Inflammation Triggers Chondrocyte Ferroptosis in TMJOA via HIF-1α/TFRC.

Inflammation and loss of articular cartilage are considered the major cause of temporomandibular joint osteoarthritis (TMJOA), a painful condition of the temporomandibular joint (TMJ). To determine the cause of TMJ osteoarthritis in these patients, synovial fluid of TMJOA patients was compared prior to and after hyaluronic lavage, revealing substantially elevated levels of interleukin (IL) 1ß, reactive oxidative stress (ROS), and an overload of Fe3+ and Fe2+ prior to lavage, indicative of ferroptosis as a mode of chondrocyte cell death. To ask whether prolonged inflammatory conditions resulted in ferroptosis-like transformation in vitro, we subjected TMJ chondrocytes to IL-1ß treatment, resulting in a shift in messenger RNA sequencing gene ontologies related to iron homeostasis and oxidative stress-related cell death. Exposure to rat unilateral anterior crossbite conditions resulted in reduced COL2A1 expression, fewer chondrocytes, glutathione peroxidase 4 (GPX4) downregulation, and 4-hydroxynonenal (4-HNE) upregulation, an effect that was reversed after intra-articular injections of the ferroptosis inhibitor ferrostatin 1 (Fer-1). Our study demonstrated that ferroptosis conditions affected mitochondrial structure and function, while the inhibitor Fer-1 restored mitochondrial structure and the inhibition of hypoxia-inducible factor 1α (HIF-1α) or the transferrin receptor 1 (TFRC) rescued IL-1ß-induced loss of mitochondrial membrane potential. Inhibition of HIF-1α downregulated IL-1ß-induced TFRC expression, while inhibition of TFRC did not downregulate IL-1ß-induced HIF-1α expression in chondrocytes. Moreover, inhibition of HIF-1α or TFRC downregulated the IL-1ß-induced MMP13 expression in chondrocytes, while inhibition of HIF-1α or TFRC rescued IL-1ß-inhibited COL2A1 expression in chondrocytes. Furthermore, upregulation of TFRC promoted Fe2+ entry into chondrocytes, inducing the Fenton reaction and lipid peroxidation, which in turn caused ferroptosis, a disruption in chondrocyte functions, and an exacerbation of condylar cartilage degeneration. Together, these findings illustrate the far-reaching effects of chondrocyte ferroptosis in TMJOA as a mechanism causing chondrocyte death through iron overload, oxidative stress, and articular cartilage degeneration and a potential major cause of TMJOA.

Clonal hematopoiesis related TET2 loss-of-function impedes IL1ß-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1ß is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1ß promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1ß administration, which is resisted by Tet2-deficient HSPCs, and thus IL1ß enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1ß-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

Untangling the Complex Interplay between Social Isolation, Anorexia, Sarcopenia, and Mortality: Insights from a Longitudinal Study.

BACKGROUND: Social isolation is a pervasive and debilitating condition that has adverse prognostic impacts. This condition often co-occurs with other geriatric syndromes, further exacerbating negative health outcomes. Given these considerations, the present study aims to elucidate the roles of social isolation in older adults with anorexia of aging and/or sarcopenia with respect to long-term mortality using a nationally representative cohort study. METHODS: Data were obtained from the Taiwan Longitudinal Study on Aging (TLSA), with a sample size of 3,762 study participants aged 50 years and older. Data from 1999 (wave 4) to 2015 (wave 9) were analyzed. The TLSA questionnaire was used to define social isolation, anorexia, and sarcopenia. Logistic regressions were employed to explore the associations between social isolation, anorexia, and sarcopenia. The Cox proportional hazard model was utilized to examine the synergistic effects of social isolation and anorexia or sarcopenia on 16-year all-cause mortality. RESULTS: After controlling for demographic information and comorbidities, older adults with social isolation were significantly associated with anorexia (adjusted odds ratio [aOR] 1.46 [95% confidence interval: 1.00-2.12, p=0.0475]) and sarcopenia (aOR 1.35 [95% CI: 1.12-1.64, p=0.0021]). Furthermore, the synergistic effects of social isolation with anorexia (aOR 1.65 [95% CI: 1.25-2.18, p=0.0004]) or sarcopenia (aOR 1.65 [95% CI: 1.42-1.92, p<0.0001]) were both significantly associated with higher risks of all-cause mortality, while social isolation alone revealed borderline statistical significance. CONCLUSIONS: Our findings indicate that social isolation is closely linked to anorexia and sarcopenia among middle-aged and older adults. Additionally, social isolation significantly exacerbates the long-term mortality risk associated with anorexia of aging and sarcopenia. However, social isolation alone appears to have borderline long-term mortality risk in this cohort. These findings underscore the importance of addressing social isolation in older adults with anorexia and/or sarcopenia to optimize their health outcomes and mitigate long-term mortality risk.

Dietary rational targeting of redox-regulated genes.

Nutrigenomics is the study of how food and associated nutrients affect gene expression. This field sits at the intersection of diet, the genome and health with the ultimate goal of exploiting its understanding to design a precision nutrition strategy for humans. We have studied diet and nutrigenomics in the context of something we call "dietary rational gene targeting." Here, healthy diet is used to alter disease-causing gene expression back toward the normal to treat various diseases and conditions while lowering treatment cost and toxicity. In this paper, we discuss the use of this strategy to modulate the expression of redox-associated genes to improve human health. Most human disorders are associated, at least to some extent, with oxidative stress and so treatments (including diet) that target redox-related genes have major potential clinical significance. Healthy dietary options here are wide-ranging and include whole foods and botanical-based beverages. In some cases, botanical supplements may also be useful gene modulators although their health benefits are less clear. Key redox gene targets for these dietary agents include antioxidant genes, related transcription factors, detoxification genes, and DNA repair genes. Other important considerations include bioavailability, the contribution of the microbiome, and advancing technologies. In this review, specific examples of redox associated genes and pathologies and their potential treatment with healthy diet are presented to illustrate our approach. This will also serve as a foundation for the design of future clinical studies to improve diet-related health.

Prospective randomized controlled trial comparing treatment efficacy and tolerance of picosecond alexandrite laser with a diffractive lens array and triple combination cream in female asian patients with melasma.

BACKGROUND: Recent evidence suggests melasma to be a photoaging disorder. Triple combination creams (TCC: fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05%) remain the gold standard treatment. Picosecond alexandrite laser treatment using a diffractive lens array (DLA) has been identified to be effective for improving photoaging conditions. OBJECTIVE: We aimed to compare the efficacy and tolerance of the picosecond alexandrite laser with those of DLA and TCC in female Asian patients with melasma. METHODS: Twenty-nine patients were randomly assigned to group A1 (3 laser sessions at 4-week intervals), A2 (5 laser sessions at 4-week intervals) or B (TCC daily for at least 8 weeks and then tapered until the final evaluation). The Melasma Area, Severity Index (MASI) score and VISIA were assessed at baseline, week 12 and week 20. By week 20, the follow-up periods for groups A1 and A2 were 3 months and 1 month, respectively. RESULTS: Nine, 11 and 6 participants in groups A1, A2 and B completed the study, respectively. MASI scores were significantly improved in all 3 groups at weeks 12 and 20. In groups A1, A2 and B, the improvement rates at week 20 were 53%, 38% and 50%, respectively. VISIA® analysis additionally revealed a significant improvement in spots, porphyria, pores and brown spots after 3 laser sessions (P < 0.05). Group A2 showed greater improvements than group A1 in terms of spots, wrinkles and pores; however, only red areas were significantly different (P < 0.001). All side-effects in the 3 groups were transient and gradually subsided after 1-3 months. CONCLUSION: Picosecond alexandrite laser treatment using DLA showed comparable efficacy with TCC for the treatment of melasma. Improvements in texture, spots, wrinkles and pores were observed in the laser groups. Patients with melasma lesions that exhibit telangiectasia may benefit from additional laser treatment sessions.

Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

[Clinical evaluation of two transalveolar methods for sinus augmentation with placing 1 204 implants immediately].

Objective: To compare the clinical outcomes of posterior maxillary implant surgery when using the regular transalveolar approach or with the crestal approach-sinus (CAS-KIT), a device for maxillary sinus membrane elevation by the crestal approach using a special drilling system and hydraulic pressure. Methods: In this retrospective study 887 patients during Jan 2012 to July 2015 in Hangzhou Dental Hospital with underwent either regular transalveolar approach or CAS-KIT approach for maxillary augmentation; whereas 11 patients dropped out for the reason of serious membrane perforations. Totally, 876 patients with 1 204 plants, placed immediately after transalveolar maxillary augmentation, were included in this study. The data analysis was performed by radiological measures to assess the changes in height of maxillary sinus floor after the transalveolar augmentation at different time points. In addition, the complications after surgery, failure rates, osseointegration condition and the performance of rehabilitation were evaluated as well. Results: Five hundred and three patients were experienced with regular transalveolar approach, and 7 patients were drop out for the serious membrane perforations. Thus, 496 patients received 653 implants in this group; the average lifted range in maxillary sinus floor height changes was (4.08±3.45) mm. The complications were minor membrane perforations during procedure in 64 patients, postoperative maxillary sinus infection happening in 2 patients and 13 patients experienced rehabilitation failure. Three hundred and eighty-four patients had CAS-KIT approach with 4 patients dropped out. Three hundred and eighty patients get 551 implants with the mean lifted range of (8.36±4.07) mm in maxillary sinus floor height changes. Minor membrane perforations during procedure occurred in 31 people and 2 got postoperative maxillary sinus infection. The 4 year overall survival rate of 1 204 implants was 97.26%, with four implants fell off after 3 months of rehabilitation and one implant occurred after one year of rehabilitation. Conclusions: The regular transalveolar sinus lift technique is easier and time saving, but the compromised lifting range in maxillary sinus floor height and the comparatively high occurrence of intraoperative membrane perforations should be concerned. Using CAS-KIT could be an alternative method to perform maxillary sinus augmentation with a reduced incidence of complications. There was no statistically difference in implant failure rates and incidence of postoperative maxillary sinus infection between two groups.

Investigation of the antiphase dynamics of the orthogonally polarized passively Q-switched Nd:YLF laser.

The antiphase dynamics of Q-switched orthogonally polarized emissions have been thoroughly investigated. A Nd:YLF crystal with the anisotropic thermal lensing effect is used as the gain medium for achieving dual polarized laser. By using the Cr4+:YAG saturable absorber, the passively Q-switched output shows intriguing switching dynamics, where the number of pulses for both polarized components within one switching period is directly determined by the power ratio between the orthogonally polarized emissions. Experimental results reveal that the pulse energies of every single pulse for both orthogonally polarized states are equal with the maximum value of 223 µJ. The pulse durations for π- and σ-polarization are measured to be 15 ns and 11 ns and the corresponding peak power levels are up to 15.0 kW and 20.3 kW, respectively.

[Effect of traditional Chinese medicine on osseointegration and bone absorption of implants].

Implantation of the base bone in the implant after effective and rapid bone binding and prevention and treatment of bone resorption, to ensure the success of planting surgery is of great significance. This article reviews the mechanism of traditional Chinese medicine promoting bone integration and the etiopathological mechanism of bone resorption, and expounds the influence of traditional Chinese medicine on osseointegration and bone resorption.

NF-κB inhibits the differentiation of hysteromyoma cells by reducing myocardin expression.

OBJECTIVE: To investigate the effect of nuclear factor-kappaB (NF-κB) on the myocardin-mediated differentiation of hysteromyoma cells. MATERIALS AND METHODS: Expression levels of myocardin in hysteromyoma cells from patients with hysteromyoma were detected. Normal uterine smooth muscle cells were used as control group. Overexpression of myocardin in hysteromyoma cells was achieved through lentivirus infection. Changes in expression levels of uterine smooth muscle cell maker p21, p57, Cyclin D1, PCNA, SM22α, and αSMA were detected. Hysteromyoma cells with lentivirus infection were stimulated by lipopolysaccharide (LPS), and changes in expression levels of myocardin were detected. RESULTS: Compared with normal uterine smooth muscle cells, the expression level of myocardin in hysteromyoma cells was extremely low, or even undetectable, and expression levels of smooth muscle cell differentiation markers were also minimal, and cells were in the de-differentiated state. Expression of exogenous myocardin can improve the expression of smooth muscle cell differentiation markers to induce cell re-differentiation. LPS stimulation can activate NF-κB to inhibit myocardin expression, thereby inducing cell dedifferentiation. CONCLUSIONS: NF-κB can inhibit the differentiation of hysteromyoma cells by decreasing the expression level of myocardin.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-glucoside potentiates self-renewal of human dental pulp stem cells via the AMPK/ERK/SIRT1 axis.

AIM: To evaluate the effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) on cell proliferation and examine the mechanisms of THSG-enhanced proliferative potential in human dental pulp stem cells (hDPSC). METHODOLOGY: After treatment with THSG, hDPSC were collected. Cell viability was determined by MTS assay, while messenger RNA (mRNA) expressions of proliferation and stem cell markers were analyzed using real-time PCR. Flow cytometry was also conducted to analysis protein expression of stem cell markers. A colony-forming unit assay of hDPSC was carried out. Cellular telomerase activity was also identified using real-time PCR. In addition, proliferation-related proteins involved in the effects of THSG on hDPSC were analyzed by Western blotting. Data were analyzed using one-way analysis of variance and two-tailed Student's t-test. RESULTS: Cell viability, colony-forming rates and telomerase activities of hDPSCs were enhanced after THSG treatment. mRNA expressions of proliferation markers (including expressions of NAD+-dependent histone deacetylase sirtuin 1 (SIRT1), proliferating cell nuclear antigen (PCNA), cyclin D1 and ribonucleotide reductase subunit M2 (RRM2)) increased significantly after THSG treatment (P < 0.05). Treatment with THSG for 3 h significantly augmented SIRT1 protein expression (P < 0.05). Furthermore, activities of proliferation-related proteins (including AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) had also significantly increased at 3 h (P < 0.05). After THSG treatment, increased gene and protein expressions of pluripotent-like stem cell markers (including NANOG, OCT4, and SOX2) were observed. CONCLUSIONS: 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-glucoside treatment enhanced the renewal ability and proliferative potential of hDPSCs via the AMPK/ERK/SIRT1 axis, which may provide a novel autogenic cell-based therapeutic strategy in regenerative dentistry.

[Bainbridge-Ropers syndrome with ASXL3 gene variation in a child and literature review].

Objective: To investigate the clinical manifestations and genetic features of a child with Bainbridge-Ropers syndrome caused by ASXL3 gene variation and review the literature. Methods: Clinical data and genetic features were collected and analyzed from a child with Bainbridge-Ropers syndrome who was diagnosed in Bao'an Maternity and Child Health Hospital in November 2016. "ASXL3" and "Bainbridge-Ropers" were used as key words to search at China National Knowledge Infrastructure, Wangfang Data Knowledge Service Platform, PubMed and Human Gene Mutation Database up to June 2017. Results: A 2(9/12) years old girl was presented with psychomotor retardation, feeding difficulty, hypotonia and specific craniofacial phenotype. She showed severe growth retardation (height: 84 cm, body weight: 8.0 kg (both were less than 3(rd) percentile rank of the children at the same age) and head circumference: 46 cm(=3rd percentile rank)), without obvious abnormalities in laboratory tests and neuroimaging tests. A de novo heterozygous nonsense variation: c.3349C>T(p.R1117*) in ASXL3 gene was identified by the whole exome sequencing, and the novel variation was classified into pathologic variant based on Standards and guidelines for the interpretation of sequence variants from ACMG. According to literature retrieval, no Chinese cases with ASXL3 variation had been reported. Totally 28 cases including the present girl harboring ASXL3 variations with detailed clinical information were reported. Thirty-one variations in ASXL3 gene were involved, including 1 missense variation and 30 loss of function variations, which were all de novo variations. Conclusions: The clinical features of Bainbridge-Ropers syndrome include severe psychomotor retardation, feeding difficulties, hypotonia and specific facial features. The heterozygous nonsense variation in ASXL3 gene is the cause of the patient. All the pathogenic variations in ASXL3 gene are de novo and loss of function variations.

A haplotype of the dopamine transporter gene modulates regional homogeneity, gray matter volume, and visual memory in children with attention-deficit/hyperactivity disorder.

BACKGROUND: The dopamine transporter gene (DAT1) and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine whether a DAT1 haplotype affected functional and structural brain alterations in children with ADHD and whether those alterations were associated with visual memory. METHOD: We recruited a total of 37 drug-naïve children with ADHD (17 with the DAT1 rs27048 (C)/rs429699 (T) haplotype and 20 without the CT haplotype) and 37 typically developing children (17 with the CT haplotype and 20 without the CT haplotype). Visual memory was assessed by the pattern recognition memory (PRM) and spatial recognition memory (SRM) tasks. We analyzed functional and structural brain architecture with regional homogeneity (ReHo) and gray matter volume (GMV). RESULTS: The CT haplotype was associated with decreased ReHo in the left superior occipital gyrus, cuneus, and precuneus; and decreased GMV in the left superior occipital gyrus, cuneus, and precuneus, and in the right angular gyrus. Significant interactions of ADHD and the CT haplotype were found in the right postcentral gyrus for ReHo and in the right supplementary motor area for GMV. For the ADHD-CT group, we found negative correlations of total correct responses in PRM and SRM and positive correlations of mean latency of correct responses in PRM with the GMV in the left superior occipital gyrus, cuneus, and precuneus. CONCLUSIONS: Our findings suggest that the DAT1-related GMV alterations in the posterior cortical regions may contribute to visual memory performance in children with ADHD.

[Experts consensus on the management of the right heart function in critically ill patients].

To establish the experts consensus on the right heart function management in critically ill patients. The panel of consensus was composed of 30 experts in critical care medicine who are all members of Critical Hemodynamic Therapy Collaboration Group (CHTC Group). Each statement was assessed based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) principle. Then the Delphi method was adopted by 52 experts to reassess all the statements. (1) Right heart function is prone to be affected in critically illness, which will result in a auto-exaggerated vicious cycle. (2) Right heart function management is a key step of the hemodynamic therapy in critically ill patients. (3) Fluid resuscitation means the process of fluid therapy through rapid adjustment of intravascular volume aiming to improve tissue perfusion. Reversed fluid resuscitation means reducing volume. (4) The right ventricle afterload should be taken into consideration when using stroke volume variation (SVV) or pulse pressure variation (PPV) to assess fluid responsiveness.(5)Volume overload alone could lead to septal displacement and damage the diastolic function of the left ventricle. (6) The Starling curve of the right ventricle is not the same as the one applied to the left ventricle,the judgement of the different states for the right ventricle is the key of volume management. (7) The alteration of right heart function has its own characteristics, volume assessment and adjustment is an important part of the treatment of right ventricular dysfunction (8) Right ventricular enlargement is the prerequisite for increased cardiac output during reversed fluid resuscitation; Nonetheless, right heart enlargement does not mandate reversed fluid resuscitation.(9)Increased pulmonary vascular resistance induced by a variety of factors could affect right heart function by obstructing the blood flow. (10) When pulmonary hypertension was detected in clinical scenario, the differentiation of critical care-related pulmonary hypertension should be a priority. (11) Attention should be paid to the change of right heart function before and after implementation of mechanical ventilation and adjustment of ventilator parameter. (12) The pulmonary arterial pressure should be monitored timingly when dealing with critical care-related pulmonary hypertension accompanied with circulatory failure.(13) The elevation of pulmonary aterial pressure should be taken into account in critical patients with acute right heart dysfunction. (14) Prone position ventilation is an important measure to reduce pulmonary vascular resistance when treating acute respiratory distress syndrome patients accompanied with acute cor pulmonale. (15) Attention should be paid to right ventricle-pulmonary artery coupling during the management of right heart function. (16) Right ventricular diastolic function is more prone to be affected in critically ill patients, the application of critical ultrasound is more conducive to quantitative assessment of right ventricular diastolic function. (17) As one of the parameters to assess the filling pressure of right heart, central venous pressure can be used to assess right heart diastolic function. (18). The early and prominent manifestation of non-focal cardiac tamponade is right ventricular diastolic involvement, the elevated right atrial pressure should be noticed. (19) The effect of increased intrathoracic pressure on right heart diastolic function should be valued. (20) Ttricuspid annular plane systolic excursion (TAPSE) is an important parameter that reflects right ventricular systolic function, and it is recommended as a general indicator of critically ill patient. (21) Circulation management with right heart protection as the core strategy is the key point of the treatment of acute respiratory distress syndrome. (22) Right heart function involvement after cardiac surgery is very common and should be highly valued. (23) Right ventricular dysfunction should not be considered as a routine excuse for maintaining higher central venous pressure. (24) When left ventricular dilation, attention should be paid to the effect of left ventricle on right ventricular diastolic function. (25) The impact of left ventricular function should be excluded when the contractility of the right ventricle is decreased. (26) When the right heart load increases acutely, the shunt between the left and right heart should be monitored. (27) Attention should be paid to the increase of central venous pressure caused by right ventricular dysfunction and its influence on microcirculation blood flow. (28) When the vasoactive drugs was used to reduce the pressure of pulmonary circulation, different effects on pulmonary and systemic circulation should be evaluated. (29) Right atrial pressure is an important factor affecting venous return. Attention should be paid to the influence of the pressure composition of the right atrium on the venous return. (30) Attention should be paid to the role of the right ventricle in the acute pulmonary edema. (31) Monitoring the difference between the mean systemic filling pressure and the right atrial pressure is helpful to determine whether the infusion increases the venous return. (32) Venous return resistance is often considered to be a insignificant factor that affects venous return, but attention should be paid to the effect of the specific pathophysiological status, such as intrathoracic hypertension, intra-abdominal hypertension and so on. Consensus can promote right heart function management in critically ill patients, optimize hemodynamic therapy, and even affect prognosis.

[The ocular involvement in the transthyretin-related familial amyloid polyneuropathy].

Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP), which is caused by mutant TTR, is a rare but fatal autosomal dominant disease. TTR is synthesized by the liver (95%) , the choroid plexus of the brain and the retinal pigment epithelium. FAP leads to peripheral neuropathy, and the main ocular manifestations are vitreous opacity (yellowish cotton-like), secondary glaucoma and keratoconjunctivitis sicca. Liver transplantation has proven to be the most effective treatment for TTR-FAP. Nowadays, tafamidis is the only drug approved for TTR-FAP (early stage). However, neither liver transplantation nor tafamidis is capable to halt the progression of ocular involvement. Panretinal photocoagulation could damage the retinal pigment epithelium, and thus prevent the progression. Recent investigations on TTR-FAP and its ocular involvement are reviewed in this article. (Chin J Ophthalmol, 2017, 53: 783-785).

MiR-181b modulates EGFR-dependent VCAM-1 expression and monocyte adhesion in glioblastoma.

Tumor-associated macrophages (TAMs) originate as circulating monocytes, and are recruited to gliomas, where they facilitate tumor growth and migration. Understanding the interaction between TAM and cancer cells may identify therapeutic targets for glioblastoma multiforme (GBM). Vascular cell adhesion molecule-1 (VCAM-1) is a cytokine-induced adhesion molecule expressed on the surface of cancer cells, which is involved in interactions with immune cells. Analysis of the glioma patient database and tissue immunohistochemistry showed that VCAM-1 expression correlated with the clinico-pathological grade of gliomas. Here, we found that VCAM-1 expression correlated positively with monocyte adhesion to GBM, and knockdown of VCAM-1 abolished the enhancement of monocyte adhesion. Importantly, upregulation of VCAM-1 is dependent on epidermal-growth-factor-receptor (EGFR) expression, and inhibition of EGFR effectively reduced VCAM-1 expression and monocyte adhesion activity. Moreover, GBM possessing higher EGFR levels (U251 cells) had higher VCAM-1 levels compared to GBMs with lower levels of EGFR (GL261 cells). Using two- and three-dimensional cultures, we found that monocyte adhesion to GBM occurs via integrin α4ß1, which promotes tumor growth and invasion activity. Increased proliferation and tumor necrosis factor-α and IFN-γ levels were also observed in the adherent monocytes. Using a genetic modification approach, we demonstrated that VCAM-1 expression and monocyte adhesion were regulated by the miR-181 family, and lower levels of miR-181b correlated with high-grade glioma patients. Our results also demonstrated that miR-181b/protein phosphatase 2A-modulated SP-1 de-phosphorylation, which mediated the EGFR-dependent VCAM-1 expression and monocyte adhesion to GBM. We also found that the EGFR-dependent VCAM-1 expression is mediated by the p38/STAT3 signaling pathway. Our study suggested that VCAM-1 is a critical modulator of EGFR-dependent interaction of monocytes with GBM, which raises the possibility of developing effective and improved therapies for GBM.

The zinc-finger transcriptional factor Slug transcriptionally downregulates ERα by recruiting lysine-specific demethylase 1 in human breast cancer.

Estrogen receptor α (ERα) is related with epithelial-mesenchymal transition, invasion and metastasis, and serves as an important therapeutic predictor and prognostic factor in breast cancer patients. The triple negative breast cancer (TNBC) is characterized by loss of hormone receptors and human epidermal growth factor receptor 2 (Her2), and lacks effective targeted therapy with poor prognosis. Unfortunately, the molecular mechanisms of ERα deficiency, which becomes hormone independent and results in resistance to endocrine therapy, remain to be elucidated in breast cancer. In this study, we observed an inverse correlation between Slug, a zinc-finger transcriptional repressor, and ERα expression in both human breast cancer tissues and cell lines. In ERα-negative breast cancer patients, high Slug messenger RNA expression showed obviously shorter relapse-free survival. We found that Slug binds to the E-box located in the promoter of estrogen receptor 1 gene (ESR1) to suppress its expression. More specifically, Slug recruits lysine-specific demethylase 1 (LSD1) to the E-box and thereby inhibits ERα expression by demethylating H3K4me2, which is evidenced by the interaction between Slug and LSD1. Moreover, the amount of H3K4me2 binding to the E-box was significantly increased after LSD1 knockdown in MDA-MB-231 cells. Functionally, the ability to proliferate, invade and metastasize was significantly suppressed after knockdown of either Slug or LSD1 alone, or both simultaneously. Taken together, these results suggest that Slug transcriptionally inhibits ERα expression by recruiting LSD1 to the ESR1 promoter in breast cancers. Thus, targeted inhibition of Slug and LSD1 may restore ERα and lead to resensitization to hormone therapy, providing a novel therapeutic strategy for ERα-negative breast cancer patients, especially for TNBC.

Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis.

Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1ß (IL-1ß) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E2 (PGE2) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.