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Reducing the bidentate ether species formed from the chemisorption between PO and acid sites in the TS/H2O2 system is key to achieving stable operation of the HPPO process.

A protic solvent (ROH/H2O) acts as a mediator to promote the proton transfer during H2O2 activation.

LMB-100 is a novel immune-conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB-100 ± nab-paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity. On Arm A, participants (n = 20) received standard 30-minute LMB-100 infusion with nab-paclitaxel. Although clinical efficacy was observed, the combination caused intolerable capillary leak syndrome (CLS), a major toxicity of unclear etiology that affects many immunotoxin drugs. Participants developing CLS experienced rapid elevations in IFNγ and IL-8 compared to those without significant CLS, along with midcycle increases in Ki-67- CD4 T cells that were CD38, HLA-DR, or TIM3 positive. Additionally, a strong increase in activated CD4 and CD8 T cells and a concurrent decrease in Tregs were seen in the single Arm A patient achieving a partial response. In Arm B, administration of single agent LMB-100 to participants (n = 20) as a long infusion given over 24-48 h was investigated based on pre-clinical data that this format could reduce CLS. An optimal dose and schedule of long infusion LMB-100 were identified, but no clinical efficacy was observed even in patients receiving LMB-100 in combination with nab-paclitaxel. Despite this, both Arm A and B participants experienced increases in specific subsets of proliferating CD4 and CD8 T cells following Cycle 1 treatment. In summary, LMB-100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.

With the prevailing use of smartphones and location-based services, vast amounts of trajectory data are collected and used for many applications. When trajectory data are sent to a third-party research institute for analytical applications, the privacy of users would be severely disclosed. For example, the relationship between users will be revealed from the correlation between trajectories. In this paper, we propose a method for releasing trajectory datasets without revealing correlation between trajectories, called RDPT. In RDPT, we first quantify the trajectory correlation and convert the problem of protecting trajectory correlations into reducing the trajectory similarities of users and preserving the utility of the perturbed trajectories. Based on the insight, we model a multi-objective optimization problem and solve the problem with the particle swarm optimization algorithm modified to satisfy differential privacy. Then we generate synthetic trajectories and the correlations between trajectories are reduced. We conduct extensive experiments on three real trajectory datasets. The experimental results show that RDPT achieves almost equivalent data utility to and better privacy than the existing methods.

Flow chart of dose level patient enrollment

Figure

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months).Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Supplementary Data from Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy

Purpose:This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI).Patients and Methods:A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability.Results:Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS.Conclusions:CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

Purpose: Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models.Experimental Design: A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab.Results: We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice.Conclusion: Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. Clin Cancer Res; 17(10); 3181–92. ©2011 AACR.

Supplementary Table S1 from Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Antitumor Activity against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of Response

Supplementary Figures S1-S2; Supplementary Tables S1-S3.

Figure

Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non–small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity.Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (6; P = 0.028).Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition. Clin Cancer Res; 17(5); 1190–9. ©2011 AACR.

Supplemental Data legends

Supplementary Methods from Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer

Supplementary Tables 1-3 from Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer

Supplementary Figures 1-5 from Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer

The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR–positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. Cancer Res; 70(16); 6497–508. ©2010 AACR.

Purpose: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). Patients and Methods: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. Results: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7–33.5], median PFS was 3.6 months (95% CI, 2.1–5.5), and median OS was 10.4 months (95% CI, 5.8–19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. Conclusions: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

The distribution of titanium (Ti) active sites in the framework of TS-1 zeolite is one of the critical factors affecting its catalytic performance, since it can influence accessibility of the Ti active sites and the catalytic utilization of Ti atoms. Here, TS-1 zeolite with homogeneous distribution of titanium atoms in the framework (named BUS-TS-1) is successfully synthesized via bottom-up strategy at high basicity conditions, and BUS-TS-1 zeolite exhibits better catalytic performance for both olefin and alkane oxidation. The comprehensive explorations on the crystallization behavior of BUS-TS-1 zeolite show that, the gripper-like silicon species, as condensed matter in Q2 and Q3 states (detected by 29Si NMR), can be obtained by the condensation of tetraethyl orthosilicate (TEOS) at high alkalinity conditions. The gripper-like silicon species can condense with Ti-OH to form stable and isolated Si-O-Ti species, so that the phase transfer rates of Si and Ti species match during the entire crystallization process, resulting in the homogeneous distribution of Ti atoms. This work offers a useful strategy for the synthesis of high-performance catalysts by regulating the distribution of Ti active-site within TS-1 framework.

Propane nonoxidative dehydrogenation (PDH) is a promising route to produce propylene with the development of shale gas exploration technology. Co-based catalysts with low cost and low toxicity could activate C-H effectively, but they suffer from deactivation with coke formation. In this work, a catalyst formed by incorporating highly dispersed Co sites into a Silicalite-1 zeolite framework (Co-Silicalite-1) is synthesized by a hydrothermal protocol in the presence of ammonia, which exhibits superior propane dehydrogenation catalytic performance with 0.0946 mmol C3H6·s-1·gCo-1 and propylene selectivity higher than 98.5%. It also shows outstanding catalytic stability and coking resistance in a 3560 min time-on-stream. Combined characterization results demonstrate that the tetrahedrally coordinated Co2+ site serves as the PDH catalytic active site, which is stabilized by Si-O units of the zeolite framework. Incorporation of Co sites into the zeolite framework could avoid the reduction of Co species to metallic Co. Moreover, the catalytic performance is improved by the enhanced propane adsorption and propylene desorption.

The key to high efficiency of utilization of hydrogen peroxide (H2O2) over titanosilicate/H2O2 systems was discovered thanks to a comprehensive catalytic investigation. The H2O2 utilization efficiency depended chiefly on the competition between the epoxidation and decomposition pathways of the H2O2 reaction. In terms of the epoxidation pathway, the formation of Ti OOH species could be promoted by enhancing the intrinsic catalytic activity of titanosilicates by improvement of Lewis acid strength. Meanwhile, the ability of active “O” to transfer to reactants could be enhanced by improving the nucleophilicity of alkene (reactant), the surface hydrophobicity of zeolites, and the Oα–Oβ polarizations of Ti OOH species. These were beneficial for the increase of H2O2 utilization efficiency. In the ineffective decomposition pathway, the self-decomposition of H2O2 hardly occurred within a short period of time and at a low temperature, while the oxidative decomposition of H2O2 (OD) with Ti OOH species was mainly responsible for low H2O2 utilization efficiencies. The stability of Ti OOH species could be improved by enhancing the hydrogen-bonding interactions with the addition of hydrogen-bond acceptors and the proper solvent, which was helpful for suppressing OD. Thus, the synergistic effect of regulating the intrinsic catalytic activity of titanosilicates for the formation of Ti OOH species, adjusting the hydrogen-bonding interactions for the stability of Ti OOH species, and enhancing the ability of active “O” to transfer to reactants was the key to achieving high utilization efficiency of H2O2 over titanosilicates/H2O2 systems. These discoveries could provide beneficial ideas for designing a highly efficient titanosilicates-catalyzed epoxidation system.

A thorough investigation of the nature of the Ti species in the boron-containing Ti-MWW zeolite has been carried out. It was found that the inactive extra-framework TiO6 species can cover up the zeolite Lewis-acid property through the weak atomic binding forces between the “Ti(IV)” atom and “O” atom (TiO6 species). The nitric acid treatment could remove these TiO6 species easily from the as-synthesized Ti-MWW(P), followed by exposure of the zeolite Lewis acidity. Importantly, the formation of new Ti(OSi)3OH species with a strong Lewis-acid strength, is facilitated in the modification process. Thereby, the modified Ti-MWW zeolite has an improved catalytic activity in alkene epoxidation reactions. The removal of framework B(IV) species around the TiO4 species is an essential step because it can accelerate the transformation of perfect Ti(OSi)4 species to the defective Ti(OSi)3OH species in zeolites. Moreover, the strategy to construct Ti(OSi)3OH species was also applied successfully in boron-containing Ti-MCM-56 zeolites. Considering active species environment can be modulated effectively with the removal of framework tetra-coordinate boron, this strategy could also be beneficial for the preparation of other high-performance titanosilicates.

The exploration of efficient catalysts with more accessible active titanium species based on the titanosilicate zeolites is in incremental demands for the construction of the high utilization active centers to the various reactions. Here, we report an active oxidation catalyst MWW-type titanosilicate (Al-Ti-MWW) with more “Ti” active species distributed on the zeolite surface obtained through the implantation of the heteroatom aluminum to the conventional Ti-MWW synthesis. Combined with the overall measurements, it was deduced that more “Ti” species were regulated to evenly distributed in the zeolite crystal, which was due to the competitive occupancy of the heteroatom Al, B and Ti over T locations. Consequently, the bulky-substrate reaction results such as the cyclohexene epoxidation reaction and cyclohexanone ammoximation reaction showed that the Al-Ti-MWW catalyst had a superior catalytic oxidation activity than that of conventional Ti-MWW. It is believed that the application of the convenient treatment method could provide an effective strategy for designing high-performance titanosilicate catalysts.

Propane nonoxidative dehydrogenation (PDH) is a promising route to produce propylene with the development of shale gas exploration technology. Co-based catalysts with low cost and low toxicity could activate C-H effectively, but they suffer from deactivation with coke formation. In this work, a catalyst formed by incorporating highly dispersed Co sites into a Silicalite-1 zeolite framework (Co-Silicalite-1) is synthesized by a hydrothermal protocol in the presence of ammonia, which exhibits superior propane dehydrogenation catalytic performance with 0.0946 mmol C

Selenoproteins play important roles in many cellular functions and biochemical pathways in mammals. Our previous study showed that the deficiency of the 15 kDa selenoprotein (Selenof) significantly reduced the formation of aberrant crypt foci (ACF) in a mouse model of azoxymethane (AOM)-induced colon carcinogenesis. The objective of this study was to examine the effects of Selenof on inflammatory tumorigenesis, and whether dietary selenium modified these effects. For 20 weeks post-weaning, Selenof-knockout (KO) mice and littermate controls were fed diets that were either deficient, adequate or high in sodium selenite. Colon tumors were induced with AOM and dextran sulfate sodium. Surprisingly, KO mice had drastically fewer ACF but developed a similar number of tumors as their littermate controls. Expression of genes important in inflammatory colorectal cancer and those relevant to epithelial barrier function was assessed, in addition to structural differences via tissue histology. Our findings point to Selenof’s potential role in intestinal barrier integrity and structural changes in glandular and mucin-producing goblet cells in the mucosa and submucosa, which may determine the type of tumor developing.

Several variants of SARS-CoV-2 have emerged. Those with mutations in the angiotensin-converting enzyme (ACE2) receptor binding domain (RBD) are associated with increased transmission and severity. In this study, we developed both antibody quantification and functional assays. Analyses of both COVID-19 convalescent and diagnostic cohorts strongly support the use of RBD antibody levels as an excellent surrogate to biochemical neutralization activities. Data further revealed that the samples from mRNA vaccinated individuals had a median of 17 times higher RBD antibody levels and a similar degree of increased neutralization activities against RBD-ACE2 binding than those from natural infections. Our data showed that N501Y RBD had 5-fold higher ACE2 binding than the original variant. While antisera from naturally infected subjects had substantially reduced neutralization ability against N501Y RBD, all blood samples from vaccinated individuals were highly effective in neutralizing it. Thus, our data indicates that mRNA vaccination is far more effective than natural immunity in generating highly effective neutralizing antibodies. It further suggests a potential need to maintain high RBD antibody levels to control the more infectious SARS-CoV-2 variants.

With the popularity of smart devices and social applications, vast amounts of trajectory data are generated that can be used for traffic planning, etc. However, when trajectory data are applied in these applications, the private information contained in the trajectories can be revealed. In this paper, we focus on trajectory correlation, which can reveal the social relations of users and further cause severe breaches of privacy. We present a method for correlated trajectory publication with differential privacy, called CTP. First, we discretize the continuous geographical space of raw trajectories to obtain a grid space via an adaptive grid partition method with the Laplace mechanism and convert the trajectories from locations into cells. Then, we quantify the trajectory correlation using the cell visit probability vectors of raw trajectories of the cell mode and turn to reducing the similarity of two cell visit probability vectors for the protection of trajectory correlation. Second, based on the correlations extracted from raw trajectories of the cell mode, we design a constrained optimization problem. By solving it via particle swarm optimization, which is modified to satisfy differential privacy, we can obtain an updated cell visit probability vector of a given trajectory, thus weakening the correlations between the given trajectory and other trajectories. Finally, based on the updated probability vector, we synthesize a trajectory corresponding to the given trajectory. We perform experiments on real trajectory datasets. The experimental results show that CTP is stable and achieves a better trade-off between the data utility and the privacy than the existing methods.

Hollow core–shell structured TS-1@S-1 zeolite (HCS-TS) was prepared successfully for the first time, which exhibited excellent activity in the epoxidation of alkenes. Combining TEM, UV-vis, UV-Raman, pyridine-IR, solid-state MAS NMR, XPS and so on characterization, the improvement in the catalytic performance of hollow core–shell structured TS-1@S-1 zeolite was credited to the newly formed superior active sites: defective Ti(OSi)3(OH) species in HCS-TS and six-coordinated titanium active species in uncalcined HCS-TS (HCS-TSP). Interestingly, these two different titanium active species in the samples could be constructed through calcination or not in the same synthesis process. A possible formation mechanism was investigated in detail; it indicated that the hollowing treatment of TS-1 in the first step was conducive to the construction of the new superior active sites in the samples, and there was a synergistic effect on the formation of these active sites between TPAOH and TEOS in the second step of the synthesis process. This strategy is feasible to enhance the catalytic performance of TS-1, and is suitable for the synthesis of TS-1 on an industrial scale.