Impact of anatomical variations of the left ventricular outflow tract on stroke volume calculation by Doppler echocardiography in aortic stenosis.

BACKGROUND: Accurate calculation of stroke volume (SV) by Doppler echocardiography is important for the assessment of aortic stenosis (AS), which may be impacted by anatomical variations of left ventricular outflow tract (LVOT). METHODS: Patients with AS (n = 64) were studied using computed tomography (CT) and transthoracic echocardiography (TTE). Anatomical variations of LVOT areas were measured at (a) the aortic annulus (Aa ); (b) 5 mm (A5 ); and (c) 10 mm below the annulus (A10 ) by CT. LVOT diameters were also measured by 2D TTE at these three levels for calculation of LVOT areas. Stroke volumes (SV) were calculated using continuity equation. The impacts of anatomical variations of LVOT on SV calculation were evaluated. RESULTS: Anatomical LVOT area increased from Aa to A10 (5.0 ± 0.9 cm2 vs 5.8 ± 1.9 cm2 , P < .01). Differences between TTE-calculated LVOT areas and anatomical areas were most significant at A10 due to elongation of mediolateral diameters with variable changes in anteroposterior diameters (5.8 ± 1.9 cm2 vs 3.4 ± 1.1 cm2 , P < .001). Although mean calculated SV by TTE was not significant at different LVOT levels (Aa 69 ± 22 mL, vs A5 66 ± 21 mL, vs A10 66 ± 28 ± 22 mL, P > .05), the most significant variations in individuals were at A10 levels (ΔSV: 8.2 ± 6.4 mL, 12 ± 9%). CONCLUSION: Variations of LVOT anatomy in individuals with AS significantly impact the SV calculated by Doppler echocardiography. These features should be taken into account for AS diagnosis and a clinical decision-making for intervention.

RAB14 activates MAPK signaling to promote bladder tumorigenesis.

Bladder cancer (BC) is a fatal invasive malignancy accounting for approximately 5% of all cancer deaths in humans; however, the underlying molecular mechanisms and potential targeted therapeutics for BC patients remain unclear. We report herein that RAB14 was overexpressed in BC tissues and cells with high metastatic potential and its abundance was significantly associated with lymph node metastasis (P = 0.001), a high-grade tumor stage (P = 0.009), poor differentiation (P < 0.001) and unfavorable prognoses of BC patients (P = 0.003, log-rank test). Interference by RAB14 mediated a reduction in the TWIST1 protein and inhibited cell migration and invasion (P < 0.05). Moreover, silencing RAB14 reduced cell proliferation and induced apoptosis in vitro and suppressed tumorigenesis in a mouse xenograft model. We demonstrated that RAB14-promoted BC cancer development and progression were associated with activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signaling through upregulation of MAPK1/MAPK8 and downregulation of dual-specificity protein phosphatase 6/Src homology 2 domain containing transforming protein/Fos proto-oncogene, AP-1 transcription factor subunit (FOS). We provide evidence that RAB14 acts as a tumor promoter and modulates the invasion and metastatic potential of BC cells via activating the MAPK pathway.

Association of homocysteine, folate, and white matter hyperintensities in Parkinson's patients with different motor phenotypes.

OBJECTIVE: To investigate the association of homocysteine (Hcy), folate, and white matter hyperintensities in Parkinson's disease (PD) with different motor phenotypes. METHODS: Of the PD patients, 176 were included. Based on the Unified Parkinson's Disease Rating Scale, the PD patients were classified into postural instability gait disorder (PIGD) and non-PIGD phenotypes. According to the Fazekas score, patients were divided into the none/mild white matter hyperintensity (WMH) group and the moderate/severe WMH group. The relationship of Hcy, folate, and white matter hyperintensities (WMHs), and the motor phenotype of PD were analyzed. RESULTS: PD-PIGD patients had higher proportion of moderate/severe WMHs, Hcy levels, and lower folate levels than PD-non-PIGD patients (p all ≤ 0.001). In the subgroup analysis, patients with both PD-PIGD and moderate/severe WMHs had the highest Hcy and lowest folate levels compared with others. Binary logistic regression analysis showed that age, folate, and Hcy were independent risk factors for WMHs. In an a priori-determined stratified analysis, after adjustment for confounding factors, the odds ratio of WMHs was 8.01 (95% CI 2.700-23.767, p trend = 0.001) in the patients with Hcy levels in the highest quintile compared with the lowest quintile and 16.81 (95% CI 4.74-59.65, p trend < 0.001) in the patients with folate levels in the lowest quintile compared with the highest quintile. CONCLUSIONS: Our data showed a close association between WMHs and Hcy, folate especially in PD-PIGD patients. It can be speculated that higher Hcy and lower folate probably played important roles in the development of WMHs and motor heterogeneity in PD.

Cardiac-Specific Overexpression of Silent Information Regulator 1 Protects Against Heart and Kidney Deterioration in Cardiorenal Syndrome via Inhibition of Endoplasmic Reticulum Stress.

BACKGROUND/AIMS: Increased endoplasmic reticulum (ER) stress contributes to development of cardiorenal syndrome (CRS), and Silent Information Regulator 1 (SIRT1), a class III histone deacetylase, may have protective effects on heart and renal disease, by reducing ER stress. We aimed to determine if SIRT1 alleviates CRS through ER stress reduction. METHODS: Wild type mice (n=37), mice with cardiac-specific SIRT1 knockout (n=29), or overexpression (n=29), and corresponding controls, were randomized into four groups: sham MI (myocardial infarction) +sham STNx (subtotal nephrectomy); MI+sham STNx; sham MI+STNx; and MI+STNx. To establish the CRS model, subtotal nephrectomy (5/6 nephrectomy, SNTx) and myocardial infarction (MI) (induced by ligation of the left anterior descending (LAD) coronary artery) were performed successively to establish CRS model. At week 8, the mice were sacrificed after sequential echocardiographic and hemodynamic studies, and then pathology and Western-blot analysis were performed. RESULTS: Neither MI nor STNx alone significantly influenced the other healthy organ. However, in MI groups, STNx led to more severe cardiac structural and functional deterioration, with increased remodeling, increased BNP levels, and decreased EF, Max +dp/dt, and Max -dp/dt values than in sham MI +STNx groups. Conversely, in STNx groups, MI led to renal structural and functional deterioration, with more severe morphologic changes, augmented desmin and decreased nephrin expression, and increased BUN, SCr and UCAR levels. In MI+STNx groups, SIRT1 knockout led to more severe cardiac structural and functional deterioration, with higher Masson-staining score and BNP levels, and lower EF, FS, Max +dp/dt, and Max -dp/dt values; while SIRT1 overexpression had the opposite attenuating effects. In kidney, SIRT1 knockout resulted in greater structural and functional deterioration, as evidenced by more severe morphologic changes, higher levels of UACR, BUN and SCr, and increased desmin and TGF-ß expression, while SIRT1 overexpression resulted in less severe morphologic changes and increased nephrin expression without significant influence on BUN or SCr levels. The SIRT1 knockout but not overexpression resulted in increased myocardial expression of CHOP and GRP78. Cardiac-specific SIRT1 knockout or overexpression resulted in increased or decreased renal expression of CHOP, Bax, and p53 respectively. CONCLUSIONS: Myocardial SIRT1 activation appears protective to both heart and kidney in CRS models, probably through modulation of ER stress.

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

Diastolic dysfunction predicts the risk of contrast-induced nephropathy and outcome post-emergency percutaneous coronary intervention in AMI patients with preserved ejection fraction.

Patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF) are at high risk of contrast-induced nephropathy (CIN). However, the risk factors of CIN in AMI patients with preserved LVEF remain largely unknown now. The present study explored the relationship between LV diastolic function and CIN in this patient cohort. The present prospective cohort study enrolled 379 AMI patients with preserved LVEF (≥ 50%) who underwent emergency percutaneous coronary interventions (PCI). Transthoracic echocardiography was performed before PCI using a portable echocardiography system. Diastolic function was graded as normal, indeterminate and diastolic dysfunction according to the current recommendation of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. A total of 88 patients (23.2%) developed CIN. Multivariate logistic regression analysis showed that both diastolic dysfunction (DD) and the mitral E velocity to mitral annular tissue Doppler E' velocity ratio (E/E') were independent predictors of CIN (P < 0.001). Other independent risk factors of CIN included increased Mehran score, ST-segment-elevation myocardial infarction, higher HbA1c and left anterior descending lesion, as well as the use of diuretics. Multivariate Cox regression analysis found that CIN, DD, higher N-terminal pro-B-type natriuretic peptide and HbA1c were independent predictors of MACE 2 years after AMI. Diastolic dysfunction determined before emergency PCI is linked with increased risk of CIN in AMI patients with preserved LVEF. CIN and diastolic dysfunction are independent predictors of MACE at 2 years in this patient cohort.

Insulin upregulates GRIM-19 and protects cardiac mitochondrial morphology in type 1 diabetic rats partly through PI3K/AKT signaling pathway.

Insulin is involved in the development of diabetic heart disease and is important in the activities of mitochondrial complex I. However, the effect of insulin on cardiac mitochondrial nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 subunit of retinoic-interferon-induced mortality 19 (GRIM-19) has not been characterized. The aim of this study was to investigate the effect of insulin on the mitochondrial GRIM-19 in the hearts of rats with streptozotocin (STZ)-induced type 1 diabetes. Protein changes of GRIM-19 were evaluated by western blotting and reverse transcription-quantitative polymerase chain reaction. Furthermore, the effects of insulin on mitochondrial complex I were detected in HeLa cells and H9C2 cardiac myocytes. During the development of diabetic heart disease, the cardiac function did not change within the 8 weeks, but the mitochondrial morphology was altered. The hearts from the rats with STZ-induced diabetes exhibited reduced expression of GRIM-19. Prior to the overt cardiac dilatation, mitochondrial alterations were already present. Following subcutaneous insulin injection, it was demonstrated that GRIM-19 protein was altered, as well as the mitochondrial morphology. The phosphoinositide 3-kinase inhibitor LY294002 had an effect on insulin signaling in H9C2 cardiacmyocytes, and decreased the level of GRIM-19 by half compared with that in the insulin group. The results indicate that insulin is essential for the control of cardiac mitochondrial morphology and the GRIM-19 expression partly via PI3K/AKT signaling pathways.

Protective Effects of Salvianolate on Contrast-Induced Nephropathy after Primary Percutaneous Coronary Intervention: A Prospective Multicenter Randomized Controlled Trial.

OBJECTIVES: This study's aim was to evaluate the protective effects of salvianolate on contrast-induced nephropathy after primary percutaneous coronary intervention (PPCI) compared with normal saline (NS) hydration. METHODS: We enrolled patients with acute myocardial infarction who underwent PPCI in 3 centers in Shanghai. The patients were randomly assigned to the salvianolate group or the NS group. The incidence of CIN, the changes in renal function parameters, and the occurrence of adverse events after the procedure were compared between the 2 groups. We used a multivariate logistic regression analysis to determine the independent correlates of CIN after PPCI. RESULTS: A total of 484 patients were finally included in the statistical analysis. Compared with the control group, salvianolate reduced the incidence of CIN (9.1 vs. 16.3%, p = 0.018) after PPCI. The renal function parameters after PPCI in the salvianolate group were superior to those of the control group (p < 0.05). The composite adverse events rate was significantly lower in the salvianolate group within 1 month after the procedure (9.5 vs. 15.5%, p = 0.046). A higher peak of troponin I and loop diuretic therapy were the independent correlates of CIN after PPCI. CONCLUSIONS: Salvianolate reduces the incidence of CIN and protects renal function after PPCI, and the effects were superior to those of NS hydration.

Interference of GSM mobile phones with communication between Cardiac Rhythm Management devices and programmers: A combined in vivo and in vitro study.

To investigate interference, and how to avoid it, by high-frequency electromagnetic fields (EMFs) of Global System for Mobile Communications (GSM) mobile phone with communication between cardiac rhythm management devices (CRMs) and programmers, a combined in vivo and in vitro testing was conducted. During in vivo testing, GSM mobile phones interfered with CRM-programmer communication in 33 of 65 subjects tested (50.8%). Losing ventricle sensing was representative in this study. In terms of clinical symptoms, only 4 subjects (0.6%) felt dizzy during testing. CRM-programmer communication recovered upon termination of mobile phone communication. During in vitro testing, electromagnetic interference by high-frequency (700-950 MHz) EMFs reproducibly occurred in duplicate testing in 18 of 20 CRMs (90%). During each interference, the pacing pulse signal on the programmer would suddenly disappear while the synchronous signal was normal on the amplifier-oscilloscope. Simulation analysis showed that interference by radiofrequency emitting devices with CRM-programmer communication may be attributed to factors including materials, excitation source distance, and implant depth. Results suggested that patients implanted with CRMs should not be restricted from using GSM mobile phones; however, CRMs should be kept away from high-frequency EMFs of GSM mobile phone during programming.

Distinct phosphotyrosine-dependent functions of the ShcA adaptor protein are required for transforming growth factor ß (TGFß)-induced breast cancer cell migration, invasion, and metastasis.

The ErbB2 and TGFß signaling pathways cooperate to promote the migratory, invasive, and metastatic behavior of breast cancer cells. We previously demonstrated that ShcA is necessary for these synergistic interactions. Through a structure/function approach, we now show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGFß-induced migration and invasion of ErbB2-expressing breast cancer cells. We further demonstrate that the tyrosine phosphorylation sites within ShcA (Tyr(239)/Tyr(240) and Tyr(313)) transduce distinct and non-redundant signals that promote these TGFß-mediated effects. We demonstrate that Grb2 is required specifically downstream of Tyr(313), whereas the Tyr(239)/Tyr(240) phosphorylation sites require the Crk adaptor proteins to augment TGFß-induced migration and invasion. Furthermore, ShcA Tyr(313) phosphorylation enhances tumor cell survival, and ShcA Tyr(239)/Tyr(240) signaling promotes endothelial cell recruitment into ErbB2-expressing breast tumors in vivo, whereas all three ShcA tyrosine residues are required for efficient breast cancer metastasis to the lungs. Our data uncover a novel ShcA-dependent signaling axis downstream of TGFß and ErbB2 that requires both the Grb2 and Crk adaptor proteins to increase the migratory and invasive properties of breast cancer cells. In addition, signaling downstream of specific ShcA tyrosine residues facilitates the survival, vascularization, and metastatic spread of breast tumors.

Myocardial infarction worsens glomerular injury and microalbuminuria in rats with pre-existing renal impairment accompanied by the activation of ER stress and inflammation.

Deterioration of renal function occurs after chronic heart failure in approximately one-third of patients, particularly in those with pre-existing renal impairment such as diabetic nephropathy. Impaired renal function in these patients is always associated with a worse prognosis. However, the mechanisms underlying such deterioration of renal function are still largely unknown. In three separate protocols, we compared 1) sham operation (Ctr, n = 10) with surgically induced myocardial infarction (MI, n = 10); 2) unilateral nephrectomy (UNX, n = 10) with UNX + MI (n = 10); and 3) STZ-induced type 1 diabetes (DB, n = 10) with DB + MI (n = 10). The differences between combined injury models (UNX + MI, DB + MI) and simple MI were also examined. Renal remodeling, function, ER stress (CHOP and GRP78) and inflammation (infiltration of inflammatory cells, NF-κB p65) were evaluated 12 weeks after MI. In common SD rats, MI activated less glomerular ER stress and inflammation, resulting in a minor change of glomerular remodeling and microalbuminuria. However, MI significantly increased the glomerular expression of GRP78 and CHOP in UNX and DB rats. In addition, it also promoted the infiltration of CD4+ T cells, particularly inflammatory cytokine (IFN-γ, IL-17, IL-4)-producing CD4+ T cells, and the expression of NF-κB p65 in the glomeruli. By contrast, significant glomerular fibrosis, glomerulosclerosis, podocyte injury and microalbuminuria were found in rats with UNX + MI and DB + MI. MI significantly increased chronic glomerular injury and microalbuminuria at 12 weeks in rats with pre-existing renal impairment, i.e., UNX and DB, but not common SD rats. These changes were accompanied by increased glomerular ER stress and immune-associated inflammation.

Finite element analysis of endoscopic cross-overtop decompression for single-segment lumbar spinal stenosis based on real clinical cases.

Introduction: For severe degenerative lumbar spinal stenosis (DLSS), the conventional percutaneous endoscopic translaminar decompression (PEID) has some limitations. The modified PEID, Cross-Overtop decompression, ensures sufficient decompression without excessive damage to the facet joints and posterior complex integrity. Objectives: To evaluate the biomechanical properties of Cross-Overtop and provide practical case validation for final decision-making in severe DLSS treatment. Methods: A finite element (FE) model of L4-L5 (M0) was established, and the validity was verified against prior studies. Endo-ULBD (M1), Endo-LOVE (M2), and Cross-Overtop (M3) models were derived from M0 using the experimental protocol. L4-L5 segments in each model were evaluated for the range of motion (ROM) and disc Von Mises stress extremum. The real clinical Cross-Overtop model was constructed based on clinical CT images, disregarding paraspinal muscle influence. Subsequent validation using actual FE analysis results enhances the credibility of the preceding virtual FE analysis. Results: Compared with M0, ROM in surgical models were less than 10°, and the growth rate of ROM ranged from 0.10% to 11.56%, while those of disc stress ranged from 0% to 15.75%. Compared with preoperative, the growth rate of ROM and disc stress were 2.66%-11.38% and 1.38%-9.51%, respectively. The ROM values in both virtual and actual models were less than 10°, verifying the affected segment stability after Cross-Overtop decompression. Conclusion: Cross-Overtop, designed for fully expanding the central canal and contralateral recess, maximizing the integrity of the facet joints and posterior complex, does no significant effect on the affected segmental biomechanics and can be recommended as an effective endoscopic treatment for severe DLSS.

Comparison of the Efficacy and Safety Between Intravenous Thrombolysis, Direct Endovascular Therapy, and Bridging Therapy for Acute Basilar Artery Occlusion in Cerebral Infarction Patients.

OBJECTIVE: To compare the efficacy and safety of intravenous thrombolysis, direct endovascular therapy (EVT), and bridging therapy (BT = intravenous thrombolysis + EVT) for acute basilar artery occlusion cerebral infarction. METHODS: One hundred and fourteen patients with acute basilar artery occlusion cerebral infarctions admitted between January 2020 and August 2023 were selected. Differences in the reperfusion rate, prognosis, incidence of stroke-associated pneumonia, and mortality rate were compared among the 3 groups. RESULTS: There was no statistically significant difference in the percentage of patients who achieved successful reperfusion (86.8% vs. 84.2%) or complete reperfusion (72.1% vs. 68.4%) between the direct EVT and BT groups (both P > 0.05). There were no statistically significant differences in the rates of symptomatic intracranial hemorrhage (3.7% vs. 10.3% vs. 10.5%, P = 0.763). There were statistically significant differences in the rates of good prognosis (modified ranking scale score 0-2) (59.3% vs. 30.9% vs. 26.3%, P = 0.021), stroke-related pneumonia (29.6% vs. 66.2% vs. 36.8%, P = 0.002), and mortality (14.8% vs. 48.5% vs. 42.1%, P = 0.010) among the 3 treatment groups. According to the binary logistic regression analysis, a good prognosis was independently associated with a baseline National Institutes of Health Stroke Scale score ≤ 10 (odds ratio, 3.714; 95% confidence interval, 1.207-11.430; P = 0.022) and the incidence of stroke-associated pneumonia (odds ratio, 0.640; 95% confidence interval, 0.484-0.845; P = 0.002). CONCLUSIONS: Although there were differences in prognosis, mortality, and incidence of complications among the 3 treatment groups, after adjusting for confounding factors, prognosis was independently correlated only with the baseline NIHSS score and stroke-associated pneumonia but not with treatment methods.

FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

Mitochondrial dysfunction in pulmonary artery endothelial cells (PAECs) is related to the pathogenesis of pulmonary hypertension (PH). The mitochondrial receptor protein FUN14 domain containing 1 (FUNDC1) was found to be involved in pulmonary artery smooth muscle cell proliferation in PH. However, its role in PAECs remains unclear. We investigated FUNDC1 expression in the pulmonary artery endothelium in both monocrotaline-induced animal models and TNF-α-stimulated cell models. Additionally, the effect of FUNDC1 on PAECs proliferation and its possible mechanism were also investigated. We observed decreased FUNDC1 protein levels in animals and in vitro in PAECs. FUNDC1 deficiency in PAECs upregulated the expression of the deubiquitination enzyme ubiquitin-specific peptidase 15 (USP15), enhanced dynamin-related protein1 (Drp1)-mediated mitochondrial division, and increased mitochondrial ROS levels via the deubiquitination of Drp1. Additionally, FUNDC1 deficiency increased aerobic glycolysis, the production of ATP and lactic acid, and glucose uptake. FUNDC1 overexpression inhibited PAECs proliferation. Moreover, FUNDC1 overexpression in combination with a mitochondrial division or aerobic glycolysis inhibitor enhanced its inhibitory effect on cell proliferation. Our study findings suggest that FUNDC1 deficiency induced by inflammation can promote PAECs proliferation by regulating mitochondrial dynamics and cell energy metabolism via the USP15/Drp1 pathway.

Effect of cerebral small vessel disease on cognitive impairment in Parkinson's disease.

OBJECTIVES: To explore the association between cerebral small vessel disease (cSVD) and cognitive impairment (CI) in Parkinson's disease (PD). METHODS: 81 PD patients were recruited into the study from September 2018 to December 2020. The demographic characteristics and radiologic and laboratory data were collected. Cognitive assessments were carried out using the Montreal Cognitive Assessment. The association between cSVD and cognitive impairment was analyzed using univariate and binary logistic regression analysis. RESULTS: The binary logistic regression analysis showed that, after correcting for age, educational years, hyperhomocysteinemia, hypertension, and diabetes mellitus, total cSVD scores (OR 1.55, 95% CI 1.07-2.27, P = 0.02), the presence of paraventricular white matter hyperintensity (PVH) (OR 11.78, 95% CI 3.08-45.01, P < 0.001), white matter hyperintensity (WMH) (OR 7.95, 95% CI 2.28-27.79, P = 0.001), and perivascular space (PVS) (OR 6.66, 95% CI 2.08-21.40, P = 0.001) were independent risk factors for PD-CI. CONCLUSION: The presence of cSVD was associated with cognitive dysfunction in patients with PD. It may be beneficial to manage cSVD to prevent the progression of cognitive impairment in patients with PD.

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone.

INTRODUCTION: Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. METHODS: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors. RESULTS: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5. CONCLUSIONS: Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.

Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations.

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.

Lncrna FGD5-AS1 Aggravates Myocardial Ischemia-Reperfusion Injury by Sponging Mir-129-5p.

Background: LncRNA FGD5-AS1 regulates the pathogenesis of many human diseases. We aimed to elucidate the function of lncRNA FGD5-AS1 and the regulatory mechanism of lncRNA FGD5-AS1/miR-129-5p in myocardial ischemia-reperfusion (I/R) injury. Methods: Myocardial I/R injury mice model and H/R treated H9c2 cells were established. RT-qPCR and Western blot analysis were used to detect the mRNA and protein expression. Cell viability was detected by MTT assay. Dual luciferase reporter assay was applied to confirm the relationship between lncRNA FGD5-AS1 and miR-129-5p. Results: LncRNA FGD5-AS1 was upregulated in myocardial I/R injury mice models and H/R treated H9c2 cells. Functionally, knockdown of lncRNA FGD5-AS1 promoted cell viability and inhibited apoptosis in H/R treated H9c2 cells. In addition, lncRNA FGD5-AS1 directly targets miR-129-5p. Upregulation of lncRNA FGD5-AS1 weakened the protective effect of miR-129-5p on myocardial I/R injury. Conclusion: LncRNA FGD5-AS1 aggravates myocardial I/R injury by downregulating miR-129-5p.

Photoacoustic image-guided corpus cavernosum intratunical injection of adipose stem cell-derived exosomes loaded polydopamine thermosensitive hydrogel for erectile dysfunction treatment.

Stem cell-derived exosomes (SC-EXO) was an emerging therapeutic agent in regenerative medicine. Intratunical injection of SC-EXO is considered as a prospective approach for erectile dysfunction (ED) treatment. However, high vascularization of cavernous body makes effective retention a major challenge for SC-EXO intratunical injection. In this study, a Polydopamine nanoparticles (PDNPs) incorporated poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PDNPs-PELA) thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes (EXO). The hydrogels exhibited sol-gel transition at body temperature. Moreover, the in-situ polymerization of PDNPs using poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PELA) block copolymer as a template was found to be more stable dispersion in the gel system. After being encapsulated into the hydrogel, EXO shows sustained release behavior within two weeks. In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons, increase of the cavity's pressure, thereby restoring the erectile function. In particular, since the PDNPs in thermosensitive gels have excellent photoacoustic performance, the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging. These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.