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Introduction Tigecycline is a potential alternative to trimethoprim–sulfamethoxazole in treating Stenotrophomonas maltophilia infections due to its potent in vitro antimicrobial activity. Clinical evidence regarding the use of tigecycline in the treatment of S. maltophilia infections is scarce. In this study, we assessed the efficacy of tigecycline treating ventilator-associated pneumonia (VAP) due to S. maltophilia in comparison with fluoroquinolones. Methods This is a multicenter retrospective cohort study of patients admitted between January 2017 and December 2020 with the diagnosis of VAP caused by S. maltophilia receiving either tigecycline or fluoroquinolones as the definitive therapy ≥ 48 h. Clinical outcomes including 28-day mortality, clinical cure and microbiological cure were analyzed. Results Of 82 patients with S. maltophilia VAP included, 46 received tigecycline, and 36 received fluoroquinolones; 70.7% of patients had polymicrobial pneumonia, and the appropriate empiric therapy was applied to only 14.6% of patients. The overall 28-day mortality was 39%. Compared with patients receiving fluoroquinolones, tigecycline therapy resulted in worse clinical cure (32.6% vs. 63.9%, p = 0.009) and microbiological cure (28.6% vs. 59.1%, p = 0.045), while there was no statistical difference between 28-day mortality (47.8% vs. 27.8%, p = 0.105) in the two groups. Similar results were also shown in the inverse probability of treatment weighted univariable regression model and multivariable regression model. Conclusions The standard dose of tigecycline therapy was associated with a lower clinical and microbiological cure rate but not associated with an increased 28-day mortality in patients with S. maltophilia VAP compared with fluoroquinolones. Considering the unfavorable clinical outcomes, we therefore recommend against using the standard dose of tigecycline in treating S. maltophilia VAP unless new clinical evidence emerges. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00516-5.

Aim: The role of plasma heat shock protein 90 alpha (HSP90α) in colorectal cancer patients remains unclear. This study aimed to evaluate the relationship between HSP90α and the occurrence and development of colorectal cancer through diagnosis and prognosis value.Methods: 635 colorectal cancer patients and 295 healthy controls were recruited. The HSP90α was measured by using the ELISA kit in all objects and the immune cells and common biomarkers as CEA, AFP, CA125, CA153 and CA199 were measured in all colorectal cancer patients. The relationship between plasma HSP90α with clinical features, common tumor markers and immune cells were also conducted. The survival analysis endpoint was progression-free survival (PFS).Results: The levels of plasma HSP90α were significantly higher in colorectal cancer patients compared to healthy controls [51.4 (ng/ml) vs. 43.7 (ng/ml), p < 0.001]. In additional, the levels of plasma HSP90α were associated with gender and disease progress as stage, lymphatic and distant metastasis. Furthermore, plasma HSP90α was closed correlation with CEA, CA125, CA199 and percentage of B cells. However, the initial expression level of plasma HSP90α failed to show a prognostic value for progression-free survival in colorectal cancer.Conclusion: The plasma Hsp90α was remarkable higher in colorectal cancer and correlated with common tumor biomarkers and immune cells. Plasma Hsp90α levels were associated with disease progress but a poor diagnosis performance and also failed to show a prognostic value in colorectal cancer.

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.

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides neuroprotective effects, which can alleviate brain injury and inflammation induced by stroke. Previous studies have suggested that CXCR4 reduces the pyroptosis of LPS-stimulated BV2 cells. The purpose of this study was to evaluate the antipyroptosis effects and mechanisms of CXCR4 after SAH. SAH animal model was induced via endovascular perforation. A total of 136 male Sprague-Dawley rats were used. Recombinant human cysteine-X-cysteine chemokine ligand 12 (rh-CXCL-12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitor of CXCR4, AMD3100, was administered intraperitoneally at 1 h before SAH. The neurobehavior tests were assessed, followed by performing Western blot and immunofluorescence staining. The Western blot results suggested that the expressions of endogenous CXCL-12, CXCR4, and NLRP1 were increased and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on neurons, microglia, and astrocytes. Rh-CXCL-12 treatment improved the neurological deficits and reduced the number of FJC-positive cells, IL-18-positive neurons, and cleaved caspase-1(CC-1)-positive neurons after SAH. Meanwhile, rh-CXCL-12 treatment increased the levels of CXCL-12 and CXCR4, and reduced the levels of NLRP1, IL-18, IL-1β, and CC-1. Moreover, the administration of AMD3100 abolished antipyroptosis effects of CXCL-12 and its regulation of CXCR4 post-SAH. The CXCR4/NLRP1 signaling pathway may be involved in CXCL-12-mediated neuronal pyroptosis after SAH. Early administration of CXCL-12 may be a preventive and therapeutic strategy against brain injury after SAH.

This is the first report of ceftazidime–avibactam resistance caused by the blaKPC-33 mutation through the D179Y variant during the treatment of blaKPC-2-positive Klebsiella pneumoniae-related infections in China. The blaKPC-33-containing K. pneumoniae was susceptible to meropenem–vaborbactam, cefepime–zidebactam, tigecycline, and polymyxin B. The blaKPC-33 gene was located on a 77 551-bp transformable plasmid harboring qnrS1 and blaLAP-2. Detecting blaKPC-33-positive K. pneumoniae clinical strains is important for infection control.

Background Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted anti-inflammatory effects in a variety of nervous system diseases. This study aimed to investigate the anti-inflammatory effects of recombinant human CSF1 (rh-CSF1) and the underlying mechanisms in a rat model of HIE. Methods A total of 202 10-day old Sprague Dawley rat pups were used. HI was induced by the right common carotid artery ligation with subsequent exposure of 2.5-h hypoxia. At 1 h and 24 h after HI induction, exogenous rh-CSF1 was administered intranasally. To explore the underlying mechanism, CSF1R inhibitor, BLZ945, and phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, were injected intraperitoneally at 1 h before HI induction, respectively. Brain infarct area, brain water content, neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results The expressions of endogenous CSF1, CSF1R, PLCG2, protein kinase C epsilon type (PKCε), and cAMP response element-binding protein (CREB) were gradually increased after HIE. Rh-CSF1 significantly improved the neurological deficits at 48 h and 4 weeks after HI, which was accompanied by a reduction in the brain infarct area, brain edema, brain atrophy, and neuroinflammation. Moreover, activation of CSF1R by rh-CSF1 significantly increased the expressions of p-PLCG2, p-PKCε, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1β and TNF-α. Inhibition of CSF1R and PLCG2 abolished these neuroprotective effects of rh-CSF1 after HI. Conclusions Our findings demonstrated that the activation of CSF1R by rh-CSF1 attenuated neuroinflammation and improved neurological deficits after HI. The anti-inflammatory effects of rh-CSF1 partially acted through activating the CSF1R/PLCG2/PKCε/CREB signaling pathway after HI. These results suggest that rh-CSF1 may serve as a potential therapeutic approach to ameliorate injury in HIE patients.

Objectives To assess the efficacy of corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Design, setting Observational study in the two COVID-19-designated hospitals in Wuhu, Anhui province, China, 24 January - 24 February 2020. Participants Thirty-one patients infected with the severe acute respiratory coronavirus 2 (SARS-CoV-2) treated at the two designated hospitals. Main outcome measures Virus clearance time, length of hospital stay, and duration of symptoms, by treatment type (including or not including corticosteroid therapy). Results Eleven of 31 patients with COVID-19 received corticosteroid treatment. Cox proportional hazards regression analysis indicated no association between corticosteroid treatment and virus clearance time (hazard ratio [HR], 1.26; 95% CI, 0.58-2.74), hospital length of stay (HR, 0.77; 95% CI, 0.33-1.78), or duration of symptoms (HR, 0.86; 95% CI, 0.40-1.83). Univariate analysis indicated that virus clearance was slower in two patients with chronic hepatitis B infections (mean difference, 10.6 days; 95% CI, 6.2-15.1 days). Conclusions Corticosteroids are widely used when treating patients with COVID-19, but we found no association between therapy and outcomes in patients without acute respiratory distress syndrome. An existing HBV infection may delay SARS-CoV-2 clearance, and this association should be further investigated.

OBJECTIVE. This study aims to assess correlations of the time from symptom onset to diagnosis and treatment with the time to disease resolution and CT scores as based on findings from sequential chest CT examinations. MATERIALS AND METHODS. Thirty patients with coronavirus disease (COVID-19) confirmed by reverse transcription-polymerase chain reaction analysis underwent chest CT examinations. Five patients who did not have positive CT findings or who had not yet fulfilled criteria for discharge from the hospital were excluded. CT scores were determined according to CT findings and lung involvement. The time from symptom onset to diagnosis and treatment was recorded for each patient, and on the basis of this information, patients with COVID-19 were divided into group 1 (patients for whom this interval was ≤ 3 days) and group 2 (those for whom this interval was > 3 days). The CT scores for each group were fitted using a Lorentzian line-shape curve to show the variation tendency during treatment. The differences in age, sex, and last CT scores determined before discharge between the two groups were analyzed, and correlations of the time from symptom onset to diagnosis and treatment with the time to disease resolution as well as with the highest CT score also underwent statistical analysis. RESULTS. A total of 25 subjects were enrolled in the study. The fitted tendency curves for group 1 and group 2 were significantly different, with peak points showing that the estimated highest CT score was 10 and 16 for each group, respectively, and the time to disease resolution was 6 and 13 days, respectively. The Mann-Whitney test showed that the last CT scores were lower for group 1 than for group 2 (p = 0.025), although the chi-square test found no difference in age and sex between the groups. The time from symptom onset to diagnosis and treatment had a positive correlation with the time to disease resolution (r = 0.93; p = 0.000) as well as with the highest CT score (r = 0.83; p = 0.006). CONCLUSION. Timely diagnosis and treatment are key to providing a better prognosis for patients with COVID-19.

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.

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.

8027 Background: Activating mutations of the RAS genes NRAS, KRAS, and HRAS ( RASmut) occur in up to 50% of MM and portend poor survival and high recurrence rates. MM cells with RASmut are susceptible to inhibition of germinal center kinase (GCK), resulting in IKAROS degradation independent of cereblon (CRBN). Selinexor is a selective inhibitor of nuclear export (SINE) compound that can induce IKAROS degradation through CRBN-independent pathways to overcome immunomodulatory drug resistance. We explored the benefit of selinexor treatment for pts with RASmut MM. Methods: In the randomized BOSTON study, pts with MM after 1-3 therapies received weekly XVd or twice weekly Vd. In the single-arm STORM study pts with penta-treated, triple class refractory MM were treated with twice weekly Xd. Both treatment regimens are now FDA approved. Mutations were assessed post-hoc by exome sequencing of 119 and 52 pts from BOSTON and STORM, respectively. Pts were considered RASmut if their MM had NRAS, KRAS or HRAS mutations in codons 12, 13 or 61. Results: There were 54 pts (45%) with RASmut in BOSTON (XVd = 26, Vd = 28), and 17 (33%) in STORM. In BOSTON, pts with RASmut MM treated with XVd had significantly longer progression-free survival (PFS) than those treated with Vd (median [med] = 12.9 vs 6.7 months [mo], hazard ratio [HR] = 0.48 [95% CI 0.24-0.97], p = 0.039). For pts treated with Vd, those with RASmut had significantly shorter overall survival (OS) compared to RASwild-type (WT) (med = 16.8 mo vs not reached [NR], HR = 2.87 [95% CI 1.03-7.99], p = 0.035). PFS was not significantly different (med = 6.74 vs 9.82 mo, HR = 1.64 [95% CI 0.88-3.07], p = 0.122). Amongst pts on XVd, there was no difference in survival between RASmut and RASWT pts (PFS: med = 12.8 vs 12.9 mo, HR = 1.08 [95% CI 0.52-2.26], p = 0.83; OS: med = NR vs NR, HR = 0.94 [95% CI 0.36-2.45], p = 0.91). In STORM, pts with RASmut had shorter OS compared to RASwt pts (med = 6.1 vs NR, HR = 2.05 [95% CI 1.22-5.19], p = 0.010). Preliminary studies to explore the mechanisms of action related to RASmut MM sensitivity to XVd demonstrated that selinexor treatment in vitro leads to downregulation of GCK. Conclusions: Despite typically having the worst outcomes, pts with RASmut MM had a similar benefit from XVd as RASWT MM, showing that the XVd combination can overcome RASmut. Mechanistically, selinexor induced down regulation of GCK and enhanced killing of RASmut MM cells. With a manageable safety profile, the XVd regimen could provide a viable treatment option to improve survival of pts with MM with RAS mutations. Clinical trial information: NCT03110562. [Table: see text]

Introduction: RAS oncogenes are the most frequently mutated gene family in human cancers. 50% of newly diagnosed multiple myeloma patients carry a RAS/MAPK pathway mutation, with a rising percentage in the relapsed situation1. Thus, targeting RAS mutations in multiple myeloma will increase therapeutic efficiency and potentially overcome drug-resistance. Unfortunately, RAS mutations have been considered "undruggable" due to a lack of traditional small molecule binding pockets on the proteins. Therefore, key component in the RAS/MAPK pathway may represent an alternative therapeutic target for MM. Germinal center kinase (GCK), also named mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), is an upstream activator in the MAPK pathway. Indeed, we recently discovered the critical role of GCK in RAS mutated (RASmut) MM cell survival and growth. GCK knockdown in RASmut MM cells induced MM cell growth inhibition both in vitro and in vivo. However, the detailed mechanism is yet to be defined. Methods and Results: Our previous data showed that GCK knockdown induces MM cell growth inhibition, associated with the blockage of MKK4/7-JNK phosphorylation and the downregulation of critical transcriptional factors (TFs) including IKZF1/3, BCL-6, and c-MYC proteins. To confirm that GCK knockdown downregulates IKZF1/3 etc at protein level but not mRNA level, we conducted real-time PCR on GCK knockdown MM cells and compared the expression of GCK and TFs to the empty vector (EV) infected MM cells. Results showed that shRNA induced GCK silencing only led to the significantly decreased GCK mRNA, however, did not affect IKZF1 and c-MYC expressions at mRNA level. Consistent with the effects of GCK knockdown, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 proteins, inhibited MM cell proliferation and induced cell apoptosis. 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. Importantly, our data showed that IMiDs-resistant RPMI-8226 MM cells have high expression of GCK. GCK knockdown and inhibition induced IKZF1 downregulation, triggered growth inhibition and cell apoptosis in RPMI-8226 cells, suggesting that GCK regulates IKZF1 degradation via a CRBN-independent mechanism. To confirm this hypothesis, we silenced CRBN in N-Rasmut H929 MM cells by shRNA lentiviral infection and examined the response to IMiDs and GCK inhibitor. CRBN knockdown was confirmed by western blotting. CRBN silencing in H929 cells resulted in lenalidomide (LEN) resistance, evidenced by the WTS proliferation assay. In contrast, CRBN silencing failed to rescue N-Rasmut H929 MM cells from TL4-12 induced proliferation inhibition and IKZF1 downregulation, confirming that GCK regulated IKZF1 and cell growth is independent of CRBN. Conclusion: Taken together, our data demonstrated that GCK inhibition induces cell growth inhibition and triggers apoptosis especially in RASmut MM cells. Importantly, GCK inhibitor 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. GCK inhibitors may represent a novel therapy for the treatment of RASmut MM patients, especially those who are resistant to IMiDs as well as with refractory or relapsed MM. References Walker, B.A., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol33, 3911-3920 (2015). Disclosures Marcireau: Sanofi: Current Employment. Lentzsch:Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Sorrento: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celularity: Consultancy; Magenta: Current equity holder in private company; Sanofi: Research Funding.

The relationship between the critical buckling loads of functionally graded material (FGM) Levinson beams (LBs) and those of the corresponding homogeneous Euler-Bernoulli beams (HEBBs) is investigated. Properties of the beam are assumed to vary continuously in the depth direction. The governing equations of the FGM beam are derived based on the Levinson beam theory, in which a quadratic variation of the transverse shear strain through the depth is included. By eliminating the axial displacement as well as the rotational angle in the governing equations, an ordinary differential equation in terms of the deflection of the FGM LBs is derived, the form of which is the same as that of HEBBs except for the definition of the load parameter. By solving the eigenvalue problem of ordinary differential equations under different boundary conditions clamped (C), simply-supported (S), roller (R) and free (F) edges combined, a uniform analytical formulation of buckling loads of FGM LBs with S-S, C-C, C-F, C-R and S-R edges is presented for those of HEBBs with the same boundary conditions. For the C-S beam the above-mentioned equation does not hold. Instead, a transcendental equation is derived to find the critical buckling load for the FGM LB which is similar to that for HEBB with the same ends. The significance of this work lies in that the solution of the critical buckling load of a FGM LB can be reduced to that of the HEBB and calculation of three constants whose values only depend upon the through-the-depth gradient of the material properties and the geometry of the beam. So, a homogeneous and classical expression for the buckling solution of FGM LBs is accomplished.

Background To compare the clinical characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL), to find out valuable, relevant indicators for differential diagnosis. Methods The clinical, endoscopic and pathological data of 67 cases (54 cases of Crohn’s disease and 13 cases of primary intestinal lymphoma) admitted by the PLA Army General Hospital in the last seven years were analysed retrospectively. Results The average age of CD was lower than that of PIL, but the course of CD was longer than that of PIL (p Abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy or intestinal resection), and multi-site lesions were more common in CD than in PIL (p The biopsy diagnosis rate of PIL was 92.3%, while 85.1% of CD’s pathological manifestations were non-specific inflammation. So the biopsy diagnosis rate of PIL was significantly higher than that of CD (p Two patients were initially diagnosed with CD based on the clinical comprehensive analysis. The clinical symptoms disappeared, and the colonoscopy achieved mucosal healing after treatment. But the patients‘ symptoms repeated, and they were eventually diagnosed as PIL. Conclusions The clinical and endoscopic characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL) are similar, but they have their own characteristics. Therefore, the differential diagnosis is difficult. The diagnosis of CD is more supported by young, long course of the disease, abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy, resection), and multi-site lesions. Short disease duration, abdominal mass and single-site lesion are more common in PIL. Biopsy diagnosis rate of PIL is higher than that of CD. In the case of the diagnosis of PIL after CD treatment, misdiagnosis, a combination of the two and drug induction should be considered.

Background To evaluate the efficacy and safety of Infliximab (IFX) in the management of refractory ulcerative colitis (UC) and UC with extra-intestinal manifestations. Methods The clinical data for 36 cases including refractory UC patients and UC patients with special extra-intestinal manifestations, who all accepted treatment with IFX, were analysed retrospectively. Results Among all the 36 cases, 33 were refractory UC (5 with extra-intestinal manifestations) and another 3 with special extra-intestinal manifestations (2 with perianal abscess and 1 with ankylosing spondylitis). After treatment with IFX, 13 patients achieved clinical remission, of whom 3 achieved mucosal healing, 15 achieved clinical response and 8 failed to respond. The total effective rate of IFX treatment was 77.78%, remission rate 36.11%; Among 8 cases with extra-intestinal manifestations, 5 patients‘ extra-intestinal manifestations improved and the efficacy rate was 62.5%. No serious adverse events occurred during observation. Conclusions IFX is effective and safe in the management of refractory UC and extra-intestinal manifestations.

Objectives This study aims to explore the clinical profiles and onset age-related difference of executive dysfunctions and behavioral changes in early drug-naive patients with Parkinson's disease (PD). Methods A cross-sectional analysis on 419 early stage drug-naive PD patients was conducted. The frontal assessment battery (FAB) was used to assess executive functions and the frontal behavioral inventory (FBI) was used to assess behavioral changes. Results Executive dysfunctions were detected in 113 patients (27.0%), and 219 patients (52.3%) displayed varied degrees of behavioral changes. The most frequent affected domain for the FAB was lexical fluency (31.7%), while the three most frequent affected domains for the FBI were apathy (26.0%), irritability (24.3%) and inattention (20.8%). Compared to the early-onset PD (EOPD) patients, the late-onset PD (LOPD) patients exhibited significantly higher frequent damage in FAB especially similarities, motor series, and conflicting instructions as well as lower frequent damage in lexical fluency. The frequencies of FBI-abnormal were not different between the two groups. Multivariate analyses indicated that age at PD onset was independently associated with FAB total score and its subscores including lexical fluency, motor series, conflicting instructions and go-no go task, but it has no relationship with FBI total score and its subscores. Conclusions Executive deficits and behavioral changes are common in the early stage of PD. Age at PD onset is independently associated with the performance of executive functions. However, behavioral changes in PD may be not affected by onset age.

Background In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. Methods Primary and advanced (relapsed from parental) University of Michigan squamous cell carcinoma cell lines were tested for sensitivity to cisplatin and gene expression profiles were compared between primary (cisplatin sensitive) and the relapsed (cisplatin resistant) cell lines by using Agilent microarrays. Additionally, differentially expressed genes phosphorylated AKT, and BAG-1, and BCL-xL were evaluated for expression using HNSCC tissue arrays. Results Advanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phosphorylated AKT, BAG-1, and BCL-xL were observed in advanced HNSCC compared to in that of primary HNSCC. Conclusion Increased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1289-2) contains supplementary material, which is available to authorized users.

BACKGROUND The aim of this study was to use a three-dimensional (3D) visualization technology to illustrate and describe the anatomical features of the penile suspensory ligamentous system based on the Visible Human data sets and to explore the suspensory mechanism of the penis for the further improvement of the penis-lengthening surgery. MATERIAL AND METHODS Cross-sectional images retrieved from the first Chinese Visible Human (CVH-1), third Chinese Visible Human (CVH-3), and Visible Human Male (VHM) data sets were used to segment the suspensory ligamentous system and its adjacent structures. The magnetic resonance imaging (MRI) images of this system were studied and compared with those from the Visible Human data sets. The 3D models reconstructed from the Visible Human data sets were used to provide morphological features of the penile suspensory ligamentous system and its related structures. RESULTS The fundiform ligament was a superficial, loose, fibro-fatty tissue which originated from Scarpa's fascia superiorly and continued to the scrotal septum inferiorly. The suspensory ligament and arcuate pubic ligament were dense fibrous connective tissues which started from the pubic symphysis and terminated by attaching to the tunica albuginea of the corpora cavernosa. Furthermore, the arcuate pubic ligament attached to the inferior rami of the pubis laterally. CONCLUSIONS The 3D model based on Visible Human data sets can be used to clarify the anatomical features of the suspensory ligamentous system, thereby contributing to the improvement of penis-lengthening surgery.

Facility Management (FM) is well known for its interdisciplinary knowledge and along with the growing number of green buildings and low-carbon buildings, the FM system become increasingly complex. Many practitioners consider Building Information Modeling (BIM) as the most important technology to bring about improvements. The purpose of this paper is to develop a BIM-enabled FM system which integrates FM, BIM and building management system to improve information sharing and monitoring, FM system control, and equipment management. A case study is implemented to validate the feasibility of the BIM-enabled FM system. Four functionalities are demonstrated in detail: Equipment Information Monitoring (EIM), Dynamic Data Display and Warning (D3W), Energy-Saving Analysis (ESA), and Intelligent Fire Escape Route (IFER). The results show that BIM-enabled FM system facilitates the FM more accurate, timely, safe and efficient.

Summary Background Three-dimensional digital models, animations, and simulations have been used in the plastic surgical field for surgical education and training and patient education. In penile lengthening surgery, proper patient selection and well-designed surgical interventions are necessary; however, no such surgical or patient education tool exists. Methods Using magnetic resonance images as references, a preliminary three-dimensional digital model of the penis with its adjacent structures was constructed using Amira 5. This preliminary model was imported into Maya 2009, a computer modeling and animation software program, for processing to correct many defects. The refined model was used to create digital animation of penile lengthening surgery, including ordered steps of the procedure, using Maya 2009 and Adobe After Effects CS4. Results A three-dimensional digital animation was created to illustrate penile lengthening surgery. All major surgical steps were demonstrated, including exposure, transversal incision of the fundiform ligament, partial division and release of the suspensory ligament. Conclusions Three-dimensional digital models and animations of penile lengthening surgery may serve as resources for patient education to facilitate patient selection and resident education outside the operating room.

As one of the most developed cities in China, Shenzhen has experienced a rapid urban construction in the last 30 years and features a highly modernized city now. Since 2002, to facilitate constructions of larger and more complex public projects, Shenzhen government founded the Public Works Department (PWD) to centralize management of all public construction projects except transportation and water sector. After operation, the PWD of Shenzhen has significantly reduced projects durations and corruptions, increased quality, gain of investment and safety in the last decade. However, there are problems existing in the system which mainly include the lack of communication among authorities and between authorities and PWD, poor project decision-making methods, inadequate and obsolete construction management and lack of implementation of innovations in AEC sector. These gaps need to be bridged to improve project management of public projects further. This paper however, focus on regulatory reforms to facilitate permitting processes, and discuss possible methods of reform taking references from international literatures.

For a long time, there have existed a variety of problems in the management of public projects including overinvestment, slow construction progress, poor quality and corruption. Although many efforts have been done for a long time, the essential problems have not been solved at present. The main reason can be explained by no comprehensive measures from the aspects of system, the legal system and the mechanism at the same time. According to the experience of developing countries, this paper put forward the management of specialized organizations could be brought into guarantee the centralization, specialization, unification and investment efficiency of public projects. Then an innovative framework of public project management system has been built based on the centralized management system of Municipal Public Works Bureau in Shenzhen, which is a typical model of reform in China.

The spatial transformation is an important part of existing industrial buildings renovation, but the traditional ways of spatial transformation focused on theoretical analysis, and lacked quantitative research. The Space Syntax theory is introduced into the existing industrial building renovation in this paper. A space model of Chongqing Industrial Museum & Creative Park was built with convex space using the connectivity, depth, integration to measure the permeability, convenience and distribution degree of the space, to analyze its spatial form quantitatively and explore the effect of spatial arrangement on function. Taking the functional orientation into consideration, analyze whether the transformation plan is reasonable, put forward reasonable transformation strategies, and provide reference for future industrial building renovation.

According to the characteristics of quasi-public goods, this paper analyzes the adaptability of supplying quasi-public goods by PPP moderns. Transaction costs of three different pattern, government’s supply, enterprise’s supply and PPP patterns are made qualitative comparisons, while this paper analyzes the ways of innovation in supply entity in the case of market failure. At last approach of decreasing transaction cost has been discussed and both enterprise and government need to revolute for pushing the development of PPP modern had been proved.

Developing IPD (Integrated Project Delivery) in projects requires the operable implementation scheme that can improve productivity and earn more profits. And it is important to provide incentives tied to achieving project goals. This paper suggested cooperative game theory as the method for analyzing profit distribution in IPD project and determined the designer, construction contractor, owner, BIM consultant as the key participants according the degree of importance in IPD projects. The main purpose of this paper is to: (1) Building the framework of BIM platform and using information sharing to guarantee the achievement of IPD project. (2) Exploring the profit distribution model of IPD according to various cooperative game theoretic solution methods. (3) Using the Shapley value to achieve the distribution of profits and the FCE (Fuzzy Comprehensive Evaluation) methods to quantize the risk of each index, while the AHP (Analytic Hierarchy Process) was used to give the weight. (4) Exploring the application of the identified allocation rules based on the case study of Autodesk Inc.

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 investigate the multiple attribute decision making problems for evaluating physical education teaching effectiveness with triangular fuzzy information. We utilize the triangular fuzzy weighted average (TFWA) operator to aggregate the triangular fuzzy information corresponding to each alternative and get the overall value of the alternatives, then rank the alternatives and select the most desirable one(s) according to the possibility degree between the overall value of the alternatives. Finally, an illustrative example for evaluating physical education teaching effectiveness with triangular fuzzy information is given.

Dynamic buckling of functionally graded materials truncated conical shells subjected to normal impact loads is discussed in this paper. In the analysis, the material properties of functionally graded materials shells are assumed to be graded in the thickness direction according to a simple power law distribution in terms of the volume fractions of the constituents. Geometrically nonlinear large deformation and the initial imperfections are taken into account. Galerkin procedure and Runge–Kutta integration scheme are used to solve nonlinear governing equations numerically. From the characteristics of dynamic response obtain critical loads of the shell according to B-R criterion. From the research results it can be found that gradient properties of the materials have significant effects on the critical buckling loads of FGM shells.

Yanan sports practice spirit is an integral part of the Chinese national spirit wealth treasure, so inheriting and developing the spirit still has very strong realistic meaning nowadays. This paper analyzed the specific ways of inheriting and developing the spirit from the Internet perspective. Thr ough an in-depth analysis, it was believed that the Internet was a very necessary way to put forward the spirit. As a platform for information dissemination, internet has been widely used in various fields, it has incomparable advantages that the traditional platform do not have. Today, inheriting and carrying forward the spirit, developing sports industry in new era should not only use the traditional media, but also exploit main kinds of Internets including theme web site, blog and BBS forum and son on regarded as the new Medias. It is not difficult to believe that, with the combination of Internet and traditional media, the propaganda, the inheritance and the development of Yanan sports spirit in now and future will be full of sound and color.

The purpose of the study is to evaluate a new immunochemical fecal occult blood test method (Hemosure IFOBT), and compare it to the Guaiac-based chemical method (CFOBT) for colorectal cancer detection. A hypothetical sequential method (SFOBT), in which IFOBT was used only as a confirmatory test for CFOBT, was also evaluated. A total of 324 patients were recruited from 5 major hospitals in Beijing, China. For each patient, 3 consecutive stool samples were collected for simultaneous CFOBT and IFOBT tests, followed by colonoscopic examination. We compared the sensitivity and specificity of the 3 methods (CFOBT, IFOBT and SFOBT) in two settings, with the first 2 consecutive samples versus all 3 samples. Although the sensitivity for the detection of cancer and large (20 mm) or multiple adenoma was similar for all 3 methods in the three-sample setting, in the two-sample setting IFOBT had higher sensitivity than SFOBT for detecting cancer (87.8% vs. 75.5%, respectively, p0.05) and large (20 mm) or multiple adenomas (65.4% vs. 42.3%, respectively, p0.05). The IFOBT also had a higher specificity than the CFOBT (89.2% vs. 75.5%, respectively, p0.01) in "normal" individuals defined by colonoscopy in the three-sample setting. Comparing two-sample setting to the three-sample setting, both CFOBT and SFOBT showed significant loss of sensitivity for the detection of cancer as well as adenoma, whereas the sensitivity for IFOBT did not change significantly. Overall, IFOBT with two-sample testing showed compatible sensitivity and specificity to the three-sample testing, and had a lower relative cost per cancer detected than the three-sample testing. In conclusion, the new Hemosure IFOBT with two consecutive stool samples appears to be the most cost-effective approach for colon cancer screening.

Introduction A congenital lower lip nevus is common, but a lower lip length lesion of more than 40% is hard to excise simply, without any distortion. We designed a lower lip bilateral advanced skin flap to restore the wound surface after completely and successfully removing the nevus. Case presentation A 13-year-old Mongolian girl was referred to us with a giant congenital lower lip nevus. The lesion covered nearly half of her lower lip. We designed a lower lip bilateral advanced skin flap to restore the wound surface, after completely removing the nevus without advanced repair. Conclusions This case report demonstrates a case of a lower lip length defect of more than 40%, repaired by direct closure without dysfunction. It was a successful attempt that minimized the subsequent scar and dysfunction.

This paper is concerned with one of the most important tasks in construction management—scheduling of construction project—and shows how to optimize the overall construction schedule. The current optimization methods seem to provide very little support for construction project managers, as the managers require a schedule based on the simultaneous considerations of several factors, such as investment allocation, total cost, resource supply, and weather. With a view of systematization, the paper first quantitatively analyzes the factors that influence the overall construction schedule. It then indicates that the optimization of overall construction schedule must be closely combined with the investment allocation, resource supply, and weather. The relationships between these factors are analyzed, and their mathematical submodels are established. Based on these submodels, a mathematical model is then established with the objective of the best economic benefit (the lowest construction cost). Finally, the solut...

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

Background: c-Myc is one of the most frequently altered genes across a vast array of human cancers. Overexpression of c-Myc is observed in up to 30% of cases of diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive lymphoma. Although DLBCL can be cured in 60-70% patients, a substantial minority of patients with DLBCL still die from their lymphoma. There is emerging evidence that c-Myc expression is an adverse risk factor independent of the cell-of-origin classification. To date no drugs that directly target c-Myc have been approved for the treatment of any cancer. In fact, since c-Myc is involved in many normal cellular functions, direct c-Myc inhibitors may be associated with significant toxicity. The goal of our study is to develop novel strategies targeting c-Myc that will have an improved therapeutic index. The c-Myc protein has a very short half-life of less than 30 minutes, and its translation is highly dependent on the eukaryotic initiation factor 4F (eIF4F). eIF4F is activated by the mammalian target of rapamycin (mTOR), which is regulated not only by the PI3K-AKT pathway but also the proteasome pathway. These observations led us to hypothesize that if the proteasome and PI3K pathways cooperate in the activation of mTOR and its downstream target eIF4F, then combinations of proteasome and PI3K inhibitors should potently suppress eIF4F dependent translation of c-Myc and the growth of c-Myc dependent lymphoma. Methods: Cytotoxicity was studied in lymphoma cell lines and primary lymphoma cells using Cell TiterGlo. The Bliss additivism model was used to determine the expected inhibition of cell growth. The difference of the expected and observed levels of inhibition was used to calculate the excess over Bliss (EOB) values. EOB values above 0 indicate synergy, with higher values indicating higher levels of synergy. Mechanisms of synergy were determined through interrogation of PI3K/AKT/mTOR pathway and its downstream targets. Expression of c-Myc was investigated at the translation and transcription levels, using a combination of Western blot, qPCR, and a bi-cistronic luciferase reporter we developed to study cap dependent translation. Gene expression profiling (GEP) studies were conducted using RNAseq, and analyzed by the Fisher t-test and running enrichment score (RES) between different treatment groups. Results: We used a high-throughput platform to screen the cytotoxicity of two PI3Kdelta inhibitors (TGR-1202 & idelalisib/Cal-101), two proteasome inhibitors (bortezomib & carfilzomib), and four combination pairs using these drugs. We found that TGR-1202 and Cal-101 caused only minimal to mild inhibition of lymphoma cells, while bortezomib and carfilzomib caused potent inhibition as single agents. The combination of TGR-1202 and carfilzomib was consistently the most synergistic doublet, while the combination of Cal-101 and bortezomib the least synergistic in numerous lymphoma cell lines studied to date (Figure 1). TGR-1202 and carfilzomib were also highly synergistic in primary lymphoma cells, while Cal-101 and bortezomib were not. Importantly, normal lymphocytes were resistant to the combination of TGR-1202 and carfilzomib. At the molecular level, only the combination of TGR-1202 and carfilzomib potently inhibited mTORC1 dependent phosphorylation of 4E-BP1, leading to marked reduction of c-Myc protein (Figures 2 & 3). In contrast, the combination of TGR-1202 and carfilzomib produced no reduction of the mRNA level of c-Myc (Figures 3). A luciferase reporter demonstrated that the synergistic combination TGR-1202 and carfilzomib specifically inhibited the translation downstream of the 5'UTR of c-Myc (Figure 3). GEP studies confirmed that the canonical c-Myc target genes were potently downregulated at the level of transcription by the combination of TGR-1202 and carfilzomib (Figure 3). These results demonstrate that TGR-1202 and carfilzomib in combination potently inhibited the translation of c-Myc and the c-Myc transcriptional program, which appears to be primarily through disruption of the PI3Kdelta and proteasome pathways that converge on mTOR. Ongoing experiments are focused on confirmation of these observations in vivo. Further, a phase I/II clinical trial evaluating this combination regimen in aggressive c-Myc driven lymphomas is being planned. Disclosures Deng: TG Therapeutics: Research Funding; Gilead: Research Funding; Amgen/Onyx: Research Funding. Lentzsch:Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. O'Connor:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Research Funding; Acetylon: Consultancy, Other: Consultancy fee; Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Other: Consultancy fee; Takeda Millenium: Consultancy, Honoraria, Other: Consultancy fee, Research Funding; Novartis: Consultancy, Honoraria, Other: Consultancy fee; Seattle Genetics: Research Funding; Bayer: Consultancy, Honoraria.

Digital urban is an inevitable outcome when human civilization attains certain historical period. Digital urban could bring many benefits for human beings,such as, to increase a city's comprehensive competition ability, to promote the development of economy, to promote the progress of society and the improvement of human being's civilization,etc. The article introduces the present condition of digital urban management in Chongqing ,and gives some suggestions about how to develop digital urban management in Chongqing.

To assess project safety risk, this paper proposes a quantitative method based on BDD(Binary Decision Diagram). After constructing the BDD with fault tree of safety risk event, the method traverses the BDD and computes the occurrence probability of risk event. For the convenient implementation with computer program, it can get analysis results efficiently and accurately. So it is very suitable for the risk assessment of large projects.

To ensure the reliability of construction system, this paper proposes an enhanced factoring method. Firstly, it finds out the isomorphic sub-networks from decomposition and decreases recomputations. Secondly, it stores the network states in OBDD (ordered binary decision diagram) and decreases redundant states. These steps enhance the factoring method and make it easy to compute network reliability for large construction system of engineering project. The experiments show this method is efficient for large project.

With the rapid process of urbanization, the quantity of construction waste is increasing rapidly. At present, construction waste in our country is produced more, but utilization ratio is low, the way of handling is simple, and these lead to environment pollution, resource waste, construction waste is affecting city's construction and management, the people's health around the city is being affected too, this is against the idea of sustainable development. So, how to deal with construction waste properly in our country is a question which is deserved to research and resolve at once. The article starts from the idea of sustainable development, and gives some suggestions. These suggestions are about how to dismantle old buildings, how to decrease construction waste, how to dispose of construction waste and some suggestions about guarantee of law and policy on the basis of drawing lessons from the production and handling way of construction waste in the other countries.

Immunomodulatory derivatives of thalidomide (IMiDs) have been used for the treatment of myelodysplastic syndrome and multiple myeloma; however, the mechanism of action of IMiDs is largely unknown. The purpose of this review is to provide an overview of recent findings on the mechanism of action of IMiDs, its use as a new treatment modality for various hematologic malignancies, and problems associated with stem cell mobilization after lenalidomide treatment.Recent clinical trials revealed lenalidomide as a promising new agent for the treatment of follicular non-Hodgkin's lymphoma (NHL) and also diffuse large B-cell lymphoma. Pomalidomide was shown to be even more effective in refractory multiple myeloma than lenalidomide. New guidelines for the management of venous thromboembolism have been established. The chemokine receptor 4 (CXCR4) inhibitor, AMD-3100, is recommended for patients who have received lenalidomide and failed to mobilize stem cells after G-SCF and cyclophosphamide. Preclinical studies investigated the pleiotropic functions of IMiDs, with a particular focus on immune modulation, their effects on new targets, stem cells and disruption of plasma cell microenvironment interactions.More and more indications for the use of IMiDs in hematologic malignancies have been identified. In order to establish better clinical usage of IMiDs, it is of utmost importance to clarify the antitumor mechanism of IMiDs. Here, we provide a review on the recent advances in the development of IMiDs. New guidelines for venous thromboembolism prophylaxis and stem cell mobilization failure associated with lenalidomide treatment have been established.

Hypertrophic scar (HS) remains a major problem in plastic surgery. In order to explore the regulative effect of phosphatase and tensin homolog (PTEN) on HS, PTEN and AKT expression was detected by reverse transcription PCR, immunohistochemistry and western blot. Adenovirus-mediated PTEN overexpression in cultured hypertrophic scar fibroblasts (HSFBs) and normal skin fibroblasts was also introduced to evaluate its biological function. Our results showed that PTEN expression was significantly decreased in HS whereas p-Akt level was significantly higher in HS compared with normal skin (P < 0.01). Furthermore, we found that adenovirus-mediated PTEN overexpression led to decreased AKT activation, and significantly reduced cell proliferation and collagen synthesis of HSFBs, while increased the apoptosis. Taken together, these data suggest that PTEN inhibits proliferation and function of HSFBs through AKT pathway. Our results reveal a novel biological role for PTEN/AKT pathway in HS and suggest PTEN as a potential therapeutic target for HS treatment.