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Increasing data have indicated that late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) images is associated with the clinical prognosis of hypertrophic cardiomyopathy (HCM). Recently, pioneer studies indicated that the location of LGE in CMR images also had potential predictive value for HCM prognosis. The aim of the present study was to investigate the prognostic value of the location of LGE for HCM. This present cohort study included 557 HCM patients who underwent LGE-CMR imaging, and the LGE location was classified as LGE in interventricular septum only (IVS-LGE) and LGE outside the IVS with or without IVS involvement (other than IVS-LGE). All-cause mortality, cardiovascular mortality/cardiac transplantation, and sudden cardiac death (SCD) were evaluated. During a mean follow-up time of 83.0±37.8 months, there was a significantly higher all-cause mortality, cardiovascular mortality/cardiac transplantation, and SCD in patients with other than IVS-LGE than in those with IVS-LGE. Multivariate Cox regression suggested that other than IVS-LGE were one of independent prognostic predictors. Risk reclassification for prognosis showed that there were no differences between the prediction values of the presence of LGE and the location of LGE. The presence and location of LGE in CMR images are equally independent prognostic predictors of HCM, and other than IVS-LGE location is associated with an adverse clinical prognosis. Prognosis Trial Registration: ChiCTR-ONRC-11001902.

Background Next generation sequencing revealed frequent mutations of NRAS, KRAS or BRAF in up to 50% of newly diagnosed multiple myeloma (MM) patients. Methods Specific K- or N-RAS knockdowns led to strong decrease in MM cell viability if harbored the respective oncogenic isoform, but minimal effects were observed if only the wild-type isoform was present, presenting RAS signaling as the key driving oncogenes in the mutation bearing patients. Unfortunately, no inhibitor for RAS mutation is available for clinical use in MM. Therefore, key component in the RAS/MAPK pathway may represent an alternative therapeutic target for MM. Germinal center kinase (GCK) is an upstream activator in the MAPK pathway. Results Our data showed that GCK (MAP4K2) knockdown in MM cells induced MM cell growth inhibition, associated with the downregulation of critical transcriptional factors including IKZF1/3, BCL-6, and c-MYC proteins. Moreover, GCK silencing only led to significantly decreased GCK mRNA, however, did not affect IKZF1 expressions at mRNA level. We next tested the effects of GCK inhibitor TL4-12 on MM. Given the fact that RASMut MM cells have higher GCK expression level and are more sensitive to GCK knockdown, we compared mutated RAS MM cells with wild-type RAS MM cells. TL4-12 significantly inhibited the growth of mutated RAS MM cells, with IC50 5-10 fold lower compared to wild-type RAS MM cell lines. IKZF1/3 are the key targets of the immunomodulatory drugs (IMiDs), which are the backbone of MM therapy. IMiDs bind to cereblon (CRBN) and induce IKZF1/3 protein degradation, which subsequently lead to MM cell growth inhibition. Our data showed that GCK knockdown also downregulates IKZF1 protein level, indicating that IKZF1 is under the regulation of GCK. Concomitant treatment with proteasome inhibitor PS-341 blocked TL4-12 induced IKZF1 downregulation, suggesting that inhibition of GCK induces IKZF1 protein degradation. However, since IMiDs-resistant RPMI-8226 and JJN3 MM cells are sensitive to GCK inhibition, we hypothesized that the IKZF1 degradation mechanism induced by GCK inhibition is different from IMiDs and independent of CRBN. To confirm this hypothesis, we silenced CRBN in N-Rasmut H929 MM cells and examined the response to IMiDs and GCK inhibitor. CRBN silencing in H929 cells resulted in lenalidomide resistance. In contrast, CRBN silencing failed to rescue H929 MM from TL4-12 induced proliferation inhibition and IKZF1 downregulation, confirming that GCK regulated IKZF1 and cell growth is independent of CRBN. Conclusions Taken together, our data demonstrated that GCK inhibition induces cell growth inhibition and triggers apoptosis especially in RASmut MM cells. Importantly, GCK inhibition downregulates IKZF1 via a CRBN-independent mechanism. Our findings thus provide a rationale for the clinical evaluation of targeting GCK in RASmut MM patients and further mechanistic insight into the role of GCK in MM tumorigenesis as well as drug resistance.

A 32-year-old female with systemic lupus erythematosus (SLE) for more than 7 years, and long-term treatment with cyclophosphamide, cyclosporine, methotrexate, and tacrolimus, later found to be combined with hypertrophic cardiomyopathy (HCM) for one year. The patient denied a family history of cardiomyopathy and sudden cardiac death (SCD). Echocardiography suggested that uneven thickening of the left ventricle (LV), mainly in the lower middle segment. Cardiac magnetic resonance (CMR) showed that the walls of the left ventricular (LV) were significantly thickened, as about 21 mm, mainly in the middle and lower segments. Genetic tests showed no known or suspected pathogenic variations were found and no significant enhancement in CMR, so secondary HCM was diagnosed clinically. After symptomatic treatment, the patient was discharged, and long-term follow-up was conducted. The diagnosis of HCM, which combined with SLE or second to usage of tacrolimus, was based on symptoms, echocardiography, and CMR; no endomyocardial biopsies were performed.

Background Thyroid dysfunction in patients with morbid obesity usually resolves after bariatric surgery. However, the role of diverse types of adipose tissue in the process remains unknown. Objectives We aim to investigate the effects of visceral and subcutaneous fat on thyroid function in a Chinese population with morbid obesity who underwent sleeve gastrectomy (SG). Setting University hospital, Shanghai, China Methods Repeated measurement data of thyroid hormone and body fat were collected at 0, 3, 6, 12, 24, and 36 months after sleeve gastrectomy. Dual-energy X-ray absorptiometer and quantitative computerized tomography (CT) were used to compute visceral fat and subcutaneous fat. Repeated measures correlation (rmmcorr) package was employed for correlation analysis with generalized additive mixed model (GAMM) determining the independent factors. Results Thyroid stimulating-hormone (TSH) showed notable decrease at 36 months after surgery, coupled with reduction of BMI (38.08 kg/cm2 versus 24.28 kg/cm2), C-reactive protein (CRP), visceral adipose tissue (786.74 cm2 versus 367.44 cm2), body fat rate, and waistline (118.13 cm versus 100.87 cm). Only visceral fat, diabetes, and CRP proved to be independent variables for TSH decline, without correlation with subcutaneous fat. Conclusion The present study is first to report the effects of different types of body fat on thyroid function in a Chinese population with morbid obesity, revealing that loss of visceral fat is the key to improving endocrine and metabolic activity after bariatric surgery.

Objective: Various studies have documented the liver fatty acid-binding protein (FABP1) were closely related to liver function. However, the interrelation between the liver function and FABP1 in Chinese patients with obesity after laparoscopic sleeve gastrectomy (LSG) is unclear. Therefore, we aimed to interpret the correlation between FABP1 level and progression of liver function in obese patients, during a 12-month follow-up. Methods: This study included 131 individuals: 54 had normal weight (BMI:21.63±1.52kg/m2),77 had obesity (BMI:39.67±6.14kg/m2). The subjects were divided into three tertiles (Q1, Q2, and Q3) according to FABP1 levels: Q1, =34.30ng/ml. FABP1 levels were measured using ELISA. Results: Serum FABP1 levels were significantly higher in patients with obesity (29.71±22.35 ng/ml, P< 0.001) than normal weight individuals (13.70±9.48 ng/ml). FABP1 level was decreased at 6 and 12 months after LSG (15.00±10.27ng/mL, P Conclusion: Our results suggested obesity was strongly associated with up-regulated serum FABP1 level. In addition, the improvement of liver function was positively correlated with changes in FABP1 at 12 months in Chinese patients with obesity after LSG. Disclosure H. Ma: None. Y. Hui: None. S. Qu: None. Funding National Natural Science Foundation of China (81700752, 81970677)

With the explosive growth of data transmission requirements, the massive bursty traffic results in more frequent and serious network congestion. To deal with the burst traffic, the buffer size of the network is designed to be much larger than required. However, increasing buffer size leads to bufferbloat problem, which exacerbates network congestion. To address this problem, Active Queue Management (AQM) is proposed to cooperate with Transmission Control Protocol (TCP) congestion control mechanism. But it is hard to model dynamic AQM/TCP system and tune the parameters of conventional AQM schemes to obtain good performance under different congestion scenarios. In this paper, we aim to study the AQM scheme from a whole new perspective by leveraging emerging Deep Reinforcement Learning (DRL). A model-free approach, DRL-AQM, enables the AQM to learn the best dropping policy as human beings learn skills. DRL-AQM can capture intricate patterns in the data traffic model after trained in a simple network scenario, and leverage this to improve performance in a great variety of scenarios. There are two phases in our scheme, offline training phase and deployment phase. Once the model is trained, it can work well without any parameter-tuning in many scenarios. Experimental results show that (1) DRL-AQM outperforms conventional AQM algorithms in a variety of complex network scenarios and it is robust and insensitive to network conditions. (2) DRL-AQM keeps persistently low buffer capacity utilization without over dropping and damaging throughput. (3) DRL-AQM adapts automatically and continuously to the dynamics of the network links.

Introduction Multiple myeloma (MM)-induced bone disease remains one of its most devastating complications, caused by increased bone resorption by overactivated osteoclasts coupled with impaired bone formation. MM cells produce osteoclast-activating factors that induce osteoclast activation and extensive bone resorption. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor that is highly secreted by MM cells (Fu J etc. JCI. 2016). We also identified that the checkpoint inhibitor, programmed death-1 homolog (PD-1H/VISTA), serves as the MMP-13 receptor in osteoclasts and mediates MMP-13-dependent osteoclastogenic function which is largely blocked in Pd-1h -/-osteoclasts (Fu J etc. ASH 2019, 2020). While the inhibitory role of PD-1H/VISTA in T-cells has recently been described (ElTanbouly MA etc. Science 2020), its cellular binding proteins remain unclear, and its role in osteoclast activation andMM bone disease have not been addressed. Methods and Results To identify its interacting proteins, PD-1H-His 6 recombinant protein was expressed in mouse bone marrow mononuclear cells, the associated proteins pulled down by Ni-NTA agarose beads from cell lysates and identified by mass spectrometry. Functional annotation charting of the 75 proteins enriched in PD-1H pull-down samples (with signal ratio of PD-1H-His 6 pull-down vs control >2) indicated that almost 30% of the interacting targets were either cytoskeletal or cytoskeleton-associated proteins. Given that the F-actin cytoskeleton undergoes dynamic reorganization during osteoclast differentiation and plays critical roles in bone resorption, we further addressed the role of PD-1H in F-actin cytoskeleton regulation. Initially, osteoclasts form F-actin-rich adhesive structures, termed podosomes. At later stages, podosomes collectively rearrange into clusters and rings and finally into sealing belts to mediate osteoclast spreading, migration and bone resorption (Teitelbaum SL. Ann N Y Acad Sci. 2011). By confocal immunofluorescence microscopy, we found that PD-1H co-localized with F-actin podosome clusters, rings and sealing belts during osteoclast differentiation (Figure 1A). The functional role of PD-1H in F-actin cytoskeleton reorganization was addressed using Pd-1h -/- osteoclast wherein Pd-1h knockout lead to the disruption of podosome clusters at early stages relative to WT controls, while at later stages, Pd-1h -/-osteoclasts exhibited significantly fewer F-actin rings and belts (Figure 1B). Further, binding of MMP-13 to PD-1H increased the number of osteoclasts forming F-actin rings and belts, as well as the size of F-actin belts, which was blocked in Pd-1h -/- osteoclasts. To determine the role of PD-1H in the development of myeloma-induced lytic bone lesions, 5TGM1 myeloma cells were bilaterally intratibially injected into Pd-1h wtRag2 -/- or Pd-1h -/-Rag2 -/- mice (n=10) to induce lytic bone lesions. Three weeks following intratibial 5TGM1 injection, tibiae were harvested for micro-computed tomography. Subsequent quantitative histomorphology analyses of the trabecular and cortical bones confirmed that the knockout of Pd-1h reduced MM-induced bone destruction with significantly less decrease in trabecular bone volume (Tb. [BV/TV]), trabecular bone number (Tb. N.), trabecular bone thickness (Tb. Th.), as well as less increase in trabecular bone spacing (Tb. Sp.) and bone specific surface (Tb. [BS/BV]) compared to Pd-1h wtRag2 -/- mice. Similar effects were observed in cortical bone with less decrease in cortical bone thickness (CT. Th.), cortical bone area fraction (CT. [BA/TA]), and cortical tissue mineral density (CT. TMD) in 5TGM1 bearing Pd-1h -/-Rag2 -/- mice vs Pd-1h wtRag2 -/- mice (Table 1). Conclusions Taken together, our study, for the first time, reveals the novel role of checkpoint inhibitor, PD-1H/VISTA, in osteoclasts and myeloma bone disease. PD-1H associates with cytoskeleton proteins and regulates the F-actin cytoskeleton reorganization which is critical for osteoclast bone resorption activity. Further, PD-1H mediates MMP-13-induced osteoclast fusion, F-actin belts formation, and osteoclast activation. Pd-1h -/-in recipient mice significantly impairs MM-induced bone loss, demonstrating that PD-1H/VISTA plays a critical role in MM bone disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues, and neurological deficits. MM cells secret pro-osteoclastogenic factors which lead to osteoclast (OCL) activation. Our previous work showed that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor highly secreted by MM cells and induces OCL fusion and bone resorption independently of its proteolytic activity (JCI 2016). We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed on OCLs and mediates MMP-13 induced OCL fusion and bone resorption activity (ASH 2019). Bone resorption activity is significantly impaired in Pd-1h-/- OCLs in vitro. However, the function of PD-1H in MM bone disease has not been defined. Methods The role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model. Pd-1h-/-Rag2-/- mice were generated by crossbreeding Pd-1h-/- with Rag2-/- mice. Firefly luciferase-expressing 5TGM1 cells were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=10). 3 weeks later, tibiae were harvested for quantitative micro-CT followed by histological analysis. Results Morphological analyses of trabecular and cortical bones confirmed that Pd-1h-/- recipient mice exhibited significantly less 5TGM1-induced bone loss (P Conclusions Taken together, our study, for the first time, reveals that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation, and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/- mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment.

In this paper, a spatial-partition fast Fourier transform beam propagation method (FFT-BPM) is proposed. The theoretical analysis of this beam propagation method is carried out, and the necessary conditions for its accurate application are derived. Through high-accuracy and high-speed simulation of the propagation of light beam in the medium with large refractive index variation, the reliability of this method is demonstrated.

Introduction Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues and neurological deficits. MM cells produce osteoclast-activating factors that induce osteoclast activation, thereby leading to excessive bone resorption and lytic bone lesions1. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor that is highly secreted by MM cells. MMP-13 induces osteoclast fusion and bone-resorption via a mechanism independent of its proteolytic activity2. We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed in osteoclasts at high levels3. Binding of MMP-13 to PD-1H/VISTA induces osteoclast fusion and bone resorption activity whereas knockdown or knockout of PD-1H/VISTA largely block MMP-13 mediated effects on osteoclasts3. However, the function of PD-1H inMM bone disease in vitro or in vivo has not been previously defined. Methods and Results To confirm the role of PD-1H in MMP-13 induced bone disease in MM, we first conducted MM-osteoclast trans-well co-culture assay using murine MM cell line, 5TGM1 cells, and bone marrow mononuclear cells from Pd-1h-/- or wild type (WT) mice. 5TGM1 control cells or MMP-13 knockdown 5TGM1 cells were seeded in the upper wells of the transwell plates; while WT or Pd-1h-/- bone marrow mononuclear cells were seeded in the lower wells and cultured for osteoclast differentiation assessed by TRAP staining. Results show that 5TGM1 induced differentiation of WT osteoclasts with significantly increased osteoclast size and nuclei number/osteoclast. Consistent with our previous results2, MMP-13 knockdown blocked the 5TGM1 MM cells-induced activation of WT osteoclasts. In contrast, neither 5TGM1 MM cells nor MMP-13 knockdown cells had significant effects on Pd-1h-/- osteoclasts. Hence, knockout of Pd-1h abrogated MMP-13 mediated MM induction of osteoclasts, indicating that MMP-13/PD-1H interactions are critically involved in MM-induced osteoclast activation. The in vivo role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model2. For this purpose, Pd-1h-/-Rag2-/- mice were generated by crossbreeding C57BL/6 Pd-1h-/- with C57BL/6 Rag2-/- mice. 3x105 firefly luciferase expressing 5TGM1 cells (5TGM1-luc) were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=5). Tumor progression was monitored by weekly bioluminescence imaging (BLI). 3 weeks after tumor inoculation, tibiae were harvested for quantitative micro-CT, followed by histological analysis. Histological staining showed that intratibial injection of 5TGM1-luc MM cells induced extensive lytic lesions and trabecular bone loss in Rag2-/- mice. In contrast, in Pd-1h-/-Rag2-/- mice,the bone structure was maintained with markedly less bone loss. Morphological analyses of trabecular bone across proximal tibiae further indicated that in Rag2-/- mice, 5TGM1 induced significant changes in bone microarchitecture, with decreased bone volume fraction (bone volume/tissue volume), connective density, trabecular bone numbers, and trabecular bone thickness, as well as increased trabecular bone spacing (Table 1). In contrast, in Pd-1h-/-Rag2-/- mice, 5TGM1 failed to induce significant loss of trabecular bone, confirming the critical role of PD-1H in MM induced bone disease in vivo. Conclusions Taken together, our study, for the first time, reveal that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/-mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment. References 1. Marino S, Petrusca DN, Roodman GD. Br J Pharmacol. 2019;10.1111/bph.14889. 2. Fu J, Li S, Feng R, et al. J Clin Invest. 2016;126(5):1759-1772. 3. Fu J, Li S, Yang C, et al. Blood. 2019; 134 (Supplement_1): 3072. Disclosures Lentzsch: Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Celularity: Consultancy, Other; Magenta: Current equity holder in private company; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive disease characterized by the clinical triad of early childhood joint contractures, progressive weakness in muscles and cardiac involvement and can result in sudden death. Targeted next-generation sequencing was performed for a Chinese patient with EDMD and the previously reported mutation [NM_000117.2: c.251_255del (p.Leu84Profs*7)] in exon 3 of the emerin gene (EMD) was identified.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) presents as the progressive fibrofatty replacement of the cardiomyocytes particularly in the right ventricular wall. Here, we report two cases with ARVC. In family A, the proband carries a Desmoglein2 (DSG2) gene complex heterozygous mutation NM_001943.4:c.146G>A/p.(Arg49His)and NM_001943.3:c.1592T>G/p.(Phe531Cys). In family B, the proband carries a homozygous mutation NM_001943.3:c.1592T>G/p.(Phe531Cys).

This paper presents a new kind of electrical circuit which replace traditional resistor, capacitor and inductor with memristor, memcapacitor and meminductor. These 3 memory devices constitute a new kind of RLC circuit. The paper will show and prove the characteristics of band-pass and band-stop filter with the circuit including memristor, memcapasitor and meminductor. Unlike the traditional electrical components, the value of mem-devices is time-varying, which has higher controlability and usage. Band-pass filter and band-stop filter with mem-devices has further application such as signal processing

// Xueran Chen 1, 2 , Zhen Wang 1, 2 , Huihui Ma 3, 4 , Shangrong Zhang 1, 2 , Haoran Yang 1, 2 , Hongzhi Wang 1, 2 and Zhiyou Fang 1, 2 1 Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, China 2 Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China 3 Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, China 4 Department of Radiation Oncology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230022, China Correspondence to: Xueran Chen, email: xueranchen@cmpt.ac.cn Zhiyou Fang, email: z.fang@cmpt.ac.cn Keywords: melatonin, CCL20, epithelial–mesenchymal transition (EMT), glioma Received: July 17, 2017 Accepted: August 01, 2017 Published: August 24, 2017 ABSTRACT Tumor recurrence in gliomas is partly attributed to increased epithelial–mesenchymal transition (EMT) and enhanced tumor cell dissemination in the adjacent brain parenchyma. Thus, exploring effective strategies for against EMT-like changes in glioma invasion and recurrence will be important for glioma treatment. In this study, we investigated the roles of melatonin in hypoxia-induced EMT suppression, and found that melatonin could significantly suppress the release of the cytokine, CCL20, from cancer cells and antagonize glioma cell metastasis and invasion under hypoxic stress in glioma cells. Furthermore, our findings show that melatonin deregulates Smad7 expression to suppress TGFβ/Smad-mediated increase in CCL20 transcript levels and CCL20-induced EMT occurrence, suggesting a potential anti-EMT therapeutic role for melatonin in malignant transformation in gliomas.

Matrix metalloproteinases (MMPs) have been initially recognized for their role in degradation of extracellular matrix (ECM) and collagen remodeling. However, MMPs have been shown to play a crucial role in inflammation, tumor cell invasion, adaptive and innate immunity. Acute and chronic Graft versus Host Disease (GVHD) are characterized by distinctive histopathological features involving tissue infiltration with donor cells, tissue damage and remodeling. We therefore hypothesized that GVHD-associated organ damage may involve MMPs. We have now identified a novel immunomodulatory function for MMP-13 (alternatively called collagenase-3)and have uncovered a previously unknown role of MMP-13 in regulating GVHD.To address the function of MMP-13 in GVHD we first assesed the effect of MMP-13 on alloresponses in vitro. Using fully Major Histocompatibility Complex (MHC)-mismatched standard mixed lymphocyte reaction we demonstated that antigen presentig cells (APC) from B6.MMP-13-/-(H2b) mice led to signifcantly enhanced antigen-driven activation and proliferation of Carboxyfluorescein succinimidyl ester (CFSE)-labeled Balb/c responder splenocytes. Thus, MMP-13 deficiency in either splenocytes or bone marrow-derived dendritic cells used as stimulators resulted in enhanced proliferation, activation and IFN-gproduction in the allo-reactive lymphocyte responders. Similarly, exogenous MMP13 reduced proliferation of responder T cells as determined tested by CFSEdilution (CFSEloof CD4+T cells from 62.3% decreased to 40.6%, CFSEloof CD8+T cells from 74.1% down to 47.9%). We next assessed the impact of MMP-13 in vivousing fully MHC-mismatched rodent acute GVHD models. To study the role of host-derived MMP-13 we induced GVHD in B6.MMP-13-/-or B6.WT recipient mice following lethal TBI (1075 rad) using splenic T cells from Balb/cdonors. We observed signifcantly accelerated GVHD-related mortality (Median Survival Time 7 vs. 47 days post-transplant, p Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Proclara: Consultancy; BMS: Consultancy.

It is an important researching task for the higher education to change the traditional and purely rationalistic management ideas in the universities, to activate and strengthen the development energy. From the angle of changing the organizational model this paper researches the basic strategy of constructing university learning organizations; in another word: The organizational structure should be networking, and be oblater, opener and lexibler; and gives the architectural model of the learning organizations in the universities.

Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets for ameliorating MM-associated bone disease. We found that myeloma cells express high levels of the matrix metalloproteinase MMP-13 and determined that MMP-13 directly enhances osteoclast multinucleation and bone-resorptive activity by triggering upregulation of the cell fusogen DC-STAMP. Moreover, this effect was independent of the proteolytic activity of the enzyme. Further, in mouse xenograft models, silencing MMP-13 expression in myeloma cells inhibited the development of osteolytic lesions. In patient cohorts, MMP-13 expression was localized to BM-associated myeloma cells, while elevated MMP-13 serum levels were able to correctly predict the presence of active bone disease. Together, these data demonstrate that MMP-13 is critical for the development of osteolytic lesions in MM and that targeting the MMP-13 protein - rather than its catalytic activity - constitutes a potential approach to mitigating bone disease in affected patients.

In this paper, we mainly introduce a novel measurement system of the polarization extinction ratio(PBSBC system). Here, because the main optical components of the system is PBS and PBC, so we call this system PBSBC system. First of all, we introduce the principle of method of measuring the polarization extinction ratio by drawing a circle on the Poincare. Secondly, we present the system block diagram of PBSBC system, and design an experimental system to theoretically and experimentally investigate the performance of this system though the multiple groups of experimental data collected under the same condition. Finally, we could show that it is compatible with the analysis in PBSBC system.

We propose a communication system of Circular Polarization Shift Keying (CPolSK) with homodyne coherent detection in free-space optical (FSO) communication with Gamma-Gamma atmospheric turbulence channel. The system need no polarization coordinate alignment, thus the complexity is reduced. Meanwhile, we derived the closed bit error rate (BER) expression of the system compared with the coherent on-off keying (OOK) system. Simulation results show that CPolSK with homodyne system is highly insensitive to the phase noise and BER performance is greatly promoted compared to OOK modulation, the signal-to-noise ratio (SNR) of receiving is reduced about 8dB when the system has the same BER performance under same conditions.

Background/Aim: We studied the expression of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter (LES) in healthy individuals and in patients diagnosed with achalasia (AC) to gain a better understanding of the etiopathogenesis of AC. Patients and Methods: Our study comprised 14 randomly selected patients with AC who underwent peroral endoscopic myotomy and 14 randomly selected healthy individuals who served as controls. Venous blood samples were evaluated in all study subjects to detect the expression of interleukin-17 and interleukin-22 in the serum using an enzyme-linked immunosorbent assay. Immunohistochemistry studies were performed to evaluate LES myofilaments obtained from both groups, as well as from 12 patients diagnosed with a subendothelial non-invasive tumor and who had undergone submucosal tunneling endoscopic resection, to assess the expression of interleukin-17 and interleukin-22 in LES myofilaments. Results: Compared with that in the control group, the expression of interleukin-17 and interleukin-22 in the serum and LES, in patients with AC, was significantly increased and was positively correlated. Conclusion: Interleukin-17 and interleukin-22 are upregulated in the serum and LES in patients with AC, suggesting that both interleukin-17 and interleukin-22 are involved in the pathogenesis of AC, and that AC may be an immune-mediated inflammatory disease.

Background Sesame (Sesamum indicum L., 2n = 26) is an important oilseed crop with an estimated genome size of 369 Mb. The genetic basis, including the number and locations of quantitative trait loci (QTLs) of sesame grain yield and quality remain poorly understood, due in part to the lack of reliable markers and genetic maps. Here we report on the construction of a hitherto most high-density genetic map of sesame using the restriction-site associated DNA sequencing (RAD-seq) combined with 89 PCR markers, and the identification of grain yield-related QTLs using a recombinant inbred line (RIL) population. Result In total, 3,769 single-nucleotide polymorphism (SNP) markers were identified from RAD-seq, and 89 polymorphic PCR markers were identified including 44 expressed sequence tag-simple sequence repeats (EST-SSRs), 10 genomic-SSRs and 35 Insertion-Deletion markers (InDels). The final map included 1,230 markers distributed on 14 linkage groups (LGs) and was 844.46 cM in length with an average of 0.69 cM between adjacent markers. Using this map and RIL population, we detected 13 QTLs on 7 LGs and 17 QTLs on 10 LGs for seven grain yield-related traits by the multiple interval mapping (MIM) and the mixed linear composite interval mapping (MCIM), respectively. Three major QTLs had been identified using MIM with R2 > 10.0% or MCIM with ha2 > 5.0%. Two co-localized QTL groups were identified that partially explained the correlations among five yield-related traits. Conclusion Three thousand eight hundred and four pairs of new DNA markers including SNPs and InDels were developed by RAD-seq, and a so far most high-density genetic map was constructed based on these markers in combination with SSR markers. Several grain yield-related QTLs had been identified using this population and genetic map. We report here the first QTL mapping of yield-related traits with a high-density genetic map using a RIL population in sesame. Results of this study solidified the basis for studying important agricultural traits and implementing marker-assisted selection (MAS) toward genetic improvement in sesame. Electronic supplementary material The online version of this article (doi:10.1186/s12870-014-0274-7) contains supplementary material, which is available to authorized users.

Lenalidomide-induced upregulation of CXCR4 in CD34 + hematopoietic cells, a potential mechanism of decreased hematopoietic progenitor mobilization

We present the evolution equation of surface waves due to the two-photon photorefractive effect. It is shown theoretically that the surface waves can be supported by two-photon photorefractive media. The spatial frequency of photorefractive surface waves can be changed by an applied external electric field, which indicates a method for transforming the surface waves between high-frequency modes and low-frequency modes.

Idiopathic pneumonia syndrome (IPS) is a life-threatening acute noninfectious diffuse lung injury occurring after allogeneic bone marrow transplantation (BMT). We have recently shown that absence of STAT1 signaling in recipient APC leads to accelerated Graft Versus Host Disease (GVHD) and Transplant-associated mortality and morbidity after lethal irradiation in fully MHC-mismatched allogeneic or in non-irradiated P→F1 BMT models. We now addressed the impact of recipient Type II interferon signaling on the development of lung injury after allogeneic BMT using a non-irradiated P→F1 model. 1x107 BMCs plus 2.5x107 SPCs from C57BL/6 (B6) mice were i.v. injected into IFNγR-deficient CB6F1 (F1.GRKO) or CB6F1 wild type (WT) mice. F1.GRKO recipients had significantly reduced survival (MST 32 days post-BMT vs. not reached p Disclosures Lentzsch: Celgene: Membership on an entity's Board of Directors or advisory committees; Axiom: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract 732 Treg cells have been recognized as critical regulators of the immune response and shown to prevent the development of GVHD. However, little is known about of the role of STAT1 signaling in Treg cells during the development of GVHD. In this study, we tried to investigate how STAT1 signaling controls donor Treg development and function in the setting of GVHD. For this purpose we studied the role of STAT1 in natural and inducible Treg (nTreg and iTreg, respectively). To better understand the influence of STAT1-deficiency on the proliferation of nTreg cells, purified splenic STAT1−/− or STAT1+/+ CD4+CD25+ cells were labeled with Carboxyfluorescein succinimidyl ester (CFSE) and cultured on anti-CD3 coated plates in the presence of anti-CD28 and IL-2 for 3 days and analyzed for proliferation and viability. After 72h of in vitro culture 50% of the STAT1+/+ starting population were no longer viable compared to only 10% of STAT1−/− cells. Furthermore, we noted a significantly increased expansion of STAT1-deficient CD4+CD25+Foxp3+ Treg cells compared to STAT1+/+ Treg cells (p Disclosures: Lentzsch: Celgene Corp: Research Funding. Mapara:Resolvyx: Research Funding; Gentium: stocks.

Abstract 4079 Background: In multiple myeloma (MM), lenalidomide has impressive clinical activity in patients with both relapsed/refractory and newly diagnosed disease. Nevertheless hematopoietic stem cell transplantation (HSCT) is still the “backbone” in the treatment of newly diagnosed MM patients and very often lenalidomide treatment (as induction therapy) is combined with HSCT in order to achieve high response rates. Clinical data have shown that in up to 43% of those patients, standard mobilization of CD34+ cells with G-CSF alone failed to mobilize significant numbers of hematopoietic progenitors into peripheral blood, raising concerns about potential stem cell toxicity of lenalidomide (Mazumder et al, Leukemia 2008). Interestingly mobilization of hematopoietic progenitors with AMD-3100 (Plerixafor) overcomes mobilization failures in almost all patients previously treated with lenalidomide. The fact that AMD-3100 antagonizes the binding of chemokine stromal- cell–derived factor-1α (SDF-1α) to CXC chemokine receptor 4 (CXCR4) suggests a potential role of the CXCR4/SDF-1α axis in mediating mobilization failure after lenalidomide treatment. Subsequently, the findings noted above raised questions on: 1) the stem cell toxicity of lenalidomide; 2) the underlying mechanism that mediates the development of G-CSF resistance; and 3) the mechanism of the modulation of the CXCR4/SDF-1α axis by lenalidomide. In our previous work we showed the following. 1) Lenalidomide neither inhibited colony formation in standard colony assays nor the development of cobble stone area forming cells (CAFC) in LTC-IC assays, suggesting that lenalidomide is not stem cell toxic (Koh et al, Blood 2005). 2) We further showed that lenalidomide significantly upregulated G-CSF secretion of CD34+ cells (600%), suggesting that the high levels of G-CSF may mediate a relative resistance towards G-CSF-induced mobilization (Pal et al, Blood, 2010). Results and Methods: We analyzed why blocking CXCR4 by AMD-3100 overcomes mobilization failure to G-CSF. We first examined the CXCR4 expression profile of CD34+ cells treated with lenalidomide. Lenalidomide treatment significantly upregulated the expression of CXCR4 on cell surface after 48h treatment measured by flow cytometry. Increased expression of CXCR4 onCD34+ cells remained high with continuous treatment. Western blot assay of the hydrophobic (membrane) and the hydrophilic (cytosol) cell fraction confirmed our data showing that lenalidomide increases the expression of CXCR4 on CD34+ cell surface. Confocal microscopy showed that lenalidomide inhibited SDF-1α induced CXCR4 internalization. In accordance with the increased CXCR4 surface expression, transwell migration assay revealed that the SDF-1α-induced migration of CD34+ cells in the presence of lenalidomide significantly increased by 52% in comparison to control. Quantitation of SDF-1α showed that CXCR4 had no significant effect on the secretion of SDF-1α by CD34+ cells and in human stromal cells. Result: In conclusion, our data show that lenalidomide is not toxic to hematopoietic progenitors. The strong increase of G-CSF secretion by CD34+ cells might contribute to a desensitization of CD34+ cells to G-CSF mobilization. Primarily our data indicate that increased expression of CXCR4 followed by blocked internalization, increases binding to SDF-1α secreted by the bone marrow niche. This subsequently prohibits the mobilization of CD34+ cells. These data suggest that blocking the CXCR4 receptor by AMD-3100 disrupts this circle and finally permits the mobilization of hematopoietic cells from the bone marrow niche into peripheral blood. This study provides novel insights into the effects of lenalidomide on CD34+ cells relevant for HSCT in MM. Disclosures: Roodman: Amgen: Consultancy; Celgene Corp: Consultancy; Acceleron: Consultancy; Millennium: Consultancy. Mapara:Gentium: Equity Ownership. Lentzsch:Celgene Corp: Research Funding.

Giant enhancement of second-harmonic generation (SHG) with 83.4%/W coversion efficiency is obtained, taking advantage of photorefractive surface waves with diffusion and drift nonlinearity. In this method, the self-bending induced by diffusion nonlinearity can be utilized at the surface and can solve the phase-mismatch problem in bulk due to beam self-bending. With drift nonlinearity, an applied external electric filed and background illumination can further constringe surface waves to the surface and consequently enhance SHG, which provides the possibility and flexibility of control.

We predict the formation of electrically and optically controlled photorefractive surface waves in liquid crystal, with orientational photorefractive effects. In contrast to the case for photorefractive surface waves in inorganic crystals, the penetration depth of photorefractive surface waves in liquid crystal can be controlled by means of the applied external electric field, while the position of the photorefractive surface waves in the liquid crystal can be controlled by means of the applied external electric field and the polarization of incident light beams.

We present an improved Kretschmann configuration with nonlinear dielectric as substrate, in which long-range surface plasmon polaritons (SPPs) may appear, the modes and propagation lengths are tunable. We numerically simulated the solutions of SPP modes and their propagations. The results show that the SPP propagation length can range from tens of micrometers to tens of centimeters or even longer. The configuration proposed in this letter makes a breakthrough of the intrinsic restriction in conventional Kretschmann configuration and there exist the continuous steady SPP modes also in the range of k0e31/2>β>k0e11/2. It allows for optimization of SPP properties and makes SPP application more flexible in practices.

We introduce a type of (2+1)D surface soliton in virtue of the cooperation of nonlocal and local nonlinearities. Furthermore, taking advantage of diffusion and drift nonlinearity this type of surface soliton is demonstrated theoretically and experimentally in a storintium barium nitrate crystal. The dynamics behavior of the excitation and propagation of this type of surface soliton are studied using the beam-propagation method and the nonlinear equation of light rays.

Graft-versus-host disease (GVHD) mediated by alloreactive donor T cells is the most dreaded complication after allogeneic bone marrow transplantation (BMT). Interaction of donor T cells with host antigen presenting cells is considered to be central to the development of GVHD. Furthermore, GVHD development depends on the inflammatory response induced by the conditioning regimen. Interfering with inflammatory signaling pathways could be an approach to prevent GVHD without compromising the graft-versus-malignancy reaction. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists, such as 15-deoxy -Δ12,14-Prostaglandin J2 (15d-PGJ2) have been shown to have potent immunomodulatory effects on B and T lymphocytes as well as DCs, and recent studies have demonstrated protective effects of PPARγ agonists on animal models of autoimmunity including experimental allergic encephalomyelitis (EAE), asthma, arthritis, colitis and diabetes. There is very few data addressing the role of PPARγ agonists on GVHD. The aim of this study was to investigate the protective effect and mechanism of 15d-PGJ2 on experimental GVHD. GVHD was induced following lethal irradiation (1075 rad) using the fully MHC-mismatched strain combination BALB/c to B6. Recipients were treated with 1 mg/kg of 15d-PGJ2 i.p on days −1, +1, +3, +5 and +7 post-BMT. Treatment with 15d-PGJ2 resulted in a significantly reduced GVHD mortality (p=0.01 log rank test) with a Median Survival Time (MST) of 23 days in the control group. Median survival was not reached in the 15d-PGJ2 treatment group at the end of the observation period (day +50 post BMT). Furthermore, we found a significant reduction in donor T cell expansion of 15d-PGJ2-treated animals on day +6 post-BMT. To further delineate the mechanisms underlying its protective effect, we analyzed the effects of 15d-PGJ2 on alloantigen-driven proliferation in MLR cultures in vitro as well as development and maturation of mouse bone marrow derived- dendritic cells (DC) in vitro. Treatment with 15d-PGJ2 resulted in a dose-dependent inhibition of allo-antigen driven proliferation. Furthermore, using a 12-day culture system 15d-PGJ2 led to a significant reduction of mature DC as determined by the number of DC co-expressing CD40, CD80, CD86. Treatment for 24 hours with 5uM of 15d-PGJ2 significantly inhibited activation of the NF-κB pathway as demonstrated by abrogation of p65 and IkB-α phosphorylation in response to alloactivation and also in 15d-PGJ2 treated DC using western blot analysis. In conclusion our data support the notion that the inhibitory effect of 15d-PGJ2 on the development of GVHD involves NF-κB-dependent inhibition of DC maturation and expansion of donor T cells. Given its potent antitumor effects cyclopentenone prostaglandins could be ideal candidates for prevention of GVHD while maintaining Graft versus malignancy effects.