Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer.

Background: Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy. Methods: A retrospective review was conducted on LAPC patients treated either with IRE in combination with chemotherapy and PD-1/PD-L1 blockade (group A) or with IRE with chemotherapy alone (group B) from July 2015 to June 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS), with immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses. Results: A total of 103 patients were included in the final analysis, comprising 25 in group A and 78 in group B. The median duration of follow-up was 18.2 months (3.0-38.6 months). Group A patients demonstrated improved survival compared to group B (median OS: 23.6 vs. 19.4 months, p = 0.001; median PFS: 18.2 vs. 14.7 months, p = 0.022). The data suggest a robust immune response in group A, while adverse events related to the treatment were similar in both groups. The multivariate analysis identified the combination of IRE, chemotherapy, and PD-1/PD-L1 blockade as an independent prognostic factor for OS and PFS. Conclusion: The addition of PD-1/PD-L1 blockade to the regimen of IRE combined with chemotherapy enhanced antitumor immunity and extended survival in LAPC patients.

The Relationship Between Prognostic Nutritional Indexes and the Clinical Outcomes of Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: Nutritional status is related to the clinical outcomes of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aim of this study was to investigate the association between nutritional status, measured by the prognostic nutritional index (PNI), and adverse hospitalization outcomes in patients with AECOPD. Methods: Consecutive AECOPD patients admitted to the First Affiliated Hospital of Sun Yat-sen University between January 1, 2015 to October 31, 2021 were enrolled. We collected the clinical characteristics and laboratory data of patients. Multivariable logistic regression models were developed to assess the relationship between the baseline PNI and adverse hospitalization outcomes. A generalized additive model (GAM) was used to identify any non-linear relationship. In addition, we performed a subgroup analysis to tested the robustness of the results. Results: A total of 385 AECOPD patients were involved in this retrospective cohort study. Based on the tertiles of PNI, patients in the lower tertiles of PNI showed more worse outcome incidence (30 [23.6%] versus 17 [13.2%] versus 8 [6.2%]; p < 0.001). Multivariable logistic regression analysis revealed that the PNI were independently associated with adverse hospitalization outcomes after adjustment for confounding factors (Odds ratio [OR] = 0.94, 95% CI: 0.91 to 0.97, P < 0.0001). After adjusting for confounders, smooth curve fitting showed a saturation effect, suggesting that the relationship between the PNI and adverse hospitalization outcomes was nonlinear. Two-piecewise linear regression model suggested that the incidence of adverse hospitalization outcomes significantly decreased with PNI level up to the inflection point (PNI = 42), and PNI was not associated with adverse hospitalization outcome after that point. Conclusion: Decreased PNI levels at admission were determined to be associated with adverse hospitalization outcomes in patients with AECOPD. The results obtained in this study may potentially assist clinicians optimize risk evaluations and clinical management processes.

Irreversible tyrosine kinase inhibitors induce the endocytosis and downregulation of ErbB2.

Erb-b2 receptor tyrosine kinase 2 (ErbB2) is an oncogene that frequently overexpressed in a subset of cancers. Anti-ErbB2 therapies have been developed to treat these types of cancers. However, less is known about how anti-ErbB2 drugs affect the trafficking and degradation of ErbB2. We demonstrate that the reversible and irreversible tyrosine kinase inhibitors (TKIs) differentially modulate the subcellular trafficking and downregulation of ErbB2. Only the irreversible TKIs can induce the loss of ErbB2 expression, which is not dependent on proteasome or lysosome. The irreversible TKIs promote ErbB2 endocytosis from plasma membrane and enhance the ErbB2 accumulation at endosomes. The endocytosis of ErbB2 is mediated by a dynamin-dependent but clathrin-independent mechanism. Blocking of ErbB2 endocytosis can impair the TKI-induced ErbB2 downregulation.

Association of Red Cell Index and Adverse Hospitalization Outcomes in Chronic Obstructive Pulmonary Disease Patients with Acute Exacerbation: A Retrospective Cohort Study.

Purpose: Previous studies have shown that the red cell index (RCI) can be considered as a simple and useful method to evaluate respiratory function. However, at present its association with adverse hospitalization outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not fully understood. Our study aimed to examine the relationship between adverse hospitalization outcomes and RCI among AECOPD patients. Patients and Methods: We performed a retrospective analysis of consecutive patients from January 2015 to October 2021. In this study, RCI was the independent variable, measured at baseline, and adverse hospitalization outcome was the dependent variable. According to the RCI median (RCI=2.221), we divided 377 patients into two roughly equal groups (188 and 189, respectively). Next, the association between RCI and adverse hospitalization outcomes was explored using multivariable logistic regression models. To identify any non-linear relationship, a generalized additive model (GAM) was employed. Results: With a total of 377 patients with AECOPD, we divided them into two roughly equal groups to compare the clinical factors and RCI levels. The patients in the higher RCI group showed poorer outcome incidence (18 [9.57%] vs 31 [16.40%]; p = 0.049). After accounting for potential confounders, the results showed that RCI was positively associated with adverse hospitalization outcomes (odds ratio [OR] = 1.15, 95% CI: 1.01-1.32). In addition, a non-linear relationship was detected between RCI and adverse hospitalization outcomes, which had an inflection point of 3.2. There were odds ratios and confidence intervals of 0.8 (0.7-1.0) and 1.3 (1.2-1.4) on the left and right sides of the inflection point, respectively. Conclusion: The RCI and adverse hospitalization outcomes exhibited a non-linear relationship in the AECOPD patients. RCI is strongly positively correlated with adverse hospitalization outcomes when it was greater than 3.2.

Glutamate Receptor Interacting Protein 1 in the Dorsal CA1 Drives Alpha-amino-3-hydroxy-5-methyl-4-Isoxazolepropionic Acid Receptor Endocytosis and Exocytosis Bidirectionally and Mediates Forgetting, Exploratory, and Anxiety-like Behavior.

Endocytosis of GluA2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in CA1 of the hippocampus regulates forgetting; deficits in forgetting nociceptive memory can induce serious stress disorders. As a transporter of GluA2-containing AMPAR, the functions of glutamate receptor interacting protein 1 (GRIP1) in forgetting and possible stress responses remain unclear. Lentivirus-mediated interference of GRIP1 expression or function in the dorsal CA1 of the hippocampus in mice indicated that GRIP1 overexpression enhanced spatial memory, impaired forgetting in a Barnes maze, and induced anxiety-like behavior in the open field and elevated plus-maze test. In contrast, GRIP1 knockdown impaired learning capacity. Furthermore, inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 and GluA2-dn enhanced learning capacity, whereas GluA2-dn impaired spatial memory; inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 also decreased forgetting capacity to some extent. Importantly, inhibition of both the PDZ2 and PDZ4/5 domains of GRIP1 induced anxiety-like behavior but not GluA2-dn. Furthermore, optogenetic control of both GluA1 and GluA2 insertion into the postsynaptic membrane impaired memory and induced anxiety-like behavior. In vitro experiments showed that GRIP1-ov and -dn, inhibition of PDZ2 and PDZ4/5 domains of GRIP1, and GluA2-dn decreased glycine-induced GluA1 and GluA2 exocytosis; meanwhile, GRIP1-ov and -dn, and interference of PDZ2 and PDZ4/5 domains of GRIP1 blocked AMPA- and NMDA-induced GluA1 and GluA2 endocytosis. Overall, these results suggest that GRIP1 drives AMPA receptor endocytosis and exocytosis bidirectionally; furthermore, GRIP1-induced stabilization of anchoring postsynaptic GluA1 and GluA2 impairs forgetting and induces anxiety-like behavior. GRIP1 may provide a potential therapeutic target in posttraumatic syndromes and anxiety disorders.

Simultaneous Gemcitabine and Percutaneous CT-Guided Irreversible Electroporation for Locally Advanced Pancreatic Cancer.

Background: Irreversible electroporation (IRE) is a new local ablation technique for pancreatic cancer. The aim of this study is to analyse the safety and effectiveness of simultaneous gemcitabine and percutaneous CT-guided IRE for locally advanced pancreatic cancer (LAPC). Materials and Methods: From October 2016 to January 2018, 61 patients with LAPC who received simultaneous gemcitabine and IRE therapy (GEM-IRE group, n = 31) or IRE alone therapy (IRE group, n = 30). Routine intravenous gemcitabine chemotherapy was performed 2 weeks after IRE in both groups. Results: Technical success rates were 90.0% (27/30) and 93.3% (28/30) in the GEM-IRE and IRE groups. Compared with the IRE group, the GEM-IRE group exhibited longer overall survival (OS), local tumor progression free survival (LTPFS), and distant disease free survival (DDFS) from IRE (OS, 17.1 vs. 14.2 months, p=0.031; LTPFS, 14.6 vs. 10.2 months, p=0.045; DDFS, 15.4 vs. 11.7 months, p=0.071). Multivariate Cox regression analysis results suggested that tumor volume ≤37 cm3 and simultaneous gemcitabine with IRE were significant independent prognostic factors of OS, LTPFS, and DDFS. Four major adverse reactions occurred; all of them were resolved after symptomatic treatment. Conclusions: Simultaneous gemcitabine and percutaneous CT-guided IRE therapy model was effective and well-tolerated therapeutic strategy in LAPC patients.

Long Non-Coding RNA NEAT1 Knockdown Alleviates Rheumatoid Arthritis by Reducing IL-18 through p300/CBP Repression.

Rheumatoid arthritis (RA) is chronic inflammatory autoimmune disease. The crucial role of long non-coding RNA (lncRNA) in the progression of RA has been highlighted. Hence, this study was designed to explore the specific downstream mechanism of lncRNA nuclear-enriched abundant transcript 1 (NEAT1) in RA. Initially, the expression of NEAT1, p-p65, p300, and IL-18 in clinical tissues and cells was determined. Then, interactions among p65, NEAT1, p300, CBP, and IL-18 were investigated by immunofluorescence staining, dual luciferase reporter gene assay, RT-qPCR assay ChIP assay, and RIP assay followed by the analysis of their effects on RA in vivo and in vitro after expression alteration. The expressions of NEAT1, p-p65, p300, and IL-18 were all upregulated in the synovial tissues from the mice and patients with RA. NEAT1 silencing reduced the infiltration of CD4+ T cells and macrophages in synovial tissues, downregulated expression of blood inflammatory factors, relieved RA severity, and lowered incidence of RA in mice. Further, p-p65 could increase the expression of NEAT1 by binding to the NEAT1 promoter region, NEAT1 could co-locate and interact with p300, thus regulating the expression of IL-18 by regulating histone acetylation modification in IL-18 promoter region. NEAT1 aggravated RA via p300/CBP/IL-18 axis, representing a promising therapeutic target in RA.

Development of a Predictive Model for Mortality in Hospitalized Patients With COVID-19.

INTRODUCTION: Early identification of patients with novel corona virus disease 2019 (COVID-19) who may be at high mortality risk is of great importance. METHODS: In this retrospective study, we included all patients with COVID-19 at Huanggang Central Hospital from January 23 to March 5, 2020. Data on clinical characteristics and outcomes were compared between survivors and nonsurvivors. Univariable and multivariable logistic regression were used to explore risk factors associated with in-hospital death. A nomogram was established based on the risk factors selected by multivariable analysis. RESULTS: A total of 150 patients were enrolled, including 31 nonsurvivors and 119 survivors. The multivariable logistic analysis indicated that increasing the odds of in-hospital death associated with higher Sequential Organ Failure Assessment score (odds ratio [OR], 3.077; 95% confidence interval [CI]: 1.848-5.122; P < 0.001), diabetes (OR, 10.474; 95% CI: 1.554-70.617; P = 0.016), and lactate dehydrogenase greater than 245 U/L (OR, 13.169; 95% CI: 2.934-59.105; P = 0.001) on admission. A nomogram was established based on the results of the multivariable analysis. The AUC of the nomogram was 0.970 (95% CI: 0.947-0.992), showing good accuracy in predicting the risk of in-hospital death. CONCLUSIONS: This finding would facilitate the early identification of patients with COVID-19 who have a high-risk for fatal outcome.

Relationship between osteoporosis and benign paroxysmal positional vertigo based on evidence-based medicine and bioinformatics.

It has been reported that osteoporosis is a possible risk factor of benign paroxysmal positional vertigo (BPPV). PURPOSE: We analyzed the correlation between osteoporosis and BPPV and the possible mechanism by performing evidence-based medicine meta-analysis and bioinformatics analysis. METHODS: Initially, English articles related to osteoporosis and BPPV were obtained through PubMed and EMBASE databases. Stata12.0 software was used for meta-analysis to calculate the odd ratio (OR) and 95% confidence interval (CI) of outcome indicators, and the heterogeneity was evaluated by subgroup analysis, publication bias evaluation, and sensitivity analysis. In addition, microarray datasets related to BPPV and osteoporosis were obtained from gene expression omnibus (GEO) database to screen differentially expressed genes. At last, a mouse model of osteoporosis was established by bilateral oophorectomy for validation. RT-qPCR and Western blot analysis were performed to determine expression of related factors in mouse tissues. RESULTS: Osteoporosis was suggested as an important risk factor for BPPV through meta-analysis of these 12 articles. It was found that PPP2CA was upregulated in BPPV and low bone mineral density (BMD) samples. Moreover, PPP2CA induced dephosphorylation of BCL2, which may be involved in BPPV through regulation of BMD. Through this mechanism, silencing of PPP2CA could elevate the incidence of BPPV by promoting bone remodeling and reducing the density of otoconia around the macula. CONCLUSIONS: PPP2CA reduces BMD expression by inducing dephosphorylation of BCL2, which may be one of the mechanisms responsible for the onset of BPPV in osteoporosis.

Sorting nexin 6 interacts with Cullin3 and regulates programmed death ligand 1 expression.

Programmed death ligand 1 (PD-L1) is critical for the ability of cancer cells to evade attacks by the host immune system. However, the molecular mechanisms controlling PD-L1 expression have not been fully understood. Here, we demonstrate that sorting nexin 6 (SNX6) is a novel regulator of PD-L1 expression. Knockdown of SNX6 in cancer cells significantly decreases PD-L1 protein levels. In contrast, loss of SNX6 does not reduce PD-L1 mRNA levels. Instead, SNX6 interacts with Cullin3, an E3 ubiquitin ligase responsible for PD-L1 ubiquitination and subsequent degradation. By binding with Cullin3, SNX6 decreases the interaction between the adaptor protein speckle-type POZ protein and Cullin3, which in turn downregulates Cullin3-mediated PD-L1 ubiquitination. This research reveals a novel molecular nexus in modulating PD-L1.

Effect of Community-Acquired Pneumonia on Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Community-acquired pneumonia (CAP) is a major contributor to hospitalization for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The clinical manifestations of AECOPD with and without CAP are confusing. The difference in the survival or readmission rate of AECOPD with or without CAP remains controversial. A prospective cohort study was conducted to evaluate the clinical and laboratory characteristics and in-hospital outcomes of patients who were consecutively hospitalized due to AECOPD from May 2015 to December 2019. Grouping was based on chest computed tomography findings. Multivariable logistic regression was used to explore the predictors for early identification between CAP exacerbations and non-CAP exacerbations. Kaplan-Meier analysis was used to compare the cumulative survival rate and readmission rate for a 12-month follow-up between the two groups. A total of 378 patients with AECOPD were enrolled, including 200 patients with CAP and 178 patients without CAP. The presence of pleuritic pain, usage of ICS, and elevated levels of C-reactive protein and procalcitonin on admission were the predictors for the early discrimination between AECOPD with and without CAP. During a 1-year follow-up, the cumulative survival rate was lower in patients with AECOPD with CAP than in those with AECOPD without CAP (13.0% vs. 3.37%; HR: 4.099; 95% CI, 2.049-8.199; p < 0.001), but the readmission rate was similar in both groups. Patients with first-time exacerbation due to CAP were more likely to experience subsequent pneumonic exacerbation. CAP is frequent among patients hospitalized for AECOPD and associated with increased mortality and successive pneumonic exacerbation.

Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally Available RORγ Inverse Agonist.

Receptor-related orphan receptor γ (RORγ) has emerged as an attractive therapeutic target for the treatment of cancer and inflammatory diseases. Herein, we report our effort on the discovery, optimization, and evaluation of benzothiazole and benzimidazole derivatives as novel inverse agonists of RORγ. The representative compound 27h (designated as XY123) potently inhibited the RORγ transcription activity with a half-maximal inhibitory concentration (IC50) value of 64 nM and showed excellent selectivity against other nuclear receptors. 27h also potently suppressed cell proliferation, colony formation, and the expression of androgen receptor (AR)-regulated genes in AR-positive prostate cancer cell lines. In addition, 27h demonstrated good metabolic stability and a pharmacokinetic property with reasonable oral bioavailability (32.41%) and moderate half-life (t1/2 = 4.98 h). Significantly, oral administration of compound 27h achieved complete and long-lasting tumor regression in the 22Rv1 xenograft tumor model in mice. Compound 27h may serve as a new valuable lead compound for further development of drugs for the treatment of prostate cancer.

ABCC1 regulates cocaine-associated memory, spine plasticity and GluA1 and GluA2 surface expression.

ATP-binding cassettes C1 (ABCC1s) are expressed in the neurons of the brain, but their function in neurological diseases is far from clear. In this study, we investigated the role of ABCC1 in the hippocampus in cocaine-associated memory and spine plasticity. We also investigated the role of ABCC1 in AMPA receptors (AMPARs) surface expression in primary prefrontal cortex (PFC) neurons following dopamine treatment, which was used to mimic exposure to cocaine. We found that cocaine increased ABCC1 expression in the hippocampus, and ABCC1-siRNA blocked cocaine-induced place preference. Furthermore, a morphological study showed that ABCC1-siRNA reduced the total spine density, including thin, stubby and mushroom spines in both cocaine and basal treatments compared with controls. Meanwhile, in vitro tests showed that ABCC1-siRNA decreased GluA1 and GluA2 surface expression induced by dopamine, while a decreased number of synapses in primary PFC neurons was observed following dopamine treatment. The data show that ABCC1 in the hippocampus is critically involved in cocaine-associated memory and spine plasticity and that dopamine induces AMPARs surface expression in primary PFC neurons. ABCC1 is thus presented as a new signaling molecule involved in cocaine addiction, which may provide a new target for the treatment of cocaine addiction.

Core-binding factor beta is required for osteoblast differentiation during fibula fracture healing.

BACKGROUND: Growing evidence has implicated core-binding factor beta (Cbfb) as a contributor to osteoblast differentiation, which plays a key role in fracture healing. Herein, we aimed to assess whether Cbfb affects osteoblast differentiation after fibula fracture. METHODS: Initially, we established a Cbfb conditional knockout mouse model for subsequent studies. Immunohistochemical staining was conducted to detect the expression of proliferating cell nuclear antigen (PCNA) and collagen II in the fracture end. Next, we isolated and cultured osteoblasts from specific Cbfb conditional knockout mice for BrdU analysis, alkaline phosphatase (ALP) staining, and von Kossa staining to detect osteoblast viability, differentiation, and mineralization, respectively. Western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect the expression of osteoblast differentiation-related genes. RESULTS: The Cbfb conditional knockout mice exhibited downregulated expression of PCNA and collagen II, reduced ALP activity, and mineralization, as well as diminished expression of osteoblast differentiation-related genes. Further, Cbfb knockout exerted no obvious effects on osteoblast proliferation. CONCLUSIONS: Overall, these results substantiated that Cbfb could promote fibula fracture healing and osteoblast differentiation and thus provided a promising therapeutic target for clinical treatment of fibula fracture.

Gemcitabine plus concurrent irreversible electroporation vs gemcitabine alone for locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is a common malignant digestive system tumor that ranks as the fourth leading cause of cancer-related death in the world. The prognosis of LAPC is poor even after standard treatment. Irreversible electroporation (IRE) is a novel ablative strategy for LAPC. Several studies have confirmed the safety of IRE. To date, no prospective studies have been performed to investigate the therapeutic efficacy of conventional gemcitabine (GEM) plus concurrent IRE. AIM: To compare the therapeutic efficacy between conventional GEM plus concurrent IRE and GEM alone for LAPC. METHODS: From February 2016 to September 2017, a total of 68 LAPC patients were treated with GEM plus concurrent IRE n = 33) or GEM alone n = 35). Overall survival (OS), progression free survival (PFS), and procedure-related complications were compared between the two groups. Multivariate analyses were performed to identify any prognostic factors. RESULTS: There were no treatment-related deaths. The technical success rate of IRE ablation was 100%. The GEM + IRE group had a significantly longer OS from the time of diagnosis of LAPC (19.8 mo vs 9.3 mo, P < 0.0001) than the GEM alone group. The GEM + IRE group had a significantly longer PFS (8.3 mo vs 4.7 mo, P < 0.0001) than the GEM alone group. Tumor volume less than 37 cm3 and GEM plus concurrent IRE were identified as significant favorable factors for both the OS and PFS. CONCLUSION: Gemcitabine plus concurrent IRE is an effective treatment for patients with LAPC.

Phosphatidylinositol 4,5-bisphosphate in the Control of Membrane Trafficking.

Phosphoinositides are membrane lipids generated by phosphorylation on the inositol head group of phosphatidylinositol. By specifically distributed to distinct subcellular membrane locations, different phosphoinositide species play diverse roles in modulating membrane trafficking. Among the seven known phosphoinositide species, phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is the one species most abundant at the plasma membrane. Thus, the PI4,5P2 function in membrane trafficking is first identified in controlling plasma membrane dynamic-related events including endocytosis and exocytosis. However, recent studies indicate that PI4,5P2 is also critical in many other membrane trafficking events such as endosomal trafficking, hydrolases sorting to lysosomes, autophagy initiation, and autophagic lysosome reformation. These findings suggest that the role of PI4,5P2 in membrane trafficking is far beyond just plasma membrane. This review will provide a concise synopsis of how PI4,5P2 functions in multiple membrane trafficking events. PI4,5P2, the enzymes responsible for PI4,5P2 production at specific subcellular locations, and distinct PI4,5P2 effector proteins compose a regulation network to control the specific membrane trafficking events.

Extracellular regulated kinase 5 mediates osteoporosis through modulating viability and apoptosis of osteoblasts in ovariectomized rats.

Postmenopausal osteoporosis is a common condition characterized by the increase and activation of osteoclasts. The present study aimed to investigate the effects of extracellular signal-regulated kinase (ERK) 5 (ERK-5) on postmenopausal osteoporosis by regulating the biological behaviors of osteoblasts. Sprague-Dawley (SD) rats were ovariectomized to develop an osteoporosis model. A lentivirus packaging system was employed to generate lentiviruses capable of up- or down-regulating the expression of ERK-5 in ovariectomized rats. The femoral biomechanical properties, bone mineral density (BMD), contents of calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) and bone turnover markers in rats, as well as viability, cycle and apoptosis of osteoblasts and ALP activity in osteoblasts were measured in the ovariectomized rats so as to explore the functional significance of ERK-5 in postmenopausal osteoporosis. The femoral mechanical strength of ovariectomized rats was enhanced by overexpression of ERK-5. Meanwhile femoral BMD, and bone metabolism were increased, and bone turnover normalized in the ovariectomized rats when ERK-5 was overexpressed. Lentivirus-mediated ERK-5 overexpression in osteoblasts was observed to inhibit osteoblast apoptosis, and promote viability, accompanied with increased ALP activity. Taken together, ERK-5 could decelerate osteoblast apoptosis and improve postmenopausal osteoporosis by increasing osteoblast viability. Thus, our study provides further understanding on a promising therapeutic target for postmenopausal osteoporosis.

A novel bispecific c-MET/CTLA-4 antibody targetting lung cancer stem cell-like cells with therapeutic potential in human non-small-cell lung cancer.

A novel paradigm in tumor biology suggests that non-small-cell lung cancer (NSCLC) growth is driven by lung cancer stem cell (LCSC) like cells, but t here are still not any effective strategies to remove LCSCs. The bispecific antibody (BsAb) is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a new BsAb, BsAb-5, that can target cellular mesenchymal-to-epithelial transition factor (c-MET) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in CD166+ LCSCs with high affinity and specificity, for the first time. We showed that BsAb-5 could inhibit hepatocyte growth factor (HGF) mediated tumor development, including proliferation, migration, and apoptosis, serving as an inhibitory c-MET antibody. Moreover, we demonstrated that mechanisms responsible for BsAb-5 in CD166+ LCSCs included inducing c-MET degradation and inhibition of HGF-stimulated c-MET-Notch pathway by using AdHGF infection, nuclei location, and Western blot assays. In vivo, xenograft analysis revealed that mice on BsAb-5 group showed significantly reduced tumor volume. At the meantime, the observed antitumor effects of BsAb-5 were dependent on considerably suppressing T-regulatory cells (Tregs) and up-regulating effector T cells. On the basis of these results, we have identified a potential BsAb drug, which can effectively target c-MET and CTLA-4 in CD166+ LCSCs for the treatment of human NSCLC.

A 3-Dimensional Finite Element Analysis of Adjacent Segment Disk Degeneration Induced by Transforaminal Lumbar Interbody Fusion After Pedicle Screw Fixation.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) is an effective treatment of upper lumbar intervertebral disk herniation. However, its clinical efficacy for adjacent segment disk degeneration (ASDD) remains undefined. Therefore, the biomechanical evaluation of ASDD caused by TLIF after pedicle screw fixation (PSF) was explored via a 3-dimensional (3D) finite element analysis. METHODS: Computed tomography images of a healthy male adult volunteer were used in this study. A L3-4 3D finite element model (model) was successfully constructed using Pro/E software, which was also used to establish the L4-5 of the TLIF, PSF, and PSF + TLIF models. Under the same loading conditions, the protrusion and retraction of the adjacent intervertebral disk and the stress distribution of the annulus fibrosis, facet joint, and articular process in the TLIF, PSF, and PSF + TLIF models were all compared. RESULTS: Protrusion and retraction of the adjacent intervertebral disk were more notable in the PSF + TLIF model than in the PSF model under the same loading conditions. The stress of the annulus fibrosis of the PSF + TLIF model was stronger relative to that of the PSF model under flexion, extension, or lateral bending. The stress of the articular process of the PSF + TLIF model was also stronger than that of the PSF model under extension or lateral bending. CONCLUSIONS: This study provides evidence that TLIF may aggravate ASDD after PSF. Furthermore, the findings provided in this report represent the theoretic basis for the clinical analysis of ASDD caused by TLIF after PSF.