bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplemental oxygen therapy use among patients with fibrosing interstitial lung disease in the United States
Authors: Yang Joseph , Steffens Andrea , Olson Amy L. , Anderson Amy , Basra Gursimran , Veeranki Phani , de Andrade Joao A.
Published: February 2025

Background

Supplemental oxygen therapy is commonly prescribed in clinical practice for patients with fibrosing interstitial lung disease (ILD) to reduce breathlessness and increase physical capacity. Only a few studies have evaluated the incidence of oxygen therapy use, with evidence lacking in its use among fibrosing ILD subtypes including patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. This study aimed to estimate incidence of oxygen therapy and factors associated with oxygen therapy initiation.

Methods

This non-interventional study used US administrative claims and electronic health record data from 01 October 2015 to 30 June 2022. Patients aged ≥ 18 years with newly diagnosed fibrosing ILD (≥ 2 fibrosing ILD diagnoses in any position on different dates of service within 365 days) were included; the index date was the first date with ILD diagnosis. Patients were followed until the earlier of health plan disenrollment, death, or end of study period. Oxygen therapy use was evaluated among patients without evidence of oxygen therapy before the index date, stratified by the underlying fibrosing disease (i.e., IPF vs. non-IPF ILD). Factors associated with oxygen therapy use were evaluated using Cox proportional hazards regression.

Results

A total of 114,921 patients (IPF n = 5,555; non-IPF ILD n = 109,366) newly diagnosed with fibrosing ILD were included in the study. The mean (standard deviation) age of patients with ILD was 66.9 (14.2) years, and 47.2% were male. Patients were followed for a mean of 24 months after ILD diagnosis, during which 38% of fibrosing ILD patients initiated oxygen therapy; a higher proportion of patients with IPF initiated oxygen therapy compared to those with non-IPF ILD (68% and 36%, respectively). Factors associated with oxygen therapy initiation included IPF, higher Charlson comorbidity scores, and comorbidities that impair respiratory capacity.

Conclusions

The study findings demonstrate a substantial proportion of patients with fibrosing ILD initiated oxygen therapy following initial ILD diagnosis, with higher rates of oxygen therapy initiation observed among patients with IPF compared with non-IPF ILD. Respiratory comorbidities were key factors associated with increased initiation of oxygen therapy.
Characterization, genomic analysis and preclinical evaluation of the lytic Staphylococcus bacteriophage PSK against methicillin-resistant Staphylococcus aureus wound isolate
Authors: Zanaty Abanoub A. , Dishisha Tarek , El-Sayed-Ahmed Mohamed Abd El-Gawad , Abdel-Fattah Maha M. , Ahmed Kawkab A. , Abdelkader Karim
Published: February 2025

Background

The dissemination of multi-drug-resistant bacteria, particularly Methicillin-resistant Staphylococcus aureus (MRSA), necessitates exploring new alternatives for their control. Bacteriophages are promising antibiotic alternatives with unique features. Here, we have performed a comprehensive characterization of a newly isolated bacteriophage (PSK) and compared its therapeutic potential with vancomycin in vivo.

Methods

Sewage samples were processed and enriched with the MRSA S. aureus SK1 strain in a search for isolation of a lytic bacteriophage. The isolated bacteriophage was assessed in vitro in terms of thermal and pH stability and kinetic parameters using absorption and one step growth curve assays. Moreover, its potential antibacterial activity was evaluated against S. aureus SK1 lone and in combination of standard of care antibiotics used for treatment of wound infections. We further analyzed its genome to exclude the presence of any potential toxin or antibiotic resistance genes. Finally, its antibacterial potential and capability to alleviate wound infection were assessed using a murine wound-infection model.

Results

The lytic bacteriophage (PSK) was isolated as a new species of the genus Rosenblumvirus with a genome size of 17,571 bp that is free from potential resistance or virulence genes. PSK displays infectivity against 4/10 S. aureus strains including two vancomycin-resistant strains. Moreover, it demonstrates favorable infection kinetics of fast adsorption with latent period and burst size of 20 min and 123 PFU/infected cell, respectively. Stability analysis revealed thermal stability up to 60 °C with wide pH range stability (4–11). In vitro, PSK kills S. aureus SK1 with multiplicity of infection (MOI) as low as 10− 4 with an overall mutation frequency of 2.47 × 10− 6 CFU/mL that is further improved when combined with 0.25× MIC of oxacillin, fusidic acid or vancomycin. In vivo, a single dose of PSK in murine wound infection model exhibited a comparable performance to four doses of vancomycin, when treatment started 2 h post-infection. However, when applied 2 days post-infection, PSK demonstrates superior antibacterial activity (up to 4.58 log unit count reduction) and enhances wound closure and tissue healing.

Conclusion

These findings represent PSK as a potential vancomycin alternative effective in treating S. aureus- induced wound infections.
In vitro activity of rifampicin, rifapentine and rifabutin in combination with their 25-deacetyl-metabolites against various Mycobacterium tuberculosis lineages
Authors: Genestet Charlotte , Bourg Chloé , Hodille Elisabeth , Bahuaud Olivier , Ader Florence , Goutelle Sylvain , Dumitrescu Oana ,   On behalf of the Lyon TB study group
Published: February 2025

Objectives

Rifamycin agents (rifampicin (RIF), rifapentine (RFP), rifabutin (RFB)) are the cornerstone of tuberculosis (TB) therapy. Rifamycins are metabolized into 25-deacetyl-metabolites, which have been described has active and may contribute to in vivo drug effect. However, little is known about the combined effect of rifamycins and their metabolites across different Mycobacterium tuberculosis complex (MTBC) lineages.

Methods

This study included 14 MTBC strains representing the main lineages. Minimum inhibitory concentrations (MICs) were determined using microdilution assays for the three rifamycins and their metabolites. A checkerboard assay was used to assess drug interactions, with the fractional inhibitory concentration (FIC) index calculated for synergy or antagonism.

Results

MICs varied across rifamycins, RIF and its metabolite showed the highest MICs, followed by RFP and RFB and their respective metabolites. FIC indices for rifamycin-metabolite combinations indicated additive effects (FIC between 0.5 and 1.25), with no antagonism observed, even at clinically relevant metabolite-to-parent drug ratios, and without impact of MTBC lineage.

Conclusions

Rifamycin metabolites exhibit additive effects with parent drugs, potentially enhancing bactericidal activity. This highlights that rifamycin susceptibility testing should account for both parent drugs and their metabolites, as these metabolites also exhibit antimicrobial activity. Additionally, these findings support further pharmacokinetic/pharmacodynamic studies to optimize TB treatment regimens, particularly in relation to metabolite-to-parent drug ratios in patients.
Myelin-reactive CD8+ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis
Authors: Upadhye Mohit , Wilhelm Connor R. , Rogers Kai J. , Vemulawada Chakrapani , Borcherding Nicholas , Boyden Alexander W. , Legge Kevin L. , Karandikar Nitin J.
Published: February 2025

Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4+ T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8+ T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8+ T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease through the engagement of MHC Class-I in recipient mice. Here, we show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and CD11b+ cDC) in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to adopt a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4+ T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced CD11b+ cDC through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on CD11b+ cDC. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as Foxo3, in both cDC subsets with enrichment of pathways involved in immune regulation and T cell differentiation. Our study highlights a novel mechanism in which myelin-reactive CD8+ T cells directly interact with cDC1 and modulate CD11b+ cDC through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4+ T cell responses and reduced EAE pathogenesis.
Acute hepatic porphyria in Denmark; a retrospective study
Authors: Wagner Magnus Emil Ulrich , Frost Morten , Frystyk Jan
Published: February 2025

Background

Acute hepatic porphyria (AHP) constitutes a class of rare diseases caused by reduced function in enzymes of the heme-biosynthetic pathway. AHP includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP) and the extremely rare δ-aminolevulinic-dehydrase deficiency porphyria (ADP). This retrospective study describes characteristics of the Danish AHP patient population.

Methods

Department of Endocrinology at Odense University Hospital serves as national AHP center. We performed a 5-year retrospective description of our AHP cohort using electronic patient journals. We included general symptoms, number of acute attacks, hospitalization rates, long-term sequelae and symptoms, and grouped patients according to creatinine-adjusted urinary baseline excretion (i.e., outside attacks) of the porphyrin precursor porphobilinogen (PBG) in normal-, moderate- and high-excretion and unknown.

Results

The cohort contained 129 AHP patients, hereof 100 AIP, 12 HCP and 17 VP. Median age was 46.3 (32.1–62.0) years, and 85 (65.9%) were female. During the 5-years, 38 (29.5%) patients experienced symptoms. Hereof, 20 patients were hospitalized with acute attacks or chronic symptoms and treated with human hemin (n = 14). Most frequently reported symptoms were abdominal pain, nausea, vomiting, and neurological disturbances. Symptoms were more common in patients with high PBG baseline excretion (n = 39) as compared to those with moderate (n = 31) or normal (n = 40) PBG excretion (p = 0.002). Furthermore, females dominated the symptomatic group (68.4%).

Conclusion

As reported internationally, AHP is more commonly diagnosed and symptomatic in women, and AIP was the most frequent AHP subtype. Those with an elevated urinary baseline PBG secretion were more likely to report AHP-related symptoms.
Analysis of SMN protein in umbilical cord blood and postnatal peripheral blood of neonates with SMA: a rationale for prompt treatment initiation to prevent SMA development
Authors: Otsuki Noriko , Kato Tamaki , Yokomura Mamoru , Urano Mari , Matsuo Mari , Kobayashi Emiko , Haginoya Kazuhiro , Awano Hiroyuki , Takeshima Yasuhiro , Saito Toshio , Saito Kayoko
Published: February 2025

Background

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease caused by insufficient functional survival motor neuron protein (SMN). The SMN expression level in the spinal cord is highest during the 2nd trimester of the foetal period. We previously reported the SMN spot analysis in peripheral blood using imaging flow cytometry (IFC) as a biomarker of functional SMN protein expression. In this study, we analysed neonatal cord blood, postnatal peripheral blood, and maternal peripheral blood in presymptomatic five infants whose sibling has type 1 SMA to estimate prenatal and postnatal SMN dynamics before the onset of severe SMA.

Results

Data from 37 untreated patients with SMA showed that SMN-spot+ cells were significantly correlated with SMA clinical classification and the copy numbers of the SMN2 gene. The range of values for cord blood, converted from each SMN2 copy number statistics, was − 0.7 to + 2.0 standard deviation (SD) (0.1–24.0%) for SMN-spot+ cells in patients with SMA. Subsequent analyses of the peripheral blood of neonates ranged from − 0.8 to + 0.8 SD (0.4–15.2%). The analysis of each maternal blood, converted from carrier statistics, ranged from − 0.2 to + 2.4 SD (1.4–25.2%). A correlation was observed between the cord blood and maternal peripheral blood.

Conclusions

This study suggests that the status of the motor neuron pool in the spinal cord can be presumed by cord blood SMN-spot+ cells and that SMN protein depletion determines the timing of disease onset. As the SMN spot analysis values tended to decrease with time after birth, they may eventually lead to the development of SMA. Furthermore, a correlation was found between the SMN spot analysis values of neonatal cord blood and maternal blood, which predicts disease severity after birth. In other words, the SMN protein supplied from the mother to the foetus may suppress the development of SMA in the infant at birth, and depletion of the SMN protein may occur after birth, causing the infant to develop SMA. Our findings demonstrated the effectiveness of newborn screening and the potential of maternally mediated treatment strategies by providing a rationale for prompt treatment initiation in SMA.
Tumour mutational burden using a targeted panel approach for comprehensive tumour profiling focusing on colorectal cancer
Authors: Scott Rodney J. , Ziolkowski Andrew , Mossman David , Hipwell Michael
Published: February 2025

There is an increasing recognition that comprehensive tumour profiling (CTP) represents an important adjunct to the diagnosis of malignancy providing not only an assessment of how many mutations there are in any given tumour which reflects the probability of immune checkpoint inhibitor success, but also which mutations are associated with targeted therapies, a signature that reflects environmental insult and potentially the identification of cancers of unknown origin.

This short review describes an approach to assaying tumour mutational burden (TMB), what the difficulties are in the assessment of the TMB and what it can be applied to in regards to improving patient outcomes. A final section of the review delves into some examples of colorectal cancer studies that identify findings that suggest there remains much to learn about tumour development.
Admixture as a source for HLA variation in Neolithic European farming communities
Authors: da Silva Nicolas Antonio , Özer Onur , Haller-Caskie Magdalena , Chen Yan-Rong , Kolbe Daniel , Schade-Lindig Sabine , Wahl Joachim , Berszin Carola , Francken Michael , Görner Irina , Schierhold Kerstin , Pechtl Joachim , Grupe Gisela , Rinne Christoph , Müller Johannes , Lenz Tobias L. , Nebel Almut , Krause-Kyora Ben
Published: February 2025

Background

The northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied.

Results

We analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500–4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern populations.

Conclusions

Both early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time.
Exploring the mediating roles of motivation and boredom in basic psychological needs and behavioural engagement in English learning: a self-determination theory perspective
Authors: Liu Honggang , Wang Ying , Wang Haoyue
Published: February 2025

In second language acquisition research, the psychological factors associated with language learning have been a prominent focus. The affective turn in and introduction of positive psychology in this field have further boosted research on the roles of positive learner psychological factors (e.g. motivation) in performance (e.g. engagement). However, the theoretical lens for investigating these variables requires further clarification, and the roles of some variables (e.g. boredom) in language learning have been under-researched. Guided by this background, this study aims to explore the complex relationships between learners’ basic psychological needs, self-determined motivation, boredom and behavioural engagement among 687 Chinese senior high school EFL learners from the perspective of self-determination theory (SDT). Quantitative data collection and analysis revealed that students’ basic psychological needs directly predicted behavioural engagement. Basic psychological needs also indirectly predicted behavioural engagement through the simple mediation of boredom and the chain mediation of self-determined motivation and boredom. However, the simple mediation of self-determined motivation in the relationship between basic psychological needs and behavioural engagement was non-significant. The findings enrich the application of SDT in the language learning engagement research, providing valuable implications for teachers and educators.
Policies on artificial intelligence chatbots among academic publishers: a cross-sectional audit
Authors: Bhavsar Daivat , Duffy Laura , Jo Hamin , Lokker Cynthia , Haynes R. Brian , Iorio Alfonso , Marusic Ana , Ng Jeremy Y.
Published: February 2025

Background

Artificial intelligence (AI) chatbots are novel computer programs that can generate text or content in a natural language format. Academic publishers are adapting to the transformative role of AI chatbots in producing or facilitating scientific research. This study aimed to examine the policies established by scientific, technical, and medical academic publishers for defining and regulating the authors’ responsible use of AI chatbots.

Methods

This study performed a cross-sectional audit on the publicly available policies of 162 academic publishers, indexed as members of the International Association of the Scientific, Technical, and Medical Publishers (STM). Data extraction of publicly available policies on the webpages of all STM academic publishers was performed independently, in duplicate, with content analysis reviewed by a third contributor (September 2023—December 2023). Data was categorized into policy elements, such as ‘proofreading’ and ‘image generation’. Counts and percentages of ‘yes’ (i.e., permitted), ‘no’, and ‘no available information’ (NAI) were established for each policy element.

Results

A total of 56/162 (34.6%) STM academic publishers had a publicly available policy guiding the authors’ use of AI chatbots. No policy allowed authorship for AI chatbots (or other AI tool). Most (49/56 or 87.5%) required specific disclosure of AI chatbot use. Four policies/publishers placed a complete ban on the use of AI chatbots by authors.

Conclusions

Only a third of STM academic publishers had publicly available policies as of December 2023. A re-examination of all STM members in 12–18 months may uncover evolving approaches toward AI chatbot use with more academic publishers having a policy.
Lateral-directional wind tunnel tests of the PROSIB 19-pax aircraft model
Authors: Ciliberti Danilo , Nicolosi Fabrizio
Published: February 2025

This paper presents the power-off, lateral-directional wind tunnel tests on the fixed-wing, 19-passenger aircraft model developed within the Italian PROSIB project. The concept is an innovative small air transport airplane with distributed propellers and hybrid-electric powerplant. By measuring the aerodynamic forces and moments, the experimental investigation focused on the estimation of the power-off stability and control derivatives, highlighting the effects of the aerodynamic interference. Tests included a belly-mounted pod, simulating a battery storage unit, and two distinct empennage configurations: a body-mounted (low) horizontal tail and a T-tail (high). Numerical analyses were also used to further highlight the role of aerodynamic interference in the generation of forces and moments. For instance, wind tunnel data have shown a beneficial effect of the belly pod on the aircraft directional stability (+13%), but were in contrast with the results of numerical analyses (−30%). The measured sidewash depends also from the empennage layout, not only from the vertical tail planform area. Simulations confirmed an excessive directional stability with respect to the directional control in the ratio of 1.65, suggesting that such class of airplane should have a larger rudder chord ratio or a horn balance. Combined tests at different angles of attack and flap deflections revealed some issues on the lateral stability of the model, which are related to the velocity circulation on the wing in high-lift conditions counteracting the effective dihedral of the model’s layout. The collected dataset of aerodynamic derivatives will serve as reference for a next experimental investigation on the aero-propulsive effects and provide useful information to researchers and professionals involved in similar design studies.
Semi-airborne electromagnetic exploration of deep sulfide deposits with UAV-towed magnetometers - Part 1: Processing Modeling
Authors: Kotowski P. O. , Becken M. , Rochlitz R. , Schmalzl J. , Ueding S. , Tolksdorf P. , Wilhelm A. , Symons G.
Published: February 2025

In recent decades, global technological expansion, alongside significant shifts in information technology, energy supply and mobility, has dramatically increased the demand for certain raw materials, especially minerals. To meet future demand, new strategies and solutions are being sought. Semi-airborne electromagnetics, as an emerging method to sense conductive subsurface structures, holds high potential for mineral exploration and can be applied to uncover untapped ore deposits or re-evaluate exploited ones. This technique has been successfully implemented in multiple studies and is a core part of the DESMEX (Deep Electromagnetic Sounding for Mineral Exploration) joint project. To date, promising sites are being surveyed either employing crewed aircraft or using ground-based methods, both of which come with limitations concerning site access, survey period, achievable resolution and cost. By utilizing uncrewed aerial vehicles (UAVs) some constraints and expenses can be overcome. Taking advantage of a battery-powered 25 kg maximum takeoff weight octocopter and two complementary magnetometers, an optically pumped total-field magnetometer and an induction coil triple, we have surveyed the Hope deposit, a known, unexploited massive sulfide mineralization in Western Namibia. Time-varying electromagnetic fields, excited by grounded electric-dipole transmitters, were measured and evaluated discretely in frequency domain. Based on two-dimensional inverse modeling, we were able to image the Hope ore body and to trace it down to a depth of more than 300 m. Combined sensor data inverted along adjacent profile lines reveal an imposing, contiguous dipping conductor that can be clearly assigned to the Hope structure. To assess the significance of our results, we inverted data from the two sensor systems individually as well as jointly and carried out detailed modeling studies. Our findings are supported by available resistivity models based on audio magnetotelluric data and yield an excellent match to existing borehole probes.
Computational Modeling for Circulating Cell-Free DNA in Clinical Oncology
Authors: Nguyen Phuong Linh , Salas Sébastien , Benzekry Sébastien
Published: February 2025

PURPOSE

Liquid biopsy, specifically circulating cell-free DNA (cfDNA), has emerged as a powerful tool for cancer early diagnosis, prognosis, and treatment monitoring over a wide range of cancer types. Computational modeling (CM) of cfDNA data is essential to harness its full potential for real-time, noninvasive insights into tumor biology, enhancing clinical decision making.

DESIGN

This work reviews CM-cfDNA methods applied to clinical oncology, emphasizing both machine learning (ML) techniques and mechanistic approaches. The latter integrate biological principles, enabling a deeper understanding of cfDNA dynamics and its relationship with tumor evolution.

RESULTS

Key findings highlight the effectiveness of CM-cfDNA approaches in improving diagnostic accuracy, identifying prognostic markers, and predicting therapeutic outcomes. ML models integrating cfDNA concentration, fragmentation patterns, and mutation detection achieve high sensitivity and specificity for early cancer detection. Mechanistic models describe cfDNA kinetics, linking them to tumor growth and response to treatment, for example, immune checkpoint inhibitors. Longitudinal data and advanced statistical constructs further refine these models for quantification of interindividual and intraindividual variability.

CONCLUSION

CM-cfDNA represents a pivotal advancement in precision oncology. It bridges the gap between extensive cfDNA data and actionable clinical insights, supporting its integration into routine cancer care. Future efforts should focus on standardizing protocols, validating models across populations, and exploring hybrid approaches combining ML with mechanistic modeling to improve biological understanding.
CD40 Ligand Blockade for Prevention of Graft-Versus-Host Disease
Authors: Khimani Farhad , Ali Haris , Kim Jongphil , Cubitt Chris , Zhang Shumin , Elmariah Hany , Perez Lia , Bejanyan Nelli , Mirza Sayeef , Perna Fabiana , Jain Michael , Lazaryan Aleksandr , Liu Hien , Alsina Melissa , Castaneda Omar , Hansen Doris , Ochoa Leonel , Betts Brian , Nishihori Taiga , Locke Frederick , Mishra Asmita , Davila Marco , Nieder Michael , Anasetti Claudio , Choe Hannah , Pidala Joseph
Published: February 2025

PURPOSE

This phase I-Ib trial evaluated a novel CD40L blocking antibody, BMS-986004, for the prevention of graft-versus-host disease (GVHD) after unrelated donor allogeneic hematopoietic cell transplantation (HCT).

PATIENTS AND METHODS

A total of 34 patients were treated at three centers. The safety and biologic activity of single-dose BMS-986004 (675 mg [n = 6] and 1,500 mg [n = 6]; one-time dose) were evaluated. Safety of prolonged dosing was then examined in separate cohorts (drug administration every 2 weeks × 3 [n = 3], 5 [n = 3] or 7 doses [n = 16]). Included patients received 8/8 HLA-matched unrelated donor peripheral blood stem-cell HCT and sirolimus/tacrolimus GVHD prophylaxis. Comprehensive HCT outcome data were collected through 2 years, inclusive of GVHD outcomes, immune reconstitution and infections, and biologic correlative studies.

RESULTS

BMS-986004, a single, one-time dose of 1,500 mg was identified as the safe and biologically active single-dose regimen, and prolonged dosing cohorts demonstrated safety through the seven-dose duration regimen. In phase Ib (n = 16), grade II-IV acute GVHD was 25% with no grade III or IV acute GVHD. Moderate-severe chronic GVHD at 2 years was 18.4%. Considering all patients (n = 34), a total of five deep venous thrombosis (DVT) events occurred and no significant association was detected between DVT and serial D-dimer and TAT levels. There was no evidence for excess infectious complications or cytomegalovirus reactivation. Two-year estimates were the following: Non-relapse mortality 15.3% (95% CI, 5.4% to 29.8%), relapse 22% (95% CI, 9.5% to 37.8%), and overall survival 77.8% (95% CI, 58.7% to 88.8%).

CONCLUSION

This trial demonstrates that next-generation CD40L blocking antibodies can be used safely in HCT recipients and supports initial clinical efficacy in the prevention of GVHD. Further study is needed in larger populations to verify these outcomes.
Continuum electrostatics with capped Coulomb potential
Authors: Bossa Guilherme Volpe , Ehlert Braden , May Sylvio
Published: February 2025

For ensembles of spatially extended ions, electrostatic interaction energies can be calculated more accurately using a capped Coulomb potential, which remains constant within a fixed distance and then decays inversely with distance. When this fixed distance is small, the capped Coulomb potential transitions into a composite Coulomb-Yukawa potential, widely used in modeling dense electrolytes and ionic liquids and associated with a fourth-order derivative in Poisson's equation. To go beyond the fourth order, we develop a theoretical framework for continuum electrostatics based on the capped Coulomb potential. We derive and solve a modified Poisson equation and calculate corresponding electrostatic interaction energies. Solutions of the modified Poisson equation are shown to emerge from applying a differential operator to the potential predicted by the unmodified Poisson equation. We demonstrate that the electrostatic potential satisfying the modified Poisson equation can exhibit discontinuities at interfaces.
The spatial choreography of mRNA biosynthesis
Authors: Ventura-Gomes André , Carmo-Fonseca Maria
Published: February 2025

Properly timed gene expression is essential for all aspects of organismal physiology. Despite significant progress, our understanding of the complex mechanisms governing the dynamics of gene regulation in response to internal and external signals remains incomplete. Over the past decade, advances in technologies like light and cryo-electron microscopy (Cryo-EM), cryo-electron tomography (Cryo-ET) and high-throughput sequencing have spurred new insights into traditional paradigms of gene expression. In this Review, we delve into recent concepts addressing ‘where’ and ‘when’ gene transcription and RNA splicing occur within cells, emphasizing the dynamic spatial and temporal organization of the cell nucleus.
Economic Evaluation of Inguinal Versus Ilio-inguinal Lymphadenectomy for Patients with Stage III Metastatic Melanoma to Groin Lymph Nodes: Evidence from the EAGLE FM Randomized Trial
Authors: Mahumud Rashidul Alam , Law Chi Kin , Ospino Daniel Ariza , de Wilt Johannes H. W. , van Leeuwen Barbara L. , Allan Chris , de Lima Vazquez Vinicius , Jones Rowan Pritchard , Howle Julie , Spillane Andrew J. , Morton Rachael Lisa
Published: February 2025

Purpose

We compared health outcomes and costs of inguinal lymphadenectomy (IL) versus ilio-inguinal lymphadenectomy (I-IL) for removal of metastatic melanoma to lymph nodes of the groin in adults with stage III melanoma.

Methods

A within-trial cost-utility analysis was performed alongside an international randomized trial (EAGLE-FM) with 36 months follow-up from a health system perspective. Healthcare costs were measured by using trial records, and effectiveness measured in quality-adjusted life years (QALYs). Deterministic sensitivity analyses assessed the impact of changes in costs or quality of life on overall results. Statistical bootstrapping was employed to estimate confidence intervals around the cost-utility ratio.

Results

Among 98 trial participants (IL n = 50, I-IL n = 48), with no pelvic or distant disease clinically or on PET/CT imaging, the mean life years saved for those randomized to IL showed a small but nonsignificant increase of 0.05 years compared with those in the I-IL group (2.56 vs. 2.51 years, 95% confidence interval [CI] –0.78 to 0.87). The mean difference in QALYs gained showed a small but nonsignificant increase of 0.04 QALYs (1.95 vs. 1.91, 95% CI –0.49 to 0.57). The mean hospital stay among IL patients was 6.16 days, 1.24 days shorter than I-IL patients (7.40 days) at 36 months follow-up. Mean per-patient healthcare costs of IL surgery were AU$6938 lower than for I-IL surgery ($26,555 vs. $33,493, 95% CI –$24,360 to $10,484). Inguinal lymphadenectomy was slightly more effective and slightly less expensive) over I-IL; a finding supported by 81% of bootstrapped estimates and upheld across sensitivity analyses.

Conclusions

Our study indicates that less extensive IL surgery might be the preferred surgical strategy for metastatic melanoma to the groin when PET/CT imaging shows no pelvic disease. This surgery is likely to improve quality-adjusted survival and may reduce healthcare costs; however, the differences noted in EAGLE-FM were limited by a small sample size and were not statistically significant.

Trial Registration

Clinicaltrials.gov NCT02166788; anzctr.org.au ACTRN12614000721606.
Detection and Characterization of Natural Polyamines by High-Performance Liquid Chromatography-Atmospheric Pressure Chemical Ionization (Electrospray Ionization) Mass Spectrometry
Authors: Chesnov Sergiy , Bigler Laurent , Hesse Manfred
Published: July 2002

The application of high-performance liquid chromatography on-line coupled with atmospheric-pressure chemical-ionization mass spectrometry (HPLC-APCI-MS), electrospray-ionization mass spectrometry (ESI-MS), as well as with tandem mass spectrometry (MS/MS), for the analysis of natural products is discussed. The separation, detection and structure elucidation of polyamine-containing compounds contained in plant material and spider venoms was performed by means of these techniques. The use of the methods for biochemical investigations of diverse natural materials is proposed.
Electron Ionization Mass Spectra of 2- and 4-Chloro- and Bromo-Substituted Diphenylamines
Authors: Rezk A.M. Hassan , Sife-Eldeen Kh.A. , Rabbih M.A. , Selim Ezzat T.M.
Published: July 2002

The electron ionization mass spectra of 2- and 4-chlorodiphenylamine and 2- and 4-bromodiphenylamine are reported. All the spectra are characterized by strong molecular ion signals, corresponding to the base peak. Two primary fragmentations of significance include the expulsion of the substituents X and HX(X = halogen) from the four compounds. Further dissociation of the primary fragment ions results in the formation of some secondary decomposition ions having low or negligible relative abundances.
Metal Chelating Agents III: Mass Spectral Studies on the Semicarbazone Derivatives of Benzoin and 2-Hydroxy-1-Naphthaldehyde
Authors: Akinchan Narayan T.
Published: July 2002

The electron impact, chemical ionization, fast-atom bombardment and collision-induced mass spectra of the semicarbazone derivatives of benzoin and 2-hydroxy-1-naphthaldehyde are reported. Fragmentations of molecular and pseudomolecular ions are tabulated and rationalised.
Ortho Effects in the Dissociation of Ionized N-Chlorophenyl- and N-Bromophenyl-2-Aminobenzamidines: Intramolecular Aromatic Substitution with Cyclization to Protonated 2-(2-Aminophenyl)-1H-Benzimidazoles
Authors: Mendes Maria Anita , Rittner Roberto , Eberlin Marcos N. , Suwinski Jerzy , Szczepankiewicz W.
Published: July 2002

Electron ionization (70 eV) mass spectra, double-stage (MS2) 10 eV collision-induced dissociation (CID) product-ion mass spectra of molecular ions and triple-stage (MS3) sequential product-ion mass spectra of major fragment ions are reported for the parent N-phenyl and the isomeric ortho-, meta- and para- N-chlorophenyl- and N-bromophenyl-2-aminobenzamidines. Dissociation is greatly influenced by an ortho effect that favors the loss of ortho H atoms and particularly the loss of the ortho halogen substituents. Dissociation occurs via a two-step intramolecular aromatic substitution reaction and a distonic-ion intermediate inhibits scrambling of ring hydrogens thus favoring the loss of the ortho substituents. The ortho isomers form an abundant and diagnostic [M – X]+ fragment ion (X = Cl, Br) and are easily distinguished. Protonated 2-(1 H-benzimidazol-2-yl)-phenylammonium ions are likely formed; they dissociate mainly by NH3 loss upon CID and react readily with pyridine by proton transfer.
Matrix-Assisted Laser Desorption/Ionization and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry of Metalloporphyrazines and Metallophthalocyanines
Authors: Mørkved Eva , Kjøsen Helge , Vedde John , Uggerud Einar
Published: July 2002

High-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectra of the title compounds were obtained using a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The results show that this technique is well suited for obtaining molecule ions of the title compounds. The main peaks in the spectra are due to the molecular ion, M+• and/or the protonated molecule, MH+. Little fragmentation is observed. Isotopic masses were measured for one of the compounds with an estimated accuracy of ± 5 ppm. In addition, experiments were performed with the neat compounds, without a matrix. This direct laser desorption method is useful in some cases, but is generally not applicable for these types of compounds, even when great care is exercised in controlling the laser pulse energy.
Scope and Limitation of Matrix-Assisted Laser Desorption/Ionization Fourier Transform Mass Spectrometry for Testing the Complexing Behavior of Two Crown Ethers Derived from D-Hexopyranosides
Authors: Calba Pierre-Jean , Muller Jean-François , Schmitt-Dubessy Marie-Françoise , Joly Jean-Pierre , Chapleur Yves
Published: July 2002

The complexing abilities of two macrocycles, namely a 18-C-6 crown ether (CE1) and a 20-C-6 crown ether (CE2) towards one organic guest [protonated phenethylamine (PEAH+)], were investigated with help of matrix-assisted laser desorption/ionization (MALDI) Fourier transform mass spectrometry. A qualitative correlation between the complexation behavior of CE1 in solution and in the gas phase of the spectrometer could be established. We concluded from these results that a fine control of laser irradiance and the use of a suitable sample protocol allowed the preservation of weak molecular interactions throughout the MALDI process. The observed positive ions can be considered as being already present in the deposited solid solution and merely liberated by the laser pulse.
Backbone Cleavages of [M – H]− Anions of Peptides. New Backbone Cleavages following Cyclisation Reactions of a C-Terminal [CONH]− Group with Ser Residues and the Use of the γ Backbone Cleavage Initiated by Gln to Differentiate between Lys and Gln Residues
Authors: Brinkworth Craig S. , Dua Suresh , Bowie John H.
Published: July 2002

The [M – H]− anions of some citropin, caerin and aurein peptides, which contain both Ser residues and a C-terminal CONH2 functionality, show a number of fragmentations which occur through Ser residues. The first, the loss of CH2O from the Ser side chain, always produces pronounced peaks in the spectrum. There are two other fragmentations which are competitive with CH2O loss: these involve cleavage of the backbone of the peptide. These fragmentations involve loss of RNH2 and (RNH2 + H2O) from the [M – H]− ion of a peptide of general structure RNHCH(CH2OH)CO——NHCHR'CONH2. This effectively breaks the peptide backbone between the NH and CH of Ser. We have called these fragmentations γ and ε cleavages, respectively. These processes are initiated by molecular recognition between the C-terminal CONH− and the Ser side chain, with the formation of an H-bonded complex between the CONH− oxygen and the OH group of Ser. The ion complex, so formed, holds the nucleophilic NH− and the electrophilic CH group (of Ser) in positions which allow cyclisation to proceed and produce an intermediate which then initiates those independent processes which involve losses of RNH2 and (RNH2 + H2O), respectively. These processes have been studied theoretically using a model system at the AM1 level of theory. The isobaric residues Gln and Lys should be distinguishable using negative-ion mass spectrometry, because the Gln residue should effect a γ backbone cleavage, whereas Lys cannot. The study of a number of peptides containing Gln and/or Lys, indicates that this is the case, except when Gln is close to the C-terminal position. The Gln backbone cleavage ions are of small abundance when there are other residues present, for example Asp, which may effect facile backbone cleavage.
Letter: Characteristics of Photoelectrons Emitted in Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Experiments
Authors: Gorshkov Michael V. , Frankevich Vladimir E. , Zenobi Renato
Published: July 2002

We show a simple method to study the characteristics of electrons emitted from the metal target in matrix-assisted laser desorption/ionization (MALDI) experiments. The method is based on measurements of SF6− ion appearance curves by introducing SF6 as a buffer gas into the vacuum chamber during laser desorption. We obtained the energy distribution of emitted electrons, as well as information on their origin and on ion formation mechanisms in MALDI experiments.
Polymer Track Membranes for Extraction of Ions from Aqueous Solutions at Atmospheric Pressure
Authors: Balakin Alexander. A. , Dodonov Alexander F. , Markin Mikhail I. , Novikova Lyudmila I. , Soulimenkov Ilia V. , Talroze Victor L. , Budnik Bogdan A. , Haselmann Kim F. , Zubarev Roman A.
Published: July 2002

The possibility of the application of the electromembrane technique for production of ions of biological molecules at atmospheric pressure is demonstrated. This technique has previously only been used for extraction of ions from liquids directly into vacuum. The membrane technique for ion extraction at atmospheric pressure was tested with both time-of-flight and Fourier transform ion cyclotron resonance mass spectrometers. The mass spectra of intact molecular ions obtained from aqueous solutions of peptides and proteins are presented. The possible mechanisms of non-destructive ion extraction are discussed. The new technique is promising for achieving absolute sensitivity (charging every analyte molecule) and for performing spatially-resolved analysis of liquid biological samples.
Kinetic Shifts
Authors: Lifshitz C.
Published: July 2002

The kinetic shift is the excess energy required to observe detectable dissociation within a certain experimental time frame. Kinetic shifts are of central importance when energetic attributes are deduced from appearance energy measurements. Their importance has become of renewed interest since larger molecules are being studied mass spectrometrically. This is a review paper on the topic of kinetic shifts. It is made up of the following sections: Introduction, Definitions, Experimental methods, Statistical theories, Examples: Aromatic and polycyclic aromatic hydrocarbons, fullerenes, metal cation–water, –alcohol and –ether complexes, Conclusions.
A New Method to Study the Kinetics of Ion Decay in a Radio Frequency Quadrupole with Resonance Rotational Excitation
Authors: Soulimenkov I.V. , Kozlovski V.I. , Pikhtelev A.R. , Raznikov V.V. , Chardakova E.V. , Dodonov A.F.
Published: July 2002

A new method to study the kinetics of ion decay reactions in a radio frequency quadrupole (RFQ) with resonance rotational excitation is described. The decay reaction occurs while ions move through the RFQ and the resulting precursor-ion consumption, as well as the appearance of fragment ions, are monitored using high-resolution orthogonal time-of-flight mass spectrometry (o-ToF MS). The developed method enables one to extract absolute values of the decay rate constants using the ion drift motion under the uniform DC electrical field along the RFQ created by the segmented structure. The ion dwell time, as well as its internal temperature are calculated using the ion mobility measured under the same experimental conditions as the kinetic investigations. The values of the decay rate constants, activation energies and preexponential factors for three substances under investigation are reported.
Chiral Preferences in the Dissociation of Homogeneous Amino Acid/Metal Ion Clusters
Authors: Tao W. Andy , Cooks R. Graham , Nikolaev Eugene N.
Published: July 2002

Collision-induced dissociation (CID) of alanine or phenylalanine aggregates with various cations, including the proton, alkali metal ions, calcium and zinc, as well as the transition metals Co(II), Ni(II) and Cu(II), has been studied by tandem mass spectrometry. In these experiments, an isotopically labeled, chirally-pure amino acid (L-Ala-d3 and L-Phe-d5) is mixed with its unlabeled enantiomer and a metal salt and the clusters generated by electrospray ionization are mass-selected and subjected to CID. The relative stability of the precursor ions, as well as product-ion abundance ratios in the tandem mass spectra, are used as indicators of chiral effects on the dissociation process. It is shown that the stability of alanine aggregates during the kinetic dissociation process is independent of chirality, whereas a large chiral effect ( Rchiral ranging from 0.31 to 8.1) is observed for the clusters assembled from phenylalanine and transition metal ions. When two bulky phenylalanine molecules are covalently bound to a metal ion, the heterochiral cluster is more stable than the homochiral one. Clusters containing three or four phenylalanine molecules are loosely bound to the core ion and the homochiral cluster is more stable than the heterochiral one. It is suggested that non-covalent interactions, in particular π-cation interactions, are significant contributors to the large chiral effects. It is further suggested that the relationship between the branching ratio in the tandem mass spectrum and chirality can be used to determine the absolute configuration of chiral molecules.
Electronic Excitation Gives Informative Fragmentation of Polypeptide Cations and Anions
Authors: Haselmann K.F. , Budnik B.A. , Kjeldsen F. , Nielsen M.L. , Olsen J.V. , Zubarev R.A.
Published: July 2002

A Fourier transform mass spectrometer is a versatile instrument with a range of available fragmentation techniques. Comparison of polypeptide fragmentation patterns revealed that the techniques involving electronic excitation, such as hot-electron-capture dissociation (HECD) and electron-detachment dissociation (EDD), are even more informative than vibrational excitation (VE) techniques such as collisional activation. For dications of the peptide KIMHASELMANN, 11 eV HECD cleaved all inter-residue links in at least two places, with up to five fragments characterizing each link. For dianions of the same molecule, VE produced only one backbone cleavage whereas EDD gave ten, including five internal cleavage fragments. This is consistent with the general postulate that homogeneous electronic excitation yields more types of cleavage than near-equilibrium processes such as VE.