bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental Bisimulations for Probabilistic Higher-order Languages
Authors: Sangiorgi Davide , Vignudelli Valeria 
Published: October 2019

Environmental bisimulations for probabilistic higher-order languages are studied. In contrast with applicative bisimulations, environmental bisimulations are known to be more robust and do not require sophisticated techniques such as Howe’s in the proofs of congruence.
As representative calculi, call-by-name and call-by-value λ-calculus, and a (call-by-value) λ-calculus extended with references (i.e., a store) are considered. In each case, full abstraction results are derived for probabilistic environmental similarity and bisimilarity with respect to contextual preorder and contextual equivalence, respectively. Some possible enhancements of the (bi)simulations, as “up-to techniques,” are also presented.
Probabilities force a number of modifications to the definition of environmental bisimulations in non-probabilistic languages. Some of these modifications are specific to probabilities, others may be seen as general refinements of environmental bisimulations, applicable also to non-probabilistic languages. Several examples are presented, to illustrate the modifications and the differences.
A Novel MYCN-Specific Antigene Oligonucleotide Deregulates Mitochondria and Inhibits Tumor Growth in MYCN-Amplified Neuroblastoma
Authors: Montemurro Luca , Raieli Salvatore , Angelucci Silvia , Bartolucci Damiano , Amadesi Camilla , Lampis Silvia , Scardovi Anna Lisa , Venturelli Leonardo , Nieddu Giammario , Cerisoli Lucia , Fischer Matthias , Teti Gabriella , Falconi Mirella , Pession Andrea , Hrelia Patrizia , Tonelli Roberto 
Published: October 2019

Abstract

Approximately half of high-risk neuroblastoma is characterized by MYCN amplification. N-Myc promotes tumor progression by inducing cell growth and inhibiting differentiation. MYCN has also been shown to play an active role in mitochondrial metabolism, but this relationship is not well understood. Although N-Myc is a known driver of the disease, it remains a target for which no therapeutic drug exists. Here, we evaluated a novel MYCN-specific antigene PNA oligonucleotide (BGA002) in MYCN-amplified (MNA) or MYCN-expressing neuroblastoma and investigated the mechanism of its antitumor activity. MYCN mRNA and cell viability were reduced in a broad set of neuroblastoma cell lines following BGA002 treatment. Furthermore, BGA002 decreased N-Myc protein levels and apoptosis in MNA neuroblastoma. Analysis of gene expression data from patients with neuroblastoma revealed that MYCN was associated with increased reactive oxygen species (ROS), downregulated mitophagy, and poor prognosis. Inhibition of MYCN caused profound mitochondrial damage in MNA neuroblastoma cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS. Correspondingly, inhibition of MYCN reactivated mitophagy. Systemic administration of BGA002 downregulated N-Myc and TRAP1, with a concomitant decrease in MNA neuroblastoma xenograft tumor weight. In conclusion, this study highlights the role of N-Myc in blocking mitophagy in neuroblastoma and in conferring protection to ROS in mitochondria through upregulation of TRAP1. BGA002 is a potently improved MYCN-specific antigene oligonucleotide that reverts N-Myc–dysregulated mitochondrial pathways, leading to loss of the protective effect of N-Myc against mitochondrial ROS.

Significance:
A second generation antigene peptide oligonucleotide targeting MYCN induces mitochondrial damage and inhibits growth of MYCN-amplified neuroblastoma cells.
Targeting Semaphorin 4D in Cancer: A Look from Different Perspectives
Authors: Tamagnone Luca , Franzolin Giulia 
Published: October 2019

Abstract
Semaphorin 4D (Sema4D) plays a role in various cell types including B lymphocytes, differentiating neurons, endothelial cells, and cancer cells. Preclinical and in vitro studies have shown that Sema4D-directed antibodies in combination with immune checkpoint inhibitors reshape the tumor microenvironment by promoting recruitment of effector lymphocytes and antigen-presenting cells, while reducing immunosuppressive cell types, which ultimately leads to tumor rejection. Hence, early-stage clinical trials with combination therapies including anti-Sema4D antibodies are ongoing. In this issue of Cancer Research, Zuazo-Gaztelu and colleagues report an unexpected proinvasive effect induced by anti-Sema4D antibodies in a preclinical model of neuroendocrine pancreatic cancer (Rip1-Tag2), mediated by retrograde signaling of transmembrane Sema4D in macrophages, which increases their recruitment to tumors, SDF-1 secretion, and metastasis-promoting phenotype.
See related article by Zuazo-Gaztelu et al., p. 5328
Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma
Authors: Zhu Guo Gord , Nafa Khedoudja , Agaram Narasimhan , Zehir Ahmet , Benayed Ryma , Sadowska Justyna , Borsu Laetitia , Kelly Ciara , Tap William D. , Fabbri Nicola , Athanasian Edward , Boland Patrick J. , Healey John H. , Berger Michael F. , Ladanyi Marc , Hameed Meera 
Published: October 2019

Abstract

Purpose:
Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas.

Experimental Design:
We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient's clinical outcome.

Results:
Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma.

Conclusions:
IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.
Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy
Authors: Liu Yuting , Zugazagoitia Jon , Ahmed Fahad Shabbir , Henick Brian S. , Gettinger Scott N. , Herbst Roy S. , Schalper Kurt A. , Rimm David L. 
Published: October 2019

Abstract

Purpose:
Programmed death ligand 1 (PD-L1) is expressed in tumor cells and immune cells, and both have been associated with response to anti-PD-1 axis immunotherapy. Here, we examine the expression of PD-L1 to determine which cell type carries the predictive value of the test.

Experimental Design:
We measured the expression of PD-L1 in multiple immune cells with two platforms and confocal microscopy on three retrospective Yale NSCLC cohorts (425 nonimmunotherapy-treated cases and 62 pembrolizumab/nivolumab/atezolizumab-treated cases). The PD-L1 level was selectively measured in different immune cell subsets using two multiplexed quantitative immunofluorescence panels, including CD56 for natural killer cells, CD68 for macrophages, and CD8 for cytotoxic T cells.

Results:
PD-L1 was significantly higher in macrophages in both tumor and stromal compartment compared with other immune cells. Elevated PD-L1 in macrophages was correlated with high PD-L1 level in tumor as well as CD8 and CD68 level (P &lt; 0.0001). High PD-L1 expression in macrophages was correlated with better overall survival (OS; P = 0.036 by cell count/P = 0.019 by molecular colocalization), while high PD-L1 expression in tumor cells was not.

Conclusions:
In nearly 500 non–small cell lung cancer (NSCLC) cases, the predominant immune cell type that expresses PD-L1 is CD68+ macrophages. The level of PD-L1 in macrophages is significantly associated with the level of PD-L1 in tumor cells and infiltration by CD8+ T cells, suggesting a connection between high PD-L1 and “hot” tumors. In anti-PD-1 axis therapy–treated patients, high levels of PD-L1 expression in macrophages are associated with longer OS and may be responsible for the predictive effect of the marker.
Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer
Authors: Hurvitz Sara A. , Martin Miguel , Press Michael F. , Chan David , Fernandez-Abad María , Petru Edgar , Rostorfer Regan , Guarneri Valentina , Huang Chiun-Sheng , Barriga Susana , Wijayawardana Sameera , Brahmachary Manisha , Ebert Philip J. , Hossain Anwar , Liu Jiangang , Abel Adam , Aggarwal Amit , Jansen Valerie M. , Slamon Dennis J. 
Published: October 2019

Abstract

Purpose:
neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting.

Patients and Methods:
Postmenopausal women with stage I–IIIB HR+/HER2− breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response.

Results:
Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P &lt; 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes.

Conclusions:
Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR+/HER2− early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.
High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy
Authors: Eranki Avinash , Srinivasan Priya , Ries Mario , Kim AeRang , Lazarski Christopher A. , Rossi Christopher T. , Khokhlova Tatiana D. , Wilson Emmanuel , Knoblach Susan M. , Sharma Karun V. , Wood Bradford J. , Moonen Chrit , Sandler Anthony D. , Kim Peter C.W. 
Published: October 2019

Abstract

Purpose:
Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically “cold” tumors into responsive “hot” tumors.

Experimental Design:
We treated &lt;2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.

Results:
Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P &lt; 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment.

Conclusions:
Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.
Submucosal Saline Injection Followed by Endoscopic Ultrasound versus Endoscopic Ultrasound Only for Distinguishing between T1a and T1b Esophageal Cancer
Authors: He Long-Jun , Xie Chuanbo , Wang Zi-Xian , Li Yin , Xiao Yi-Tai , Gao Xiao-Yan , Shan Hong-Bo , Luo Lin-Na , Chen Li-Ming , Luo Guang-Yu , Yang Ping , Zeng Shuo-Chun , Xu Guo-Liang , Li Jian-Jun 
Published: October 2019

Abstract

Purpose:
To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC).

Experimental Design:
Patients with T1N0M0 stage ESCC (n = 180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). They were randomly assigned (1:1) to receive either EUS examination after 3–5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases. The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases].

Results:
Among the per-protocol population, the SSI+EUS group (n = 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for T1b staging [93.8% (95% confidence interval (CI), 88.6–99.1) vs. 65.9% (95% CI, 55.8–76.0); P &lt; 0.001]. The positive predictive value of SSI+EUS for diagnosing T1b ESCC reached 90.9% (95% CI, 81.1–100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001].

Conclusions:
SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.
Mogamulizumab Forecast: Clearer Patients, with a Slight Chance of Immune Mayhem
Authors: Larocca Cecilia , Kupper Thomas S. , LeBoeuf Nicole R. 
Published: October 2019

Abstract
Mogamulizumab, approved by the FDA for relapsed or refractory mycosis fungoides and Sézary syndrome, improves progression-free survival compared with vorinostat in the largest trial to date in cutaneous T-cell lymphoma, with particular efficacy in leukemic disease, but carries a risk of immune-mediated toxicities with concomitant depletion of regulatory T cells.
See related article by Kasamon et al., p. 7275
Non Transecting Dorsal Onlay and Ventral Inlay Buccal Mucosal Substitution Urethroplasty for Obliterative Bulbar Urethral Strictures
Authors: Rajaian Shanmugasundaram , Murugavaithianathan Pragatheeswarane , Krishnamurthy Karrthik , Murugasen Lakshman 
Published: October 2019

<b><i>Background:</i></b> Dorsal or ventral single layer repair can be impractical when there is an inadequate strip of urethra. Staged urethroplasty and non-transecting bilayer substitution urethroplasty are the other alternatives. <b><i>Objectives:</i></b> To assess the safety and outcome of non-transecting dorsal onlay and ventral inlay buccal mucosal substitution urethroplasty technique. <b><i>Method:</i></b> Between January 2014 and December 2018, 21 patients underwent non-transecting, double-layer, buccal mucosal urethroplasty for inflammatory bulbar urethral strictures. Four weeks after surgery, foley catheters were removed and voiding trial was given. Clinical examination and uroflowmetry (UFM) were done at 1, 3, and 6 months after surgery. Annual follow-up with flow rate and post-void residual assessment were also recorded. Failure was defined as a condition when there was flow rate deterioration (&#x3c;15 mL/s) or when there is stricture recurrence (&#x3c;20 Fr). <b><i>Results:</i></b> The mean age was 49.5 years. There was no significant difference in comorbidities among the patients. The mean duration of operative time was 259 min. The mean blood loss was 190 mL. The follow-up duration ranged from 12 to 66 months. The average length of stricture was 3.9 cm. The mean diameter of stricture segment was 1.96 mm. Comparison of UFM trend during follow-up was statistically significant (<i>p</i> = 0.05). One patient had Clavien-dindo grade 1, while 2 patients had grade 3b complications. Two patients had soft anastomotic site stricture and were treated successfully with endoscopic internal urethrotomy. The success rate was 90.47%. <b><i>Conclusions:</i></b> Non-transecting bilayer substitution urethroplasty is safe and has better short-term outcome in case of obliterative inflammatory urethral strictures.<b><i></i></b>
Effect of Direct Oral Anticoagulants, Warfarin, and Antiplatelet Agents on Risk of Device Pocket Hematoma
Authors: Essebag Vidal , Healey Jeff S. , Joza Jacqueline , Nery Pablo B. , Kalfon Eli , Leiria Tiago L.L. , Verma Atul , Ayala-Paredes Felix , Coutu Benoit , Sumner Glen L. , Becker Giuliano , Philippon François , Eikelboom John , Sandhu Roopinder K. , Sapp John , Leather Richard , Yung Derek , Thibault Bernard , Simpson Christopher S. , Ahmad Kamran , Toal Satish , Sturmer Marcio , Kavanagh Katherine , Crystal Eugene , Wells George A. , Krahn Andrew D. , Birnie David H. ,   for the BRUISE CONTROL Investigators*
Published: October 2019

Background:
Oral anticoagulant use is common among patients undergoing pacemaker or defibrillator surgery. BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; NCT00800137) demonstrated that perioperative warfarin continuation reduced clinically significant hematomas (CSH) by 80% compared with heparin bridging (3.5% versus 16%). BRUISE-CONTROL-2 (NCT01675076) observed a similarly low risk of CSH when comparing continued versus interrupted direct oral anticoagulant (2.1% in both groups). Using patient level data from both trials, the current study aims to: (1) evaluate the effect of concomitant antiplatelet therapy on CSH, and (2) understand the relative risk of CSH in patients treated with direct oral anticoagulant versus continued warfarin.

Methods:
We analyzed 1343 patients included in BRUISE-CONTROL-1 and BRUISE-CONTROL-2. The primary outcome for both trials was CSH. There were 408 patients identified as having continued either a single or dual antiplatelet agent at the time of device surgery.

Results:

Antiplatelet use (versus nonuse) was associated with CSH in 9.8% versus 4.3% of patients (
P
<0.001), and remained a strong independent predictor after multivariable adjustment (odds ratio, 1.965; 95% CI, 1.202–3.213;
P
=0.0071). In multivariable analysis, adjusting for antiplatelet use, there was no significant difference in CSH observed between direct oral anticoagulant use compared with continued warfarin (odds ratio, 0.858; 95% CI, 0.375–1.963;
P
=0.717).

Conclusions:
Concomitant antiplatelet therapy doubled the risk of CSH during device surgery. No difference in CSH was found between direct oral anticoagulant versus continued warfarin. In anticoagulated patients undergoing elective or semi-urgent device surgery, the patient specific benefit/risk of holding an antiplatelet should be carefully considered.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT00800137, NCT01675076.