bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
Authors: Tomé Mercedes , Pappalardo Angela , Soulet Fabienne , López José Javier , Olaizola Jone , Leger Yannick , Dubreuil Marielle , Mouchard Amandine , Fessart Delphine , Delom Frédéric , Pitard Vincent , Bechade Dominique , Fonck Mariane , Rosado Juan Antonio , Ghiringhelli François , Déchanet-Merville Julie , Soubeyran Isabelle , Siegfried Geraldine , Evrard Serge , Khatib Abdel-Majid 
Published: July 2019

Abstract

Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy.

Significance:
Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer.
Characterization and Comparison of GITR Expression in Solid Tumors
Authors: Vence Luis , Bucktrout Samantha L. , Fernandez Curbelo Irina , Blando Jorge , Smith Bevin M. , Mahne Ashley E. , Lin John C. , Park Terrence , Pascua Edward , Sai Tao , Chaparro-Riggers Javier , Subudhi Sumit K. , Scutti Jorge B. , Higa Maria G. , Zhao Hao , Yadav Shalini S. , Maitra Anirban , Wistuba Ignacio I. , Allison James P. , Sharma Padmanee 
Published: July 2019

Abstract

Purpose:
Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize the tumor microenvironment for the frequency of GITR expression in T-cell subsets from seven different human solid tumors.
Experimental Design: For mouse experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single-cell level using flow cytometry (FC). A total of 213 samples were evaluated for GITR expression by IHC, 63 by FC, and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non–small cell lung cancer (NSCLC), renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma.

Results:
The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that NSCLC, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4+ Foxp3+ T regulatory cells. IHC and FC data showed similar trends with a good correlation between both techniques.

Conclusions:
Human tumor data suggest that NSCLC, renal cell carcinoma, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.
Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study
Authors: Shusterman Suzanne , Naranjo Arlene , Van Ryn Collin , Hank Jaquelyn A. , Parisi Marguerite T. , Shulkin Barry L. , Servaes Sabah , London Wendy B. , Shimada Hiroyuki , Gan Jacek , Gillies Steven D. , Maris John M. , Park Julie R. , Sondel Paul M. 
Published: July 2019

Abstract

Purpose:
Combining anti-GD2 (disialoganglioside) mAb with GM-CSF, IL2, and isotretinoin is now FDA-approved for high-risk neuroblastoma minimal residual disease (MRD) therapy. The humanized anti-GD2 antibody conjugated to IL2 (hu14.18-IL2) has clinical activity in neuroblastoma and is more effective in neuroblastoma-bearing mice than antibody and cytokine given separately. We therefore evaluated the safety, tolerability, and antitumor activity of hu14.18-IL2 given with GM-CSF and isotretinoin in a schedule similar to standard MRD therapy.

Patients and Methods:
Hu14.18-IL2 was given at the recommended phase II dose of 12 mg/m2/day on days 4–6 of a 28-day cycle with GM-CSF (250 mg/m2/dose, days 1–2 and 8–14) and isotretinoin (160 mg/m2/day, days 11–25). Tolerability was determined on the basis of the number of unacceptable toxicities observed. Response was evaluated separately for patients with disease measurable by standard radiologic criteria (stratum 1), and for patients with disease evaluable only by I123-metaiodobenzylguanidine (I123-MIBG) scan and/or bone marrow histology (stratum 2).

Results:
Fifty-two patients with recurrent or refractory neuroblastoma were enrolled; 51 were evaluable for toxicity and 45 were evaluable for response. Four patients had unacceptable toxicities, well below the protocol-defined rule for tolerability. Other grade 3 and 4 nonhematologic toxicities were expected and reversible. No responses were seen in stratum 1 (n = 14). In stratum 2 (n = 31), 5 objective responses were confirmed by central review (3 complete, 2 partial).

Conclusions:
Hu14.18-IL2 given in combination with GM-CSF and isotretinoin is safe and tolerable. Patients with MIBG and/or bone marrow–only disease had a 16.1% response rate, confirming activity of the combination.
Tyrosine Threonine Kinase Inhibition Eliminates Lung Cancers by Augmenting Apoptosis and Polyploidy
Authors: Zheng Lin , Chen Zibo , Kawakami Masanori , Chen Yulong , Roszik Jason , Mustachio Lisa Maria , Kurie Jonathan M. , Villalobos Pamela , Lu Wei , Behrens Carmen , Mino Barbara , Solis Luisa M. , Silvester Jennifer , Thu Kelsie L. , Cescon David W , Rodriguez-Canales Jaime , Wistuba Ignacio I. , Mak Tak W. , Liu Xi , Dmitrovsky Ethan 
Published: July 2019

Abstract
The spindle assembly checkpoint maintains genomic integrity. A key component is tyrosine threonine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause genomic instability and cell death. Interrogating The Cancer Genome Atlas revealed high TTK expression in lung adenocarcinomas and squamous cell cancers versus the normal lung (P &lt; 0.001). This correlated with an unfavorable prognosis in examined lung adenocarcinoma cases (P = 0.007). TTK expression profiles in lung tumors were independently assessed by RNA in situ hybridization. CFI-402257 is a highly selective TTK inhibitor. Its potent antineoplastic effects are reported here against a panel of well-characterized murine and human lung cancer cell lines. Significant antitumorigenic activity followed independent treatments of athymic mice bearing human lung cancer xenografts (6.5 mg/kg, P &lt; 0.05; 8.5 mg/kg, P &lt; 0.01) and immunocompetent mice with syngeneic lung cancers (P &lt; 0.001). CFI-402257 antineoplastic mechanisms were explored. CFI-402257 triggered aneuploidy and apoptotic death of lung cancer cells without changing centrosome number. Reverse phase protein arrays (RPPA) of vehicle versus CFI-402257–treated lung cancers were examined using more than 300 critical growth-regulatory proteins. RPPA bioinformatic analyses discovered CFI-402257 enhanced MAPK signaling, implicating MAPK antagonism in augmenting TTK inhibitory effects. This was independently confirmed using genetic and pharmacologic repression of MAPK that promoted CFI-402257 anticancer actions. TTK antagonism exerted marked antineoplastic effects against lung cancers and MAPK inhibition cooperated. Future work should determine whether CFI-402257 treatment alone or with a MAPK inhibitor is active in the lung cancer clinic.
Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia
Authors: Moriyama Takaya , Liu Shuguang , Li Jing , Meyer Julia , Zhao Xujie , Yang Wentao , Shao Youming , Heath Richard , Hnízda Aleš , Carroll William L. , Yang Jun J. 
Published: July 2019

Abstract
Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in NT5C2 were identified as a common genomic lesion unique in relapsed ALL and were linked to acquired thiopurine resistance. However, molecular mechanisms by which NT5C2 regulates thiopurine cytotoxicity were incompletely understood. To this end, we sought to comprehensively characterize the biochemical and cellular effects of NT5C2 mutations. Compared with wild-type NT5C2, mutant proteins showed elevated 5′-nucleotidase activity with a stark preference of thiopurine metabolites over endogenous purine nucleotides, suggesting neomorphic effects specific to thiopurine metabolism. Expression of mutant NT5C2 mutations also significantly reduced thiopurine uptake in vitro with concomitant increase in efflux of 6-mercaptopurine (MP) metabolites, plausibly via indirect effects on drug transporter pathways. Finally, intracellular metabolomic profiling revealed significant shifts in nucleotide homeostasis induced by mutant NT5C2 at baseline; MP treatment also resulted in global changes in metabolomic profiles with completely divergent effects in cells with mutant versus wild-type NT5C2. Collectively, our data indicated that NT5C2 mutations alter thiopurine metabolism and cellular disposition, but also influence endogenous nucleotide homeostasis and thiopurine-induced metabolomic response. These complex mechanisms contributed to NT5C2-mediated drug resistance in ALL and pointed to potential opportunities for therapeutic targeting in relapsed ALL.
The Novel Small-Molecule SR18662 Efficiently Inhibits the Growth of Colorectal Cancer In Vitro and In Vivo
Authors: Kim Julie , Wang Chao , de Sabando Ainara Ruiz , Cole Hannah L. , Huang Timothy J. , Yang Jie , Bannister Thomas D. , Yang Vincent W. , Bialkowska Agnieszka B. 
Published: July 2019

Abstract
Krüppel-like factor 5 (KLF5), a member of the SP/KLF family of zinc finger transcription factors, is overexpressed in human colorectal cancer specimens, and this overabundance is associated with aggressive cancer development and progression. We demonstrated that mice haploinsufficient for Klf5 had reduced intestinal tumor burden in the background of germline mutation in Apc, a gatekeeper of intestinal tumorigenesis. Based on a high-throughput screening strategy, we developed ML264, a small-molecule compound that inhibits KLF5, and showed that it inhibits growth of colorectal cancer in vitro and in vivo. Through optimization efforts based on the structure of ML264, we have now identified a new lead compound, SR18662. We find that treatment with SR18662 significantly reduces growth and proliferation of colorectal cancer cells as compared with treatment with vehicle control, ML264, or SR15006 (a less optimized analogue from SAR efforts leading to SR18662). SR18662 showed improved efficacy in reducing the viability of multiple colorectal cancer cell lines. Flow cytometry analysis following SR18662 treatment showed an increase in cells captured in either S or G2–M phases of the cell cycle and a significant increase in the number of apoptotic cells, the latter a unique property compared with ML264 or SR15006. SR18662 treatment also reduces the expression of cyclins and components of the MAPK and WNT signaling pathways. Importantly, we observed a significant dose-dependent inhibition of xenograft growth in mice following SR18662 treatment that exceeded the effect of ML264 at equivalent doses. These findings support further development of SR18662 and its analogues for colorectal cancer therapy.
Weaponized Interdependence: How Global Economic Networks Shape State
Coercion
Authors: Farrell Henry , Newman Abraham L. 
Published: July 2019

Abstract
Liberals claim that globalization has led to fragmentation and decentralized networks of power relations. This does not explain how states increasingly “weaponize interdependence” by leveraging global networks of informational and financial exchange for strategic advantage. The theoretical literature on network topography shows how standard models predict that many networks grow asymmetrically so that some nodes are far more connected than others. This model nicely describes several key global economic networks, centering on the United States and a few other states. Highly asymmetric networks allow states with (1) effective jurisdiction over the central economic nodes and (2) appropriate domestic institutions and norms to weaponize these structural advantages for coercive ends. In particular, two mechanisms can be identified. First, states can employ the “panopticon effect” to gather strategically valuable information. Second, they can employ the “chokepoint effect” to deny network access to adversaries. Tests of the plausibility of these arguments across two extended case studies that provide variation both in the extent of U.S. jurisdiction and in the presence of domestic institutions—the SWIFT financial messaging system and the internet—confirm the framework's expectations. A better understanding of the policy implications of the use and potential overuse of these tools, as well as the response strategies of targeted states, will recast scholarly debates on the relationship between economic globalization and state coercion.
Differences in Response of Terrestrial Water Storage Components to Precipitation over 168 Global River Basins
Authors: Zhang Yafeng , He Bin , Guo Lanlan , Liu Daochen 
Published: July 2019

AbstractA time lag exists between precipitation P falling and being converted into terrestrial water. The responses of terrestrial water storage (TWS) and its individual components to P over the global scale, which are vital for understanding the interactions and mechanisms between climatic variables and hydrological components, are not well constrained. In this study, relying on land surface models, we isolate five component storage anomalies from TWS anomalies (TWSA) derived from the Gravity Recovery and Climate Experiment mission (GRACE): canopy water storage anomalies (CWSA), surface water storage anomalies (SWSA), snow water equivalent anomalies (SWEA), soil moisture storage anomalies (SMSA), and groundwater storage anomalies (GWSA). The responses of TWSA and of the individual components of TWSA to P are then evaluated over 168 global basins. The lag between TWSA and P is quantified by calculating the correlation coefficients between GRACE-based TWSA and P for different time lags, then identifying the lag (measured in months) corresponding to the maximum correlation coefficient. A multivariate regression model is used to explore the relationship between climatic and basin characteristics and the lag between TWSA and P. Results show that the spatial distribution of TWSA trend presents a similar global pattern to that of P for the period January 2004–December 2013. TWSA is positively related to P over basins but with lags of variable duration. The lags are shorter in the low- and midlatitude basins (1–2 months) than those in the high-latitude basins (6–9 months). The spatial patterns of the maximum correlations and the corresponding lags between individual components of the TWSA and P are consistent with those of the GRACE-based analysis, except for SWEA (3–8 months) and CWSA (0 months). The lags between GWSA, SMSA, and SWSA to P can be arranged as GWSA &gt; SMSA ≥ SWSA. Regression analysis results show that the lags between TWSA and P are related to the mean temperature, mean precipitation, mean latitude, mean longitude, mean elevation, and mean slope.
The effectiveness of adding a scapular exercise programme to physical therapy treatment in patients with distal radius fracture treated conservatively: a randomized controlled trial
Authors: Gutiérrez-Espinoza Héctor , Araya-Quintanilla Felipe , Gutiérrez-Monclus Rodrigo , Cavero-Redondo Iván , Álvarez-Bueno Celia 
Published: July 2019

Objective: To determine the effectiveness of a scapular exercise programme in addition to a physical therapy treatment in patients with distal radius fracture. Design: A single-blinded randomized controlled trial was conducted. Setting: Clinical Hospital San Borja Arriaran, Santiago, Chile. Participants: A total of 102 patients above 60 years of age with extra-articular distal radius fracture were randomly divided into two groups. Interventions: The control group ( n = 51) received a six-week physical therapy treatment; the intervention group ( n = 51) received the same treatment plus a scapular exercise programme. Outcome measures: The two groups were assessed at baseline and after the six-week treatment. The arm function was assessed with the disabilities of the arm, shoulder and hand (DASH) questionnaire; secondary outcomes were measured by the patient-rated wrist evaluation (PRWE) questionnaire and visual analogue scale (VAS). Results: A total of 102 patients, 51 in the control group (40 women; mean age of 65.3 ± 4.8 years) and 51 in the intervention group (42 women; mean age of 67.2 ± 5.4 years), were analysed. At the end of the treatment, the difference between groups for the DASH was 16.7 points ( P < 0.001), 1.5 points ( P = 0.541) for the PRWE, 0.2 cm ( P = 0.484) for the VAS at rest, and 1.7 cm ( P < 0.001) for the VAS at movement. All differences were in favour of the intervention group. Conclusion: In the short term, adding a scapular exercise programme provides a significant clinical benefit in arm function and pain relief with movement in patients above 60 years of age with extra-articular distal radius fracture treated conservatively.
Modulation of the NOP receptor signaling affects resilience to acute stress
Authors: Holanda Victor A D , Pacifico Salvatore , Azevedo Neto Joaquim , Finetti Luca , Lobão-Soares Bruno , Calo Girolamo , Gavioli Elaine C , Ruzza Chiara 
Published: July 2019

Background: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ–NOP receptor system in resilience to stress is unclear. Aims: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. Methods: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01–1 mg/kg) and MCOPPB (0.1–10 mg/kg), and the NOP antagonist SB-612111 (1–10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. Results: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. Conclusions: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
Mechanical circulatory support in cardiogenic shock from acute myocardial infarction: Impella CP/5.0 versus ECMO
Authors: Karami Mina , den Uil Corstiaan A , Ouweneel Dagmar M , Scholte Niels TB , Engström Annemarie E , Akin Sakir , Lagrand Wim K , Vlaar Alexander PJ , Jewbali Lucia S , Henriques José PS 
Published: July 2019

Background: Short-term mechanical circulatory support devices are increasingly used in cardiogenic shock after acute myocardial infarction. As no randomised evidence is available, the choice between high-output Impella or extra-corporeal membrane oxygenation (ECMO) is still a matter of debate. Real-life data are necessary to assess adverse outcomes and to help guide the treatment decision between the different devices. The purpose of this study was to compare characteristics and clinical outcomes of Impella CP/5.0 with ECMO support in patients with cardiogenic shock from myocardial infarction. Methods: A retrospective, two-centre study was performed on all cardiogenic shock from myocardial infarction patients with Impella CP/5.0 or ECMO support, from 2006 until 2018. The primary outcome was 30-day mortality. Potential baseline imbalance between the groups was adjusted using inverse probability treatment weighting, and survival analysis was performed with an adjusted log-rank test. Secondarily, the occurrence of device-related complications (limb ischaemia, access site-related bleeding, access site-related infection) was evaluated. Results: A total of 128 patients were included (Impella, N=90; ECMO, N=38). The 30-day mortality was similar for both groups (53% vs. 49%, P=0.30), also after adjustment for potential baseline imbalance between the groups (weighted log-rank P=0.16). Patients with Impella support had significantly fewer device-related complications than patients treated with ECMO (respectively, 17% vs. 40%, P<0.01). Conclusions: Patients treated with Impella CP/5.0 or ECMO for cardiogenic shock after myocardial infarction did not differ in 30-day mortality. More device-related complications occurred with ECMO compared to Impella support.
A Retrospective Review on Atypical Femoral Fracture: Operative Outcomes and the Risk Factors for Failure
Authors: Lai Yuen Shan , Chau Jackie Yee Man , Woo Siu Bon , Fang Christian , Lau Tak Wing , Leung Frankie 
Published: July 2019

Background: Atypical femoral fractures have been demonstrated to have high risks of reoperation and nonunion. The aim of this study is to evaluate whether the quality of reduction following operative fixation of atypical femoral fracture predicts failure. Methods: This is a 6.5-year retrospective review of atypical femoral fractures from 2 centers in a high-income region. A total of 56 patients with 66 fractures met our inclusion criteria. The quality of reduction was evaluated from postoperative films according to Hoskins’ modification of Baumgartner criteria for subtrochanteric fractures. Our primary outcome measure was failure of treatment, defined as either reoperation or nonunion at 12 months. Results: There were a total of 8 reoperations (12% of all fractures) and 8 nonunion (12% of all fractures), affecting a total of 12 fractures (18%) in 12 patients (21%). Closed reduction ( P = .04) and poor quality of reduction ( P = .0227 Fisher exact test) are statistically significant risk factors for failure. Conclusions: An aim for anatomical reduction with both <4 mm maximal cortical displacement and <10° angulation can improve the operative outcome of atypical femoral fractures. The addition of open reduction may be beneficial.