bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 Blockade in Colorectal Cancer by Inducing Immunogenic Cell Death and Depleting Macrophages
Authors: Limagne Emeric , Thibaudin Marion , Nuttin Lisa , Spill Aodrenn , Derangère Valentin , Fumet Jean-David , Amellal Nadia , Peranzoni Elisa , Cattan Valérie , Ghiringhelli François 
Published: October 2019

Abstract
Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti–PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti–PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.
Performance of Traditional Pretest Probability Estimates in Stable Patients Undergoing Myocardial Perfusion Imaging
Authors: Batal Omar , Malhotra Saurabh , Harinstein Matthew , Markowitz Jeremy , Hickey Gavin , Agarwal Sunil , Douglas Pamela , Soman Prem 
Published: October 2019

Background:
The yield of myocardial perfusion imaging is low in contemporary patients with suspected coronary artery disease (CAD) selected based on American College of Cardiology Foundation/American Heart Association pretest probability estimate. We compared traditional pretest estimates of CAD probability with the prevalence of abnormal myocardial perfusion single-photon emission computed tomography (MPS).

Methods:
This was a cohort study from a single academic center. Consecutive stable patients without known CAD referred for stress MPS for suspected CAD between 2004 and 2011 were identified (n=15 777). Angina typicality was determined using standard criteria. Abnormal MPS perfusion was defined as a summed stress score ≥4, ischemia as summed stress score ≥4 and summed difference score ≥2, and extensive ischemia as summed difference score ≥8 using a standard, 17-segment model of the left ventricle. The pretest probability of CAD was determined using the American College of Cardiology Foundation/American Heart Association criteria.

Results:
Overall, 14% (n=2177) of patients had abnormal MPS of whom 11% (n=1698) had ischemia and 4% (n=684) extensive ischemia. In patients with chest pain who underwent treadmill MPS (n=4764), only 27% reported angina on the treadmill. Typical angina was associated with the highest prevalence for positive MPS (33% in men and 14% in women), ischemia (30% in men and 12% in women), and extensive ischemia (22% in men and 4% in women) when compared with other symptom categories. Prevalence of MPS abnormality was substantially lower than expected based on pretest probability estimates across most sex and age groups. In multivariable analysis, the pretest probability estimate was not an independent predictor of abnormal MPS.

Conclusions:
Traditional estimates of pretest probability of CAD are not predictive of MPS perfusion abnormality and overestimate its prevalence in stable patients.
Durability and Clinical Outcomes of Transcatheter Aortic Valve Replacement for Failed Surgical Bioprostheses
Authors: Dauerman Harold L. , Deeb G. Michael , O’Hair Daniel P. , Waksman Ron , Yakubov Steven J. , Kleiman Neal S. , Chetcuti Stanley J. , Hermiller James B. , Bajwa Tanvir , Khabbaz Kamal , de Marchena Eduardo , Salerno Tomas , Dries-Devlin Jessica L. , Li Shuzhen , Popma Jeffrey J. , Reardon Michael J. 
Published: October 2019

Background:
Valve-in-valve transcatheter aortic valve replacement (TAVR) is an option when a surgical valve demonstrates deterioration and dysfunction. This study reports 3-year results following valve-in-valve with self-expanding TAVR.

Methods:
The CoreValve US Expanded Use Study is a prospective, nonrandomized, single-arm study that evaluates safety and effectiveness of TAVR in extreme risk patients with symptomatic failed surgical biologic aortic valves. Study end points include all-cause mortality, need for valve reintervention, hemodynamic changes over time, and quality of life through 3 years. Patients were stratified by presence of preexisting surgical valve prosthesis-patient mismatch.

Results:

From March 2013 to May 2015, 226 patients deemed extreme risk (STS-PROM [Society of Thoracic Surgeons Predicted Risk of Mortality] 9.0±7%) had attempted valve-in-valve TAVR. Preexisting surgical valve prosthesis-patient mismatch was present in 47.2% of the cohort. At 3 years, all-cause mortality or major stroke was 28.6%, and 93% of patients were in New York Heart Association I or II heart failure. Valve performance was maintained over 3 years with low valve reintervention rates (4.4%), an improvement in effective orifice area over time and a 2.7% rate of severe structural valve deterioration. Preexisting severe prosthesis-patient mismatch was not associated with 3-year mortality but was associated with significantly less improvement in quality of life at 3-year follow-up (
P
=0.01).

Conclusions:
Self-expanding TAVR in patients with failed surgical bioprostheses at extreme risk for surgery was associated with durable hemodynamics and excellent clinical outcomes. Preexisting surgical valve prosthesis-patient mismatch was not associated with mortality but did limit patient improvement in quality of life over 3-year follow-up.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01675440.
New Technique in Nasal Tip Plasty: Sandwich Technique Using Cartilage and Septal Bone Complex
Authors: Ahn Tae Hwan , Zheng Tao , Kang Hee Jeong , Yoo Byung Joon , Chung Jae Ho , Jeong Jin Hyeok 
Published: October 2019

Objectives: It is extremely difficult to obtain ideal tip projection and nose lengthening by septal extension graft using only septal cartilage in Asians, because their nasal septal and alar cartilages are small and weak. Therefore, we introduce a new septal extension graft using a cartilage–bone complex with the vomer and the perpendicular plate of the ethmoid bone as well as cartilage to obtain optimal outcomes. Methods: Participants included 30 patients who underwent surgery by external approach. The septal cartilage, vomer, and perpendicular plate of the ethmoid bone harvested by septoplasty were used. There were 2 layers of cartilage on each side and bone in between to create a strong cartilage–bone complex for projection and lengthening. The bony portion was placed in the tip side, and the double-layered cartilage portion was placed in the inferior portion of the caudal septum of the L-strut to create powerful fixation. Results: There were statistically significant improvements in nasal length (4.71 ± 0.65 vs 5.15 ± 0.53 cm, P value <.0001), tip projection (2.66 ± 0.40 vs 3.18 ± 0.42, P value <.0001), and nasolabial angle (94.0° ± 9.3° vs 107.2° ± 9.6°, P value <.0001) postoperatively. All patients were subjectively satisfied, and 2 different surgeons had excellent or good opinions in 28 (94%) patients. Conclusions: The sandwich technique using cartilage and bone complex results in satisfactory outcomes with stronger tip support, especially in Asians with a weak nasal tip who desire ideal tip projection and dramatic change.
Empowering Diabetes Self-Management Through Technology and Nurse Health Coaching
Authors: Miyamoto Sheridan , Henderson Stuart , Fazio Sarina , Saconi Bruno , Thiede Elizabeth , Greenwood Deborah A. , Young Heather M. 
Published: October 2019

Purpose This research explores the impact of mobile health (mHealth) technology and nurse health coaching on views of diabetes self-management (DSM) for persons living with diabetes. Methods Three focus groups (N = 24) were conducted with individuals living with type 2 diabetes who participated in a nurse health coaching and mHealth technology intervention study. Qualitative thematic analysis was used to identify overarching themes in each group. Results Major themes identified following intervention participation included enhanced perspectives about living with diabetes, increased awareness of how health behaviors influence DSM, improved support, and increased ownership of DSM. Conclusions The themes identified suggest that the mHealth technology and health coaching intervention together may have had an empowering effect on participants’ DSM. These results suggest that providing nurse health coaching with mHealth technology may help individuals ameliorate some of the challenges of living with and managing diabetes.
The Reach of an Urban Hospital System-Based Diabetes Prevention Program: Patient Engagement and Weight Loss Characteristics
Authors: Chambers Earle C. , Gonzalez Jeffrey S. , Marquez Melinda E. , Parsons Amanda , Rehm Colin D. 
Published: October 2019

Purpose The purpose of this study was to identify patient and program delivery characteristics associated with engagement and weight loss in a Diabetes Prevention Program (DPP) implemented in an urban hospital system. Methods Patient and program delivery data were collected between July 2015 and December 2017. DPP eligibility was determined based on age, body mass index (BMI), and hemoglobin A1C data via the electronic health record. Engagement was measured at 3 levels: ≤3 sessions, 4 to 8 sessions, and ≥9 sessions. Weight was measured at each DPP session. Results Among the eligible patients (N = 31 524), referrals and engagement were lower in men than women, in Spanish speakers than English speakers, in younger (18-34 years) and middle-aged (35-54 years) than older adults, and in patients receiving Medicaid than other patients. Referral and engagement were higher in patients with higher BMIs and those prescribed ≥5 medications. Current smokers were less frequently engaged. Prior health care provider contact was associated with higher engagement. Overall, 28% of DPP participants achieved ≥5% weight loss; younger and middle-aged patients and those who gained weight in the prior 2 years were less likely to lose weight. Conclusion This assessment identified characteristics of patients with lower levels of referral and engagement. The DPP staff may need to increase outreach to address barriers to referral and during all points of engagement among men, younger patients, and Spanish speakers. Future research is needed to increase understanding with regard to why referrals and engagement are lower among these groups.
Vascularization of the arteriovenous fistula wall and association with maturation outcomes
Authors: Duque Juan C , Martinez Laisel , Tabbara Marwan , Parikh Punam , Paez Angela , Selman Guillermo , Salman Loay H , Velazquez Omaida C , Vazquez-Padron Roberto I 
Published: October 2019

Background and objectives: The venous vasa vasorum is the mesh of microvessels that provide oxygen and nutrients to the walls of large veins. Whether changes to the vasa vasorum have any effects on human arteriovenous fistula outcomes remains undetermined. In this study, we challenged the hypothesis that inadequate vascularization of the arteriovenous fistula wall is associated with maturation failure. Design, setting, participants, and measurements: This case–control pilot study includes pre-access veins and arteriovenous fistula venous samples (i.e. tissue pairs) from 30 patients undergoing two-stage arteriovenous fistula creation (15 matured and 15 failed to mature). Using anti-CD31 immunohistochemistry, we quantified vasa vasorum density and luminal area (vasa vasorum area) in the intima, media, and adventitia of pre-access veins and fistulas. We evaluated the association of pre-existing and postoperative arteriovenous fistula vascularization with maturation failure and with postoperative morphometry. Results: Vascularization of veins and arteriovenous fistulas was predominantly observed in the outer media and adventitia. Only the size of the microvasculature (vasa vasorum area), but not the number of vessels (vasa vasorum density), increased after arteriovenous fistula creation in the adventitia (median vasa vasorum area 1366 µm2/mm2 (interquartile range 495–2582) in veins versus 3077 µm2/mm2 (1812–5323) in arteriovenous fistulas, p < 0.001), while no changes were observed in the intima and media. Postoperative intimal thickness correlated with lower vascularization of the media ( r 0.53, p = 0.003 for vasa vasorum density and r 0.37, p = 0.045 for vasa vasorum area). However, there were no significant differences in pre-existing, postoperative, or longitudinal change in vascularization between arteriovenous fistulas with distinct maturation outcomes. Conclusion: The lack of change in intimal and medial vascularization after arteriovenous fistula creation argues against higher oxygen demand in the inner walls of the fistula during the vein to arteriovenous fistula transformation. Postoperative intimal hyperplasia in the arteriovenous fistula wall appears to thrive under hypoxic conditions. Vasa vasorum density and area by themselves are not predictive of maturation outcomes.
Research integrity: environment, experience, or ethos?
Authors: Hofmann Bjørn , Holm Søren 
Published: October 2019

Background: Research integrity has gained attention in the general public as well as in the research community. We wanted to investigate knowledge, attitudes, and practices amongst researchers that have recently finished their PhD and compare this to their responses during their PhD fellowship. In particular, we wanted to investigate whether their attitudes are related to their experiences of their immediate research environment. Material and method: Researchers ( n = 86) awarded the PhD degree at the Faculty of Medicine at the University of Oslo in 2016 were invited to answer a questionnaire about knowledge, attitudes, and actions related to scientific dishonesty. Seventy-two responded (83.7%). The results were compared with results among first-year doctoral students who responded to the same questionnaire during 2010–2017. Results: Overall, 13% of PhDs reported that they knew of people in their immediate research environment who had committed serious forms of scientific dishonesty. A small percentage of PhDs (1.4%) indicated that they themselves had committed such acts. About 3% of the candidates had experienced pressure to commit serious forms of dishonesty and nearly a third of respondents had experienced unethical pressure with respect to authorship during the course of their fellowship. Thirteen percent reported that they had experienced unethical pressure in relation to other forms of dishonesty and 11% had experienced the consequences of some form of scientific dishonesty. Eighteen percent of the respondents believed that one or more actions, which in the literature were perceived as scientific misconduct, were not wrong. We find a connection between attitudes and the perceived research integrity of their research environment. The results also show a difference between PhD students and graduated PhDs in terms of scientific dishonesty. In some areas, the PhDs’ norms are stricter, such as for the use of statistical analysis methods, while there is little change in others, such as in misconduct in order to expedite publications. Conclusion: Many PhDs knew about serious forms of scientific misconduct from the research environment in which they are trained, and some also report misconduct themselves. Some experienced pressure to serious forms of misconduct and a large proportion of the respondents had experienced unethical pressure with respect to authorship during their fellowship. Attitudes change during the PhD studies, but ambiguously. Scientific misconduct seems to be an environmental issue as much as a matter of personal integrity.
Reprogrammed Adult Human Endothelium into Hematopoietic Stem Cells Yields Functional T Cells In Vivo
Authors: Barcia Durán José Gabriel , Lu Tyler M. , Lis Raphael , Rafii Shahin 
Published: October 2019

Abstract
During development, the hematopoietic stem cells that go on to populate the bone marrow and give rise to all blood cell lineages emerge from a specialized endothelial subpopulation. We have previously harnessed this vestigial identity to achieve the direct conversion of adult endothelial cells (ECs) into long-term engraftable hematopoietic stem and progenitor cells (rEC-HSPCs); however, to date, we had only detected and characterized functional T cells that result from the transplantation, engraftment, and differentiation of mouse rEC-HSPCs (Lis, R. et al., Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature, 545:439-445. 2017).
We first reprogrammed adult human endothelium using lentiviral vectors encoding FOSB, GFI1, SPI1, and RUNX1 (FGRS) under constitutive promoters and an inductive vascular niche (Sandler V. et al., Reprogramming of human endothelium into hematopoietic cells requires vascular niche induction. Nature, 511:312-8. 2014). The resulting rEC-HSPCs maintained exogenous expression of the four transcription factors for over 20 weeks post-transplantation into immuno-compromised NSG mice. Constitutive expression of Spi1, however, has been shown to hinder lymphoid differentiation in vivo by blocking T lymphopoiesis (Anderson, M. et al. Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage. Immunity 16:285-296. 2002). In addition, mice of the NSG strain cannot educate native B or T cells to maturity. Our system of constitutive exogenous FGRS expression was therefore unable to confer transplanted immuno-compromised mice the ability to generate an adaptive immune response.
Here, we obtained human rEC-HSPCs making use of (i) doxycycline-inducible vectors to temporarily overexpress FGRS and (ii) transgenic substrains of NSG mice (one carrying human stem cell factor, granulocyte/macrophage colony-stimulating factor, and interleukin 3; the other, human major histocompatibility complex class I as well as beta-2 microglobulin) for transplantation assays. We show that human rEC-HSPCs engraft primary- and secondary-transplanted mice for over a year at levels of up to 20% in the spleen or bone marrow. Engrafted cells differentiate into all blood lineages including phenotypically and functionally mature T cells in the absence of exogenous FGRS expression in vivo. Notably, the resulting T cells undergo TCR rearrangement and are able to clear viral particles one week post-LCMV infection. Functional and phenotypic analyses are presented in juxtaposition with experiments using cord blood-transplanted mice. These results demonstrate that our present direct conversion strategy generates bona fide human hematopoietic stem cells from adult endothelial cells.

Disclosures
Rafii: Angiocrine Bioscience: Equity Ownership.
Positive Stool Cultures Could Predict the Clinical Outcomes of Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Hu Lijuan , Wang Qi , Zhang Xiaohui , Xu Lan-Ping , Wang Yu , Yan Chen-Hua , Chen Huan , Chen Yu-Hong , Liu Kaiyan , Wang Hui , Huang Xiaojun , Mo Xiao-Dong 
Published: October 2019

Abstract
We aimed to identify the impact of stool cultures on clinical outcomes among patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) (n=332). Positive stool cultures (PSC group) were observed in 61 patients (18.4%). Enterobacteriaceae in stool specimens was associated with a higher risk of bloodstream infection, and Candida in stool specimens was associated with a higher risk of platelet engraftment failure. The cumulative incidence of non-relapse mortality at 1 year after haplo-HSCT in the PSC group was higher than that of the patients who showed persistently negative stool cultures (NSC group; 22.2% vs. 12.7%, P=0.059). The probabilities of overall survival (71.4% vs. 83.8%, P=0.031) and disease-free survival (69.6% vs. 81.0%, P=0.048) at 1 year after haplo-HSCT were significantly lower for the PSC group than those of the NSC group, particularly for patients who had Candida in their stool specimens. In multivariate analysis, Candida in stool specimens significantly increased the risk of non-relapse mortality and was associated with poorer survival. Our results showed that PSC impacted the clinical outcomes after haplo-HSCT, particularly for those who had Candida in their stool specimens.

Disclosures
No relevant conflicts of interest to declare.
Multi-Omics of Aurora Inhibition Induced Polyploidy Reveals Mechanisms of Disease Relapse in MYC/BCL2-Addicted High Grade B-Cell Lymphoma
Authors: Islam Shariful , Paek Andrew , Hammer Michael , Rangarajan Savithri , Ruijtenbeek Robert , Cooke Laurence , Weterings Eric , Mahadevan Daruka 
Published: October 2019

Abstract
Key Points MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells. Drug-induced polyploid cells re-enter cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.
Abstract
Double-hit (DH) or double-expresser (DE) diffuse large B-cell lymphomas (DLBCL) are high-grade B-cell lymphomas that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously (DOI: 10.1158/1535-7163.MCT-17-0089) we demonstrated that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape apoptosis during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanisms that underlie treatment resistance. We isolated aneuploid/polyploid populations (2n-similar, 4n and 8n) of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells (8n) revealed that following drug removal, these cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling of DIAP cells demonstrated up-regulation DNA damage, DNA replication and immune evasion pathways. In addition, the immune-kinome, AKT/MTorc1/2, and ERK/MAPK pathway are over-represented in 8n cells. Further, MYC-mediates dysregulation of the spindle assembly checkpoints by over-expression of RanGAP1, TPX2 and KPNA2. Multiple mechanisms contribute to DIAP which are amenable to novel therapeutic intervention(s) in MYC/BCL2-addicted high-grade B-cell lymphomas.

Disclosures
No relevant conflicts of interest to declare.