bluuebunny/crossref_metadata_2025_split huggingface dataset:
TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment
Authors: Azar Fadi , Deforges Jules , Demeusoit Christelle , Kleinpeter Patricia , Remy Christelle , Silvestre Nathalie , Foloppe Johann , Fend Laetitia , Spring-Giusti Clémentine , Quéméneur Eric , Marchand Jean-Baptiste 
Published: July 2024

BackgroundTG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify the tumor immune phenotype. These properties might be of particular interest for “cold” tumors, either poorly infiltrated or infiltrated with anergic T cells.Methods TG6050, an oncolytic vaccinia virus encodes single-chain human interleukin-12 (hIL-12) and full-length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. The relevant properties of TG6050 (replication, cytopathy, transgenes expression and functionality) were extensively characterizedin vitro. The biodistribution and pharmacokinetics of the viral vector, @CTLA-4 and IL-12, as well as antitumoral activities (alone or combined with immune checkpoint inhibitors) were investigated in several “hot” (highly infiltrated) and “cold” (poorly infiltrated) syngeneic murine tumor models. The mechanism of action was deciphered by monitoring both systemic and intratumoral immune responses, and by tumor transcriptome analysis. The safety of TG6050 after repeated intravenous administrations was evaluated in cynomolgus monkeys, with a focus on the level of circulating IL-12.ResultsMultiplication and propagation of TG6050 in tumor cellsin vitroandin vivowere associated with local expression of functional IL-12 and @CTLA-4. This dual mechanism translated into a strong antitumoral activity in both “cold” and “hot” tumor models (B16F10, LLC1 or EMT6, CT26, respectively) that was further amplified when combined with anti-programmed cell death protein-1. Analysis of changes in the tumor microenvironment (TME) after treatment with TG6050 showed increases in interferon-gamma, of CD8+T cells, and of M1/M2 macrophages ratio, as well as a drastic decrease of regulatory T cells. These local modifications were observed alongside bolstering a systemic and specific antitumor adaptive immune response. In toxicology studies, TG6050 did not display any observable adverse effects in cynomolgus monkeys.ConclusionsTG6050 effectively delivers functional IL-12 and @CTLA-4 into the tumor, resulting in strong antitumor activity. The shift towards an inflamed TME correlated with a boost in systemic antitumor T cells. The solid preclinical data and favorable benefit/risk ratio paved the way for the clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926trial in progress).
Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214
Authors: Mantia Charlene M , Jegede Opeyemi A , Plimack Elizabeth R , Powles Thomas , Motzer Robert J , Tannir Nizar M , Lee Chung-Han , Tomita Yoshihiko , Voss Martin H , Choueiri Toni K , Rini Brian I , Hammers Hans J , Escudier Bernard , Albigès Laurence , Rosenblatt Lisa , Atkins Michael B , Regan Meredith M , McDermott David F 
Published: July 2024

BackgroundImmunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures.MethodsData from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method.ResultsAt 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs.ConclusionsAlthough overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN.Trial registration numberNCT02231749.
Study of quasi-projectile properties at Fermi energies in $$^{48}$$Ca projectile systems
Authors:   FAZIA Collaboration, Upadhyaya S. , Mazurek K. , Kozik T. , Gruyer D. , Casini G. , Piantelli S. , Baldesi L. , Barlini S. , Borderie B. , Bougault R. , Camaiani A. , Ciampi C. , Cicerchia M. , Ciemała M. , Dell’Aquila D. , Dueñas J. A. , Fable Q. , Frankland J. D. , Gramegna F. , Henri M. , Hong B. , Kordyasz A. , Kweon M. J. , Neindre N. Le , Lombardo I. , Lopez O. , Marchi T. , Nam S. H. , Park J. , Pârlog M. , Pasquali G. , Valdré S. , Verde G. , Vient E. , Vigilante M. 
Published: July 2024

AbstractA systematic analysis of the data obtained by the FAZIA collaboration during a recent experiment with a neutron rich projectile is presented. The main goal was to compare the experimental results with the HIPSE event generator simulations to investigate the influence of the neutron rich entrance channel on the quasi-projectile fragment properties. The full isotopic range of charged particles detected in this experiment was within the limit of the resolution of the FAZIA detector. A majority of quasi-projectile fragments were detected thanks to the forward angular acceptance of the experimental setup which was confirmed through the HIPSE calculations. Essentially, the lowering of N/Z of quasi-projectile fragments with the beam energy was found to be present since the initial phase of the reaction. Thus, pre-equilibrium neutron emissions might be a possible candidate to explain such an effect.
An Interdisciplinary Survey on Origin-destination Flows Modeling: Theory and Techniques
Authors: Rong Can , Ding Jingtao , Li Yong 
Published: July 2024

Origin-destination (OD) flow modeling is an extensively researched subject across multiple disciplines, such as the investigation of travel demand in transportation and spatial interaction modeling in geography. However, researchers from different fields tend to employ their own unique research paradigms and lack interdisciplinary communication, preventing the cross-fertilization of knowledge and the development of novel solutions to challenges. This article presents a systematic interdisciplinary survey that comprehensively and holistically scrutinizes OD flows from utilizing fundamental theory to studying the mechanism of population mobility and solving practical problems with engineering techniques, such as computational models. Specifically, regional economics, urban geography, and sociophysics are adept at employing theoretical research methods to explore the underlying mechanisms of OD flows. They have developed three influential theoretical models: the gravity model, the intervening opportunities model, and the radiation model. These models specifically focus on examining the fundamental influences of distance, opportunities, and population on OD flows, respectively. In the meantime, fields such as transportation, urban planning, and computer science primarily focus on addressing four practical problems: OD prediction, OD construction, OD estimation, and OD forecasting. Advanced computational models, such as deep learning models, have gradually been introduced to address these problems more effectively. We have constructed the benchmarks for these four problems at https://github.com/tsinghua-fib-lab/OD_benckmark. Finally, based on the existing research, this survey summarizes current challenges and outlines future directions for this topic. Through this survey, we aim to break down the barriers between disciplines in OD flow related research, fostering interdisciplinary perspectives and modes of thinking.
A Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy
Authors: Furuse Junji , Ikeda Masafumi , Ueno Makoto , Furukawa Masayuki , Morizane Chigusa , Takehara Tetsuo , Nishina Tomohiro , Todaka Akiko , Okano Naohiro , Hara Kazuo , Nakai Yousuke , Ohkawa Kazuyoshi , Sasaki Takashi , Sugimori Kazuya , Yokoyama Naoyuki , Yamamoto Kouji 
Published: July 2024

Abstract

Purpose:
To evaluate the efficacy and safety of nanvuranlat [an L-type amino acid transporter 1 inhibitor] monotherapy as a later-line treatment in advanced, metastatic, and refractory biliary tract cancers.

Patients and Methods:
A multicenter, randomized, double-blind, placebo-controlled phase II study was conducted across fourteen leading Japanese cancer centers and hospitals. Nanvuranlat 25 mg/m2/day or placebo was given intravenously in cycles of 5 consecutive days, followed by 9 days off. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and disease control rate. Subgroup analysis was performed in patients with high L-type amino acid transporter 1 expression and biliary tract cancer subtypes.

Results:
A total of 211 patients were screened, of which 105 eligible patients were randomized. Among these, 70 received nanvuranlat and 35 received placebo. Nanvuranlat demonstrated an improvement in PFS when compared with placebo (HR, 0.56; 95% confidence interval, 0.34–0.90; P = 0.02). Grade 3 or higher adverse events were reported in 30.0% and 22.9% of those in the nanvuranlat and placebo groups, respectively. The overall survival was not statistically different between nanvuranlat- and placebo-treated patients. An exploratory analysis indicated that nanvuranlat is warranted to evaluate its long-term clinical benefit in patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

Conclusions:
Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory biliary tract cancer with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options.
Ipatasertib plus Paclitaxel for Patients with PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer in the IPATunity130 Phase III Trial
Authors: Dent Rebecca A. , Kim Sung-Bae , Oliveira Mafalda , Barrios Carlos , O’Shaughnessy Joyce , Isakoff Steven J. , Saji Shigehira , Freitas-Junior Ruffo , Philco Manuel , Bondarenko Igor , Lian Qinshu , Bradley Denise , Hinton Heather , Wongchenko Matthew J. , Reilly Sarah-Jayne , Turner Nicholas 
Published: July 2024

Abstract

Purpose:
In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population.

Patients and Methods:
In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, and 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS.

Results:
Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis, there was no significant difference between treatment arms in PFS [hazard ratio 1.02, 95% confidence interval (CI), 0.71–1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo]. The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73–1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results.

Conclusions:
Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.
Organ-Specific Immune Setpoints Underlie Divergent Immune Profiles across Metastatic Sites in Breast Cancer
Authors: Egelston Colt A. , Guo Weihua , Simons Diana L. , Ye Jian , Avalos Christian , Solomon Shawn T. , Nwangwu Mary , Nelson Michael S. , Tan Jiayi , Bacon Eliza R. , Ihle Kena , Schmolze Daniel , Tumyan Lusine , Waisman James R. , Lee Peter P. 
Published: July 2024

Abstract
Immune composition within the tumor microenvironment (TME) plays a central role in the propensity of cancer cells to metastasize and respond to therapy. Previous studies have suggested that the metastatic TME is immune-suppressed. However, limited accessibility to multiple metastatic sites within patients has made assessing the immune TME difficult in the context of multiorgan metastases. We utilized a rapid postmortem tissue collection protocol to assess the immune composition of numerous sites of breast cancer metastasis and paired tumor-free tissues. Metastases had comparable immune cell densities and compositions to paired tumor-free tissues of the same organ type. In contrast, immune cell densities in both metastatic and tumor-free tissues differed significantly between organ types, with lung immune infiltration being consistently greater than that in the liver. These immune profiling results were consistent between flow cytometry and multiplex immunofluorescence–based spatial analysis. Furthermore, we found that granulocytes were the predominant tumor-infiltrating immune cells in lung and liver metastases, and these granulocytes comprised most PD–L1–expressing cells in many tissue sites. We also identified distinct potential mechanisms of immunosuppression in lung and liver metastases, with the lung having increased expression of PD-L1+ antigen-presenting cells and the liver having higher numbers of activated regulatory T cells and HLA-DRlow monocytes. Together, these results demonstrate that the immune contexture of metastases is dictated by organ type and that immunotherapy strategies may benefit from unique tailoring to the tissue-specific features of the immune TME.
Lysozyme 1 Inflamed CCR2
+
Macrophages Promote Obesity-Induced Cardiac Dysfunction
Authors: Zhang Lai , Han Huian , Xu Andi , Sathe Adwait , Fu Siying , Zhao Jiaqi , Cai Wenhan , Yang Yaqing , Liu Jinting , Bai Hui , Ben Jingjing , Zhu Xudong , Li Xiaoyu , Yang Qing , Wang Zidun , Gu Yayun , Xing Chao , Schiattarella Gabriele G. , Cheng Steven Yan , Zhang Hanwen , Chen Qi 
Published: July 2024

BACKGROUND:
Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage’s role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.

METHODS:

In this study, we used single-cell RNA-sequencing analysis of Cd45
+
CD11b
+
F4/80
+
cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2
+
(C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.

RESULTS:

We find that the
Ccr2
cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2
+
CX3CR1
+
macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the
RelA
promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.

CONCLUSIONS:
Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.
Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS‐CARES Study
Authors: Blake Jason A. , Long D. Leann , Knight Amy J. , Goodin Burel R. , Crowe Michael , Judd Suzanne E. , Rhodes J. David , Roth David L. , Clay Olivio J. 
Published: July 2024

Background
Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver‐report of poststroke functioning with longitudinal cognitive outcomes.

Methods and Results

One hundred fifty‐seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) national cohort study. The Glasgow Outcome Scale and modified Rankin Scale scores collected at hospitalization discharge were included as 2 primary predictors of cognitive impairment. The number of caregiver‐reported problems and impairments at 9 months following stroke were included as a third predictor. Cognition was measured using a biennial telephone battery and included the domains of learning, memory, and executive functioning. Multiple cognitive assessments were analyzed up to 5 years poststroke, controlling for prestroke cognition and demographic variables of the stroke survivor. Separate mixed models showed significant main effects of the Glasgow Outcome Scale (b=0.3380 [95% CI, 0.14–0.5];
P
=0.0009), modified Rankin Scale (b=−0.2119 [95% CI, −0.32 to −0.10];
P
=0.0002), and caregiver‐reported problems (b=−0.0671 [95% CI, −0.09 to −0.04];
P
<0.0001) on longitudinal cognitive scores. In a combined model including all 3 predictors, only caregiver‐reported problems significantly predicted cognition (b=−0.0480 [95% CI, −0.08 to −0.03];
P
<0.0001).

Conclusions
These findings emphasize the importance of caregiver feedback in predicting cognitive consequences of stroke.
Obstructive Sleep Apnea, Platelet Aggregation, and Cardiovascular Risk
Authors: Kovbasyuk Zanetta , Ramos‐Cejudo Jaime , Parekh Ankit , Bubu Omonigho M. , Ayappa Indu A. , Varga Andrew W. , Chen Ming‐Huei , Johnson Andrew D. , Gutierrez‐Jimenez Eugenio , Rapoport David M. , Osorio Ricardo S. 
Published: July 2024

Background
Although related, the precise mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are unclear. Platelets are mediators of CVD risk and thrombosis and prior studies suggested associations of OSA and platelet activity. The aim of this study is to assess the link between OSA, platelet activity, and CVD‐related risk factors.

Methods and Results

We studied the association of OSA‐measures and platelet aggregation in participants dually enrolled in the SHHS (Sleep Heart and Health Study) and FHS (Framingham Heart Study). We applied linear regression models with adjustment for demographic and clinical covariates and explored interactions with OSA and CVD‐related factors, including age, sex, body mass index, hypertension, OSA diagnosis (apnea‐hypopnea index 4%≥5), and aspirin use. Our final sample was of 482 participants (60 years [14.00], 50.4% female). No associations were observed between apnea‐hypopnea index 4% and platelet aggregation in the main sample. Stratified analysis revealed an association in aspirin users (n=65) for our primary exposure (apnea‐hypopnea index 4%, β=0.523;
P
<0.001; n=65), and secondary exposures: hypoxic burden (β=0.358;
P
<0.001), minimum saturation (β=−0.519;
P
=0.026), and oxygen desaturation index 3% (β=74.672;
P
=0.002). No associations were detected in nonaspirin users (n=417).

Conclusions
No associations were detected between OSA and platelet aggregation in a community sample. Our finding that OSA associates with increased platelet aggregation in the aspirin group, most of whom use it for primary prevention of CVD, suggests that platelet aggregation may mediate the adverse impact of OSA on vascular health in individuals with existing CVD risk, supporting further investigation.