding structures were complicated, which brought more challenges to thyroidectomy. Thus, we do not advocate routine identification of ELN/ELN loop during the process of thyroidectomy, especially systematic identification of ELN during operation. However, this study introduces the possibility that nerve injury can be avoided by exposure of the nerve via careful dissection in the region of the superior pole of the thyroid gland to the extent that we can initiate individual ligation of the superior polar vessels, along with the help of neuromonitors, video monitors, and magnifying loupes.

Honokiol exerts protective effects on neural myelin sheaths after compressed spinal cord injury by inhibiting oligodendrocyte apoptosis through regulation of ER-mitochondrial interactions.

OBJECTIVE: To investigate the effect of honokiol on demyelination after compressed spinal cord injury (CSCI) and it's possible mechanism. DESIGN: Animal experiment study. SETTING: Institute of Neuroscience of Chongqing Medical University. INTERVENTIONS: Total of 69 Sprague-Dawley (SD) rats were randomly divided into 3 groups: sham group (n=15), honokiol group (n=27) and vehicle group (n=27). After established CSCI model by a custom-made compressor successfully, the rats of sham group were subjected to the limited laminectomy without compression; the rats of honokiol group were subjected to CSCI surgery and intraperitoneal injection of 20 mg/kg honokiol; the rats of vehicle group were subjected to CSCI surgery and intraperitoneal injection of an equivalent volume of saline.Outcome measures: The locomotor function of each group was assessed using the Basso, Beattie and Bresnahan (BBB) rating scale. The pathological changes of myelinated nerve fibers of spinal cord in 3 groups were detected by osmic acid staining and transmission electron microcopy (TME). Immunofluorescence and Western blot were used to research the experessions of active caspase-3, caspase-12, cytochrome C and myelin basic protein (MBP) respectively. RESULTS: In the vehicle group, the rats became paralyzed and spastic after injury, and the myelin sheath became swollen and broken down along with decreased number of myelinated nerve fibers. Western blot analysis manifested that active caspase-3, caspase-12 and cytochrome C began to increase 1 d after injury while the expression of MBP decreased gradually. After intervened with honokiol for 6 days, compared with the vehicle group, the locomotor function and the pathomorphological changes of myelin sheath of the CSCD rats were improved with obviously decreased expression of active caspase-3, caspase-12 and cytochrome C. CONCLUSIONS: Honokiol may improve locomotor function and protect neural myelin sheat from demyelination via prevention oligodendrocytes (OLs) apoptosis through mediate endoplasmic reticulum (ER)-mitochondria pathway after CSCI.

Liver metastases and the efficacy of the PD-1 or PD-L1 inhibitors in cancer: a meta-analysis of randomized controlled trials.

Objective: To explore the relations between liver metastases (LM) and the efficacy of the treatments with programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. Method: Pubmed, Embase, American Society of Clinical Oncology and the European Society for Medical Oncology were searched to select eligible studies about PD-1 or PD-L1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab, Avelumab, Durvalumab, and Atezolizumab). We included only the original randomized controlled trials (RCTs), including the hazard ratios (HR) of death in both patients with LM and patients without LM. Then the data were extracted for the meta-analysis. Subgroup analyses of cancer types and drug types were also performed. Results: 5293 patients [1246 (24%) patients with LM, and 4047 (76%) patients without LM] from the eight RCTs were included for the final analysis. The pooled hazard ratio (HR) of death in the patients with LM was 0.82 (95% CI, 0.71 to 0.93, P = .003) while the pooled HR in the patients without LM was 0.72 (95% CI, 0.66 to 0.79, P < .001). Additionally, no significant difference was found between the two groups (P = .137). Conclusion: No statistically significant association of liver metastases with the efficacy of treatments with PD-1 or PD-L1 inhibitors in the treatment of advanced or metastatic cancer was found in the stratified analyses. Moreover, future studies about the safety of the PD-1 or PD-L1 inhibitors in patients with or without liver metastases are warranted.

Poldip2 mediates blood-brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model.

BACKGROUND: Specific highly polarized aquaporin-4 (AQP4) expression is reported to play a crucial role in blood-brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ-interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2-mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss. METHODS AND RESULTS: Mouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh-Poldip2) was administered intranasally at 1 hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48 hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5 hour before BM induction. Western blotting, immunofluorescence staining, quantitative real-time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh-Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of ß-dystroglycan (ß-DG), zonula occludens-1 (ZO-1), occludin, and claudin-5; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated ß-DG, ZO-1, occludin, and claudin-5. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of ß-DG, ZO-1, occludin, and claudin-5. CONCLUSION: Poldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs/ß-DG pathway.

Implantation of engineered conduction tissue in the rat heart.

Engineered conduction tissues (ECTs) are cardiac conduction tissues fabricated in vitro to allow for more precisely targeted in vivo transplantation therapy. The transplantation of ECTs may be ideal for the treatment of atrioventricular conduction block and could have a significant impact on the future application of biological pacemakers. However, there is little published information regarding the conduction function of ECTs in vivo. In the present study, ECTs were constructed by seeding cardiac progenitor cells (CPCs) into a collagen sponge and were then transplanted into animal hearts to determine whether they could act as an atrioventricular conduction pathway. The results demonstrated that the transplanted ECTs were adequately vascularized at the early stage of transplantation and could survive in the atrioventricular junction area of rats. A large number of myocardial tissue (≥29% of the new muscle fiber tissue formation area in the implanted ECTs) were observed by Masson's trichrome staining at 60 days post-transplantation. Positive staining for connexin-40, connexin-43, HCN2 and cTnT was exhibited during the period of 20 to 90 days post-transplantation. This result suggested that the transplanted ECTs formed gap junctions with the allogeneic myocardium and developed into cardiac conduction tissues with certain myocardial components. Electrocardiography (ECG) confirmed that there was a clear pre-excitation syndrome in the rats transplanted with ECTs during the period of 20 to 90 days post-transplantation. The recovery rate in the rats implanted with ECTs was 61.54% within 1 h following atrioventricular block, and the heart rhythm following recovery was close to normal. By contrast, the recovery rate was only 4.17% in the rats implanted with blank collagen sponges (BCSs), and none of the sham rats exhibited atrioventricular block recovery. In conclusion, ECTs can survive and mechanically integrate with the allogeneic myocardium following transplantation into rat hearts. An atrioventricular accessory pathway similar to Kent bundles could be established between the atria and ventricles of rats following implantation. It is suggested that ECTs may be a potential substitution therapy for atrioventricular conduction block.

Role of rno-miR-124-3p in regulating MCT1 expression in rat brain after permanent focal cerebral ischemia.

This study aimed to assess the role of microRNAs (miRNAs) in regulating monocarboxylate transporter-1 (MCT1) expression in rat brain after permanent focal cerebral ischemia to identify a new target for early treatment of cerebral ischemia. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion (pMCAO) in rats. Morphology and protein expression levels of MCT1 were assessed by immunofluorescence and Western blotting. Using bioinformatics and double luciferase reporter assays, rno-miR-124-3p was selected as a direct target for rat MCT1. Expression of rno-miR-124-3p after pMCAO was detected. Then, rats were treated with rno-miR-124-3p agomir via lateral ventricle injection, and after 6 h or 24 h ischemia, rno-miR-124-3p expression and gene and protein expression of MCT-1 were detected by qRT-PCR and Western blotting. Brain infarction was identified by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Results showed that pMCAO induced brain infarction and increased the expression of MCT1. The levels of rno-miR-124-3p after pMCAO were in contrast to those of MCT1 protein in ischemic region, while declined after 3, 6 and 12 h of pMCAO in ischemic penumbra. After administration of rno-miR-124-3p agomir, MCT1 mRNA and protein levels were increased after 6 h of pMCAO, while decreased after 24 h of pMCAO. Meanwhile, rno-miR-124-3p levels increased after both times. TTC staining showed treatment with rno-miR-124-3p agomir reduced brain infarction. The role of rno-miR-124-3p in regulating MCT1 was as a positive regulator after 6 h of pMCAO, while a negative regulator after 24 h of pMCAO, however, both activities had protective effects against cerebral ischemia.