bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deconvolution of malignant pleural effusions immune landscape unravels a novel macrophage signature associated with worse clinical outcome in lung adenocarcinoma patients
Authors: Bruschini Sara , Pallocca Matteo , Sperandio Eleonora , D’Ambrosio Lorenzo , Ascenzi Francesca , De Vitis Claudia , Salvati Valentina , Esposito Antonella , Di Martino Simona , De Nicola Francesca , Paolini Francesca , Fattore Luigi , Alessandrini Gabriele , Facciolo Francesco , Foddai Maria Laura , Bassi Massimiliano , Venuta Federico , D’Ascanio Michela , Ricci Alberto , D’ Andrilli Antonio , Napoli Christian , Aurisicchio Luigi , Fanciulli Maurizio , Rendina Erino Angelo , Ciliberto Gennaro , Mancini Rita 
Published: May 2022

BackgroundImmune checkpoint inhibitors are still unable to provide clinical benefit to the large majority of non-small cell lung cancer (NSCLC) patients. A deeper characterization of the tumor immune microenvironment (TIME) is expected to shed light on the mechanisms of cancer immune evasion and resistance to immunotherapy. Here, we exploited malignant pleural effusions (MPEs) from lung adenocarcinoma (LUAD) patients as a model system to decipher TIME in metastatic NSCLC.MethodsMononuclear cells from MPEs (PEMC) and peripheral blood (PBMC), cell free pleural fluid and/or plasma were collected from a total of 24 LUAD patients and 12 healthy donors. Bulk-RNA sequencing was performed on total RNA extracted from PEMC and matched PBMC. The DEseq2 Bioconductor package was used to perform differential expression analysis and CIBERSORTx for the regression-based immune deconvolution of bulk gene expression data. Cytokinome analysis of cell-free pleural fluid and plasma samples was performed using a 48-Plex Assay panel. THP-1 monocytic cells were used to assess macrophage polarization. Survival analyses on NSCLC patients were performed using KM Plotter (LUAD, N=672; lung squamous cell carcinoma, N=271).ResultsTranscriptomic analysis of immune cells and cytokinome analysis of soluble factors in the pleural fluid depicted MPEs as a metastatic niche in which all the components required for an effective antitumor response are present, but conscripted in a wound-healing, proinflammatory and tumor-supportive mode. The bioinformatic deconvolution analysis revealed an immune landscape dominated by myeloid subsets with the prevalence of monocytes, protumoral macrophages and activated mast cells. Focusing on macrophages we identified an MPEs-distinctive signature associated with worse clinical outcome in LUAD patients.ConclusionsOur study reports for the first time a wide characterization of MPEs LUAD microenvironment, highlighting the importance of specific components of the myeloid compartment and opens new perspectives for the rational design of new therapies for metastatic NSCLC.
Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin’s lymphoma: a phase II, non-randomized controlled trial
Authors: Hochberg Jessica , Basso Jaclyn , Shi Qiuhu , Klejmont Liana , Flower Allyson , Bortfeld Kristina , Harrison Lauren , van de Ven Carmella , Moorthy Chitti , Islam Humayun , Gerard Perry , Voss Stephan , Cairo Mitchell S 
Published: May 2022

BackgroundCure rates for Hodgkin’s lymphoma are excellent, but excess short-term and long-term morbidities from treatment remain a concern. Immunotherapy targeting both tumor antigens and the immunosuppressive tumor microenvironment in children, adolescents, and young adults with Hodgkin’s lymphoma may improve early response rates and eliminate toxic chemotherapy and radiation, thus minimizing toxicity. We conducted a phase II study to evaluate the safety and overall response rate of brentuximab vedotin and rituximab in combination with risk-adapted chemotherapy in children, adolescents, and young adults with newly diagnosed classic Hodgkin’s lymphoma (cHL).MethodsThis is a prospective, phase II, non-randomized, risk-assigned study. Patients were treated and evaluated between 2012 and 2020. Eligible patients were aged ≥1 and ≤30 years old with advanced stage, intermediate-risk, and high-risk newly diagnosed cHL. Patients received four or six cycles of brentuximab vedotin (1.2 mg/kg), doxorubicin (25 mg/m2), vinblastine (6 mg/m2), dacarbazine (375 mg/m2), and rituximab (375 mg/m2). Early response was evaluated following two cycles of therapy. Involved field radiotherapy (IFRT) was restricted to high-risk patients with both bulky disease and slow response or those not in complete response at the end of chemoimmunotherapy.ResultsThirty patients were enrolled, with a median age of 15 years (4–23). There were 18 intermediate-risk and 12 high-risk patients. Toxicities included grade III mucositis (3%), infusion reaction (3%), and peripheral neuropathy (6%). There was a 100% complete response rate on completion of chemoimmunotherapy. Eighteen patients (60%) achieved a rapid early response. Four patients (13%) required IFRT. The 5-year event-free and overall survival rates were 100%, with a median follow-up of 62 months (18–105).ConclusionsImmunotherapy with brentuximab vedotin, rituximab, and risk-adapted chemotherapy is safe in children, adolescents, and young adults with newly diagnosed cHL. We have demonstrated 100% complete response and 100% event-free and overall survival rates at a median 5-year follow-up, with a significant reduction in use of more toxic chemotherapy and IFRT. A larger cohort is required to confirm these preliminary findings.Trial registration numberNCT02398240.
Can we screen less frequently for STI among PrEP users? Assessing the effect of biannual STI screening on timing of diagnosis and transmission risk in the AMPrEP Study
Authors: Jongen Vita W. , Zimmermann Hanne M.L. , Goedhart Marit , Bogaards Johannes A. , Davidovich Udi , Coyer Liza , de Vries Henry J.C. , Prins Maria , Hoornenborg Elske , Schim van der Loeff Maarten F. 
Published: May 2022

BackgroundIn many countries, HIV pre-exposure prophylaxis (PrEP) users are screened quarterly for STIs. We assessed the consequences of less frequent STI testing. We also assessed determinants of asymptomatic STI and potential for onward transmission.MethodsUsing data from the AMPrEP study, we assessed the proportion of syphilis, and genital, anal, and pharyngeal chlamydia and gonorrhoea diagnoses which would have been delayed with biannual versus quarterly screening. We assessed the potential for onward transmission by examining reported condomless anal sex (CAS) in periods after to-be-omitted visits when screening biannually. We assessed determinants of incident asymptomatic STIs using Poisson regression and calculated individual risk scores on the basis of the coefficients from this model.ResultsWe included 366 participants. Median follow-up was 47 months (IQR 43–50). 1,183STIs were diagnosed, of which 932(79%) asymptomatic. With biannual screening, 483 asymptomatic STIs (52%) diagnoses would have been delayed at 364 study visits. Of these visits, 129 (35%), 240 (66%) and 265 (73%) were followed by periods of CAS with steady, known casual or unknown casual partners, respectively. Older participants had a lower risk of asymptomatic STI (incidence rate ratio (IRR) 0.86/10-year increase, 95% CI 0.80 to 0.92), while CAS with known (IRR 1.36, 95% CI 1.10 to 1.68) and unknown (IRR 1.86, 95% CI 1.48 to 2.34) casual partners and chemsex (IRR 1.51, 95% CI 1.28 to 1.78) increased the risk. The individual risk scores had limited predictive value (sensitivity=0.70 (95% CI 0.66 to 0.74), specificity=0.50 (95% CI 0.48 to 0.51)).ConclusionReducing the STI screening frequency to biannually among PrEP users will likely result in delayed diagnoses, potentially driving onward transmission. Although determinants for asymptomatic STIs were identified, predictive power was low.
Self-gravitating anisotropic model in general relativity under modified Van der Waals equation of state: a stable configuration
Authors: Errehymy Abdelghani , Mustafa G. , Khedif Youssef , Daoud Mohammed , Alrebdi H. I. , Abdel-Aty Abdel-Haleem 
Published: May 2022

AbstractThe purpose of this paper consists in presenting models of compact stars described by a new class of exact solutions to the field equations, in the context of general relativity, for a fluid configuration which is locally anisotropic in the pressure. With current sensitivities, we considered a non-linear form of modified Van der Waals equation of state viz., $$p_{r}=\alpha \rho ^{2} +\frac{\beta \rho }{1+\gamma \rho }$$

p
r

=
α

ρ
2

+

β
ρ

1
+
γ
ρ

, as well as a gravitational potential Z(x) as a generating function by exploiting an anisotropic source of matter which served as a basis for generating the confined compact stars. The exact solutions are formed by correlating an interior space-time geometry to an exterior Schwarzschild vacuum. Then, we analyze the physical viability of the model generated and compare it with observational data of some heavy pulsars coming from the Neutron Star Interior Composition Explorer. The model satisfies all the required pivotal physical and mathematical properties in the compact structures study, offering empirical evidence in support of the evolution of realistic stellar configurations. It is shown to be regular, viable, and stable under the influence generated by the parameters coming from the theory namely, $$\alpha $$
α
, $$\beta $$
β
, $$\gamma $$
γ
, $$\delta $$
δ
, everywhere within the astral fluid in the investigated high-density regime that supports the existence of realistic heavy pulsars such as PSR J0348+0432, PSR J0740+6620 and PSR J0030+0451.
Urinary Kallidinogenase plus rt-PA Intravenous Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Wu Jing , Wu Jiang , Wang Le , Liu Jinmin 
Published: May 2022

Purpose. This research is aimed at systematically assessing the safety and effectiveness of intravenous thrombolysis (IVT) with rt-PA plus human urinary kallidinogenase (HUK) for acute ischemic stroke (AIS). Methods. The data were obtained through rigorous searching of both domestic and foreign databases from inception to 2021.7.1. Randomized controlled trials (RCTs) were included for the comparison of the efficacy of IVT plus HUK. The Cochrane risk of bias (RoB) tool and Review Manager software 5.3 were responsible for RoB assessment and statistical analyses, respectively. Results. A total of 18 articles were retrieved, including 2676 AIS patients treated with IVT within the time window. The control group used standardized rt-PA IVT, and the test group added HUK. After 14 days of combined application of HUK, the National Institute of Health Stroke Scale (NIHSS) score was significantly better in moderate stroke patients using the combination treatment versus those with IVT alone (

mean

difference

MD

=
−
3.13

; 95% confidence intervals (CI): -3.40,-2.86;

P
<
0.00001

); the NIHSS score was also statistically in severe stroke patients with combined treatment than in those with IVT alone, but the degree of recovery of patients varied greatly. After 90 days of treatment, the NIHSS (

MD
=
−
1.93

; 95% CI: -2.51,-1.34;

P
<
0.00001

) and Barthel index (BI) scores (

MD
=
22.23

; 95% CI: 18.96, 25.49;

P
<
0.00001

) of patients plus HUK were significantly better than those of patients with IVT alone, with fewer adverse events during treatment (

Relative

Risk

RR

=
0.66

; 95% CI: 0.47, 0.92;

P
=
0.02

). Conclusions. For AIS patients with IVT within the time window, HUK plus rt-PA IVT could significantly improve the neurological function recovery after 14 days and the quality of life after 90 days and reduce the adverse reactions of IVT. This trial is registered with CRD42021226975.
Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors
Authors: Munster Pamela N. , Greenstein Andrew E. , Fleming Gini F. , Borazanci Erkut , Sharma Manish R. , Custodio Joseph M. , Tudor Iulia Cristina , Pashova Hristina I. , Shepherd Stacie Peacock , Grauer Andreas , Sachdev Jasgit C. 
Published: May 2022

AbstractPurpose:Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor (GR) modulator relacorilant with taxanes can enhance antitumor activity.Patients and Methods:The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel.Results:In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P &lt; 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P &lt; 0.0001). In the heavily pretreated phase 1 population [median (range) of prior regimens: 3 (1–8), prior taxane in 75.3% (55/73)], 33% (19/57) of response-evaluable patients achieved durable disease control (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes.Conclusions:The observed preclinical, clinical, and GR-specific pharmacodynamic responses demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.
Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Response in Patients with Large B-cell Lymphoma
Authors: Monfrini Chiara , Stella Federico , Aragona Vanessa , Magni Martina , Ljevar Silva , Vella Cristina , Fardella Eugenio , Chiappella Annalisa , Nanetti Francesca , Pennisi Martina , Dodero Anna , Guidetti Anna , Corradini Paolo , Carniti Cristiana 
Published: May 2022

Abstract

Purpose:
In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting.

Experimental Design:
Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell in vivo expansion and with response and survival.

Results:
While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P &lt; 0.005) and effector (P &lt; 0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P &lt; 0.005) and naïve-like (P &lt; 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR T-cell expansion was influenced by the presence of CAR T with a CD8+ T central memory signature (P &lt; 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P &lt; 0.05).

Conclusions:
Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell in vivo proliferation that is necessary for antitumor response.
Risk perception of smokers on graphic warning labels: a qualitative study in East Nusa Tenggara, Indonesia
Authors: Ndoen Enjelita Mariance , Ndun Helga Jillvera Nathalia 
Published: May 2022

The Indonesian government has mandated Graphic warning labels (GWLs) on cigarette packages to achieve more comprehensive tobacco control interventions. However, smoking prevalence remains a public health issue in Indonesia. This current qualitative research aimed to explore the effect of cigarette GWLs on smokers’ perceptions about smoking and cigarette packaging in East Nusa Tenggara (NTT) and its influence on smoking behavior. The study participants consisted of 15 current smokers who were individually interviewed by using a semi-structured interview guide. Data were analyzed using a thematic analysis technique. Most participants perceived smoking as health-risk behavior yet lowered their risk perceptions of smoking-related diseases due to positive feelings of perceived current benefits of smoking and personal justification for smoking. None expressed any intention to quit or showed smoking behavior changes due to GWLs exposure on cigarette packages. Participants also implicitly expressed themselves as victims willing to quit but unable and unconfident to act due to smoking addiction and other stressors. In contrast, others perceived themselves as risk-taker who enjoyed smoking. Further research is still needed to provide robust evidence on GWLs effectiveness on smoking perception and smokers’ cognitive and behavioral responses. Behavior change interventions should address positive feelings experienced and rationalization made by smokers to provide effective risk communication.
Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6
Authors: Strain W. David , Frenkel Ofir , James Martin A. , Leiter Lawrence A. , Rasmussen Søren , Rothwell Peter M. , Sejersten Ripa Maria , Truelsen Thomas C. , Husain Mansoor 
Published: May 2022

Background:
GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.

Methods:

SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction
P
values. Risk of major adverse cardiovascular event was analyzed according to prior stroke.

Results:

A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46–1.00];
P
=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29–0.89];
P
=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37–0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47–1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (
P

interaction

=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (
P
interaction
>0.05 for all).

Conclusions:
Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01720446 and NCT02692716.
Carbon Fluxes during Dansgaard–Oeschger Events as Simulated by an Earth System Model
Authors: Jochum Markus , Chase Zanna , Nuterman Roman , Pedro Joel , Rasmussen Sune , Vettoretti Guido , Zheng Peisong 
Published: May 2022

Abstract
The Community Earth System Model with marine and terrestrial biogeochemistry is configured to simulate glacial climate. The integration shows transitions from warm to cold states—interstadials to stadials—and back. The amplitude of the associated Greenland and Antarctica temperature changes and the atmospheric CO2 signal are consistent with ice-core reconstructions, and so are the time lags between termination of a stadial, Antarctic temperature reversal, and the decline of the atmospheric CO2 concentration (for brevity’s sake simply referred to as CO2 from here on). The present model results stand out because the transitions occur spontaneously (without forcing changes like hosing) and because they reproduce the observed features above in a configuration that uses the same parameterizations as climate simulations for the present day (i.e., no retuning has been done). During stadials, precipitation shifts lead to reduced growth on land, which dominates the CO2 increase; the ocean acts as a minor carbon sink during the stadials. After the end of the stadials, however, the sudden reversal of the stadial anomalies in temperature, wind, and precipitation turns the ocean into a carbon source, which accounts for the continued rise of CO2 for several hundred years into the interstadial. The simulations also provide a novel possible interpretation for the observed correlation between CO2 and Antarctic temperature: rather than both being controlled by Southern Ocean processes, they are both controlled by the North Atlantic Ocean, and most of the extra CO2 may not be of Southern Hemisphere origin. If the stadials are prolonged through North Atlantic hosing, the upper ocean comes to an equilibrium, and the CO2 response is dominated by a single process: reduced export production in the North Atlantic as result of the collapsed overturning circulation. This is in contrast to the unforced simulation where the net ocean carbon flux anomaly is the sum of several regional responses of both signs and similar magnitudes. Reducing the aeolian iron deposition by half, to account for the observed reduction of Southern Hemisphere dust fluxes during stadials, reduces biological productivity and export production so that the Southern Ocean emerges as an important carbon source, at least for the three centuries up until a new equilibrium for the upper ocean is reached.

Significance Statement
The last ice age featured millennial-scale oscillations in CO2 and temperature, the latter being anticorrelated between Greenland and Antarctica. This is often referred to as the bipolar seesaw. Here, an Earth system model is described that reproduces these signals, and its results are used to explain the observed correlation between temperature and CO2. In contrast to previous idealized studies it is found that all ocean basins and the land each contribute equally to the CO2 signal.