bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bilateral visual loss as the initial presentation of chronic myeloid leukemia: a case report
Authors: Saadeldine Salah Marwan , Alammouri Yara Mohammad 
Published: September 2024

Introduction:
Chronic myeloid leukemia (CML) is the most common leukemia in adults. It can present with a wide variable range of symptoms and signs related to the phase of the disease. Ophthalmic manifestations as the first presentation of CML are unique, although they can occur during any stage of the disease. Ocular lesions in CML patients may be asymptomatic, so all patients should undergo an eye evaluation at the initial diagnosis.

Case presentation:
The authors report a case of a 17-year-old Syrian male who initially presented with progressive loss of vision, fatigue, and abdominal pain. Clinical examination showed bilateral retinal aneurysm hemorrhage, jaundice, and splenomegaly. Bone marrow biopsy results were consistent with the diagnosis of CML returning to AML. The patient was treated with intensive chemotherapy and then prepared for hematopoietic transplantation.

Discussion:
CML can present with variable symptoms and signs, but the ophthalmic manifestations are uncommon. Ophthalmic problems occur either from infiltration of neoplastic cells or from secondary causes, like thrombocytopenia, leukocytosis, hyperviscosity syndrome, or leukoembolization. In the literature, only some case reports presented eye involvement in CML as the first manifestation.

Conclusion:
Although this is a rare presentation of CML, we believe that it should be taken into consideration when managing these situations to obtain the right diagnosis and better treatment results. Collaboration between hematologists and ophthalmologists is necessary in deciding the treatment. Acute myeloid leukemia needs immediate medical attention and different treatment from CML.
Ocular thermography and clinical measurements in symptomatic and asymptomatic soft contact lens wearers
Authors: Moghadas Maryam , Nosch Daniela S. , Käser Emanuele , Klostermeier Jennifer , Santer Verena , Demian Paul , Bertolini Giovanni , Lamrani Mouad 
Published: September 2024

SIGNIFICANCE
Symptoms of dryness and discomfort are the main reasons for contact lens dropout. Clinical tests for this purpose are invasive or subjective. Ocular thermography may help to assess the ocular discomfort and dryness in a noninvasive and objective manner.

PURPOSE
This study aimed to investigate the relationship of ocular thermography with clinical measurements in habitual symptomatic and asymptomatic soft contact lens wearers.

METHODS
Forty habitual contact lens wearers were evaluated in two age- and gender-matched asymptomatic and symptomatic groups (Contact Lens Discomfort Questionnaire scores ≤8 and ≥14, respectively). Clinical measurements took place during visit 1 (with contact lens in situ and after contact lens removal) and at baseline after a 2-week washout period (visit 2). The Ocular Surface Disease Index (OSDI) questionnaire, noninvasive tear breakup time, bulbar conjunctival hyperemia, and corneal staining were assessed. Thermal cooling rate was computed in the central and lower cornea during natural blinking (30 s) and sustained eye opening (10 s).

RESULTS
Dry eye symptoms (OSDI score) were significantly higher in the symptomatic group during contact lens wear (p<0.001) and at baseline (p = 0.001). Thermal cooling rate was significantly higher in the symptomatic group in the lower cornea (10 s, p=0.013) with the contact lens in situ and in the central cornea (30 s, p=0.045) after contact lens removal. At baseline, dry eye symptoms (OSDI score) significantly correlated with cooling rate in the central cornea region for the symptomatic group (30 s: r = −0.5, p=0.03; 10 s: r = −0.63, p=0.005). Noninvasive tear breakup time correlated with cooling rate in the central cornea region at baseline in the symptomatic group (30 s, r = 0.6, p=0.005; 10 s, r = 0.55, p=0.018). Cooling rate in the central cornea region (10-s duration, p<0.0001) and noninvasive tear breakup time (p<0.0001) were identified as significant predictor variables for dry eye symptoms at baseline.

CONCLUSIONS
Noninvasive tear breakup time and thermal cooling rate were identified as significant predictor variables for contact lens–induced dry eye. These findings may suggest the potential for the additional application of ocular thermography in the evaluation of contact lens discomfort.
Heterosis across environmental and genetic space
Authors: Sandstedt Gabrielle D. , Rushworth Catherine A. 
Published: September 2024

AbstractWhen genetically divergent lineages meet again in secondary contact, hybrids may suffer negative, fitness-reducing consequences, or benefit from positive genetic interactions that result in increased fitness. Empirical studies of heterosis, a phenomenon in which hybrids outperform their inbred progenitors, are of great interest in agriculture, but are less often performed in wild systems. In this study, we leverageBoechera retrofracta, a primarily self-fertilizing wildflower species, to explore how population divergence influences fitness effects upon secondary contact. We integrated genomic data and a large-scale fitness experiment to compare fitness and heterozygosity between outbred and inbred progeny ofB. retrofracta. We show that interpopulation hybrids have increased overwintering survival compared to inbred individuals, indicative of heterosis. The magnitude of heterosis varied across genotypes and different environments, with overwintering survival increasing with genetic distance between parents. Sliding window analyses of genotyping by sequencing data show that heterozygosity varies across the genome of two species,B. retrofractaand the commonly co-occurring speciesBoechera stricta. We next compared these data withde novoF2s (intrapopulation, interpopulation, and interspecific crosses), as well as with wild-collected interpopulation crossB. retrofractaand interspecificB. strictaxB. retrofractahybrids. Wild-collected interspecific hybrids appear to be F1s, while wild-collected intraspecificB. retrofractaare consistent with more complex crossing patterns. Because outcrossing is associated with a transition to asexuality in this group, this suggests different mechanisms underlie asexuality in hybrid and non-hybrid lineages. These findings underscore the potential differences in the role of heterosis between genetic groups at different stages of divergence and its relevance following hybridization in nature.
Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial
Authors: Ager Casey R. , Obradovic Aleksandar , McCann Patrick , Chaimowitz Matthew , Wang Alexander L. E. , Shaikh Neha , Shah Parin , Pan Samuel , Laplaca Caroline J. , Virk Renu K. , Hill Jessica C. , Jugler Collin , DeFranco Grace , Bhattacharya Nilika , Scher Howard I. , DeCastro Guarionex Joel , Anderson Christopher B. , McKiernan James M. , Spina Catherine S. , Stein Mark N. , Runcie Karie , Drake Charles G. , Califano Andrea , Dallos Matthew C. 
Published: September 2024

AbstractMen with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218 – a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P) – depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/FCGR3Aon tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.
Linking ringed seal foraging behaviour to environmental variability
Authors: Nykänen Milaja , Niemi Marja , Biard Vincent , Carter Matt I. D. , Pirotta Enrico , Kunnasranta Mervi 
Published: September 2024

AbstractBackgroundForaging rates directly influence animals’ energetic intake and expenditure and are thus linked to body condition and the ability to survive and reproduce. Further, understanding the underlying processes driving a species’ behaviour and habitat use is important as changes in behaviour could result from changes in environmental conditions.MethodsIn this study, the dives of Saimaa ringed seals (Pusa hispida saimensis) were classified for the first time using hidden Markov models and telemetry data collected on individual dives, and the behavioural states of the diving seals were estimated. In addition, we used generalized additive mixed models on the foraging probability of the seals to identify environmental and temporal drivers of foraging behaviour.ResultsWe inferred three (in winter) or four (in summer) different dive types: sleeping/resting dives, shallow inactive dives, transiting dives and foraging dives, based on differences in dive metrics logged by or derived from data from telemetry tags. Long and relatively deep sleeping/resting dives were missing entirely in the winter, compensated by an increased proportion of time used for haul-out. We found profound differences in the behaviour of Saimaa ringed seals during the summer open water season compared to the ice-covered winter, with the greatest proportion of time allocated to foraging during the summer months (36%) and the lowest proportion in the winter (21%). The seals’ foraging probability peaked in summer (July) and was highest during the daytime during both summer and winter months. Moreover, foraging probability was highest at depths of 7-30 m in the winter and at depths >15 m in the summer. We also found some evidence of sex-specific foraging strategies that are adapted seasonally, with females preferring more sheltered water areas during winter.ConclusionsWe suggest that the foraging behaviour of Saimaa ringed seals is largely influenced by diel vertical movements and availability of fish, and that the seals optimize their energy acquisition while conserving energy, especially during the cold winter months. Further, the seals display some flexibility in foraging strategies, a feature that may help this endangered subspecies to cope with ongoing anthropogenic climate change.
External Control Arm with Synthetic Real-world Data for Comparative Oncology using Single Trial Arm Evidence (ECLIPSE): A Case Study using Lung-MAP S1400I
Authors: Gupta Alind , Segars Luke , Singletary David , Hansen Johan Liseth , Geale Kirk , Arora Anmol , Gomes Manuel , Sreeram Ramagopalan , Cheung Winson , Arora Paul 
Published: September 2024

2.AbstractSingle-arm trials supplemented with external comparator arm(s) (ECA) derived from real-world data are sometimes used when randomized trials are infeasible. However, due to data sharing restrictions, privacy/security concerns, or for logistical reasons, patient-level real-world data may not be available to researchers for analysis. Instead, it may be possible to use generative models to construct synthetic data from the real-world dataset that can then be freely shared with researchers. Although the use of generative models and synthetic data is gaining prominence, the extent to which a synthetic data ECA can replace original data while preserving patient privacy in small samples is unclear.ObjectiveTo compare the efficacy of nivolumab + ipilimumab combination therapy (“experimental arm”) versus nivolumab monotherapy (“control arm”) in patients with metastatic non-small cell lung cancer (mNSCLC) using real-world data from two real-world databases (“original ECA”), and synthetic data versions of these datasets (“synthetic ECA”), with the aim of validating synthetic data for use in ECA analysis.Study designNon-randomized analyses of treatment efficacy comparing the experimental arm to the (i) original ECA and (ii) synthetic ECA, with baseline confounding adjustment.Data sourcesThe experimental arm is from the Lung-MAP no-match substudy S1400I (NCT02785952) provided by National Clinical Trials Network (NCTN) in the United States. The real-world data source for the ECA is data from population-based oncology data from the Canadian province of Alberta, and from Nordic countries in Europe, specifically Denmark and Norway.
Clinical Trials for Wolfram Syndrome Neurodegeneration: Novel Design, Endpoints, and Analysis Models
Authors: Wang Guoqiao , Li Zhaolong Adrian , Chen Ling , Lugar Heather , Hershey Tamara 
Published: September 2024

AbstractObjectiveWolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.MethodsWe propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.ResultsComprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.ConclusionsFor rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs.
Antibiotic susceptibility trend estimation for India based on 2018 to 2021 data from GEARS program
Authors: Naik Roshan Ratnakar , Kalita Nehal , Maurya Rajesh Kumar , Rajan Annie 
Published: September 2024

AbstractAntimicrobial resistance (AMR) continues to be a major public threat due to dwindling supplies of effective antibiotics due to its excessive usage in humans and food producing animals. The objective of our study was to identify and predict future trends in multi-drug resistance amongst enterobacteriaceae and non-enterobacteriaceae family in India for four common broad-spectrum antibiotics. We focussed on four broad spectrum antibiotics levofloxacin, gentamicin, cefepime, and ceftazidime and classified the GEARS program study dataset into sensitive (S), intermediate(I) and resistant (R) isolates based on CLSI breakpoints. Levofloxacin (98.3%) was found to be the most susceptible broad spectrum antibiotic for treatment of non-enterobacteriaceae while it was relatively resistant (56.5%) for enterobacteriaceae treatment. As levofloxacin are among ICMR list of ‘alert antimicrobial agents’,hospitals and clinicans can exercise greater care before prescribing them.
Intergenerational transmission of the structure of the auditory cortex and reading skills
Authors: Kepinska Olga , Bouhali Florence , Degano Giulio , Berthele Raphael , Tanaka Hiroko , Hoeft Fumiko , Golestani Narly 
Published: September 2024

ABSTRACTHigh-level cognitive skill development relies on genetic and environmental factors, tied to brain structure and function. Inter-individual variability in language and music skills has been repeatedly associated with the structure of the auditory cortex: the shape, size and asymmetry of the transverse temporal gyrus (TTG) or gyri (TTGs). TTG is highly variable in shape and size, some individuals having one single gyrus (also referred to as Heschl’s gyrus, HG) while others presenting duplications (with a common stem or fully separated) or higher-order multiplications of TTG. Both genetic and environmental influences on children’s cognition, behavior, and brain can to some to degree be traced back to familial and parental factors. In the current study, using a unique MRI dataset of parents and children (135 individuals from 37 families), we ask whether the anatomy of the auditory cortex is related to reading skills, and whether there are intergenerational effects on TTG(s) anatomy. For this, we performed detailed, automatic segmentations of HG and of additional TTG(s), when present, extracting volume, surface area, thickness and shape of the gyri. We tested for relationships between these and reading skill, and assessed their degree of familial similarity and intergenerational transmission effects. We found that volume and area of all identified left TTG(s) combined was positively related to reading scores, both in children and adults. With respect to intergenerational similarities in the structure of the auditory cortex, we identified structural brain similarities for parent-child pairs of the 1st TTG (Heschl’s gyrus, HG) (in terms of volume, area and thickness for the right HG, and shape for the left HG) and of the lateralization of all TTG(s) surface area for father-child pairs. Both the HG and TTG-lateralization findings were significantly more likely for parent-child dyads than for unrelated adult-child pairs. Furthermore, we established characteristics of parents’ TTG that are related to better reading abilities in children: fathers’ small left HG, and a small ratio of HG to planum temporale. Our results suggest intergenerational transmission of specific structural features of the auditory cortex; these may arise from genetics and/or from shared environment.
Molecular recording of cellular protein kinase activity with chemical labeling
Authors: Sun De-en , Ng Siu Wang , Zheng Yu , Xie Shu , Schwan Niklas , Breuer Paula , Hoffmann Dirk C. , Michel Julius , Azorin Daniel D. , Boonekamp Kim E. , Winkler Frank , Wick Wolfgang , Boutros Michael , Li Yulong , Johnsson Kai 
Published: September 2024

AbstractProtein kinases control most cellular processes and aberrant kinase activity is involved in numerous diseases. To investigate the link between specific kinase activities and cellular phenotypes in heterogeneous cell populations andin vivo, we introduce molecular recorders of kinase activities for later analysis. Based on split-HaloTag and a phosphorylation-dependent molecular switch, our recorders become rapidly labeled in the presence of a specific kinase activity and a fluorescent HaloTag substrate. The kinase activity in a given cell controls the degree of fluorescent labeling whereas the recording window is set by the presence of the fluorescent substrate. We have designed specific recorders for four protein kinases, including protein kinase A. We apply our protein kinase A recorder for the sorting of heterogeneous cell populations and subsequent transcriptome analysis, in genome-wide CRISPR screens to discover regulators of PKA activity and for the tracking of neuromodulation in freely moving mice.
Axin1 and Axin2 regulate the WNT-signaling landscape to promote distinct mesoderm programs
Authors: Hernández-Martínez Rocío , Nowotschin Sonja , Harland Luke T.G. , Kuo Ying-Yi , Theeuwes Bart , Göttgens Berthold , Lacy Elizabeth , Hadjantonakis Anna-Katerina , Anderson Kathryn V. 
Published: September 2024

ABSTRACTHow distinct mesodermal lineages – extraembryonic, lateral, intermediate, paraxial and axial – are specified from pluripotent epiblast during gastrulation is a longstanding open question. By investigating AXIN, a negative regulator of the WNT/β-catenin pathway, we have uncovered new roles for WNT signaling in the determination of mesodermal fates. We undertook complementary approaches to dissect the role of WNT signaling that augmented a detailed analysis ofAxin1;Axin2mutant mouse embryos, including single-cell and single-embryo transcriptomics, within vitropluripotent Epiblast-Like Cell differentiation assays. This strategy allowed us to reveal two layers of regulation. First, WNT initiates differentiation of primitive streak cells into mesoderm progenitors, and thereafter, WNT amplifies and cooperates with BMP/pSMAD1/5/9 or NODAL/pSMAD2/3 to propel differentiating mesoderm progenitors into either posterior streak derivatives or anterior streak derivatives, respectively. We propose thatAxin1andAxin2prevent aberrant differentiation of pluripotent epiblast cells into mesoderm by spatially and temporally regulating WNT signaling levels.
The Role of Thermal Stability in AAV Titration of Engineered Variants
Authors: Zin Emilia A , Desrosiers Melissa , Ocari Tommaso , Labernede Guillaume , Robert Camille , Izabella Charlotte , Saubamea Bruno , Ferrari Ulisse , Dalkara Deniz 
Published: September 2024

ABSTRACTDetermining the concentration of recombinant adeno-associated virus (AAV) productions, also known as titering, is crucial not only for quality control purposes but also for comparative studies of preclinical and clinical gene therapy trials. Recently, several AAVs were engineered by inserting seven amino acids at the outermost tip of the capsid’s protruding VR-VIII loop. These variants have demonstrated increased transduction capabilities over naturally occurring AAV serotypes in several studies. However, they have also been shown to produce lower yields when titered using standard techniques, raising questions about their adequacy for clinical development and use. Here, we investigated why peptide insertion onto AAV capsids reduces their titer by examining viral stocks using electron microscopy and PCR-based titering. We reveal that the DNAse digestion step, performed to eliminate free-floating DNA prior to qPCR or ddPCR, adversely impacts engineered capsid stability due to exposure to heat, artificially lowering viral titers of engineered serotypes. Titering without heating yields significantly higher titers for these variants which have melting temperatures (Tm) close to the DNAse inactivation temperature, while titers for parental serotypes with higher Tmremain unchanged. Our findings provide an important new perspective for titering engineered variants with lower thermostability, especially when comparing their effectiveness to their parental serotypes.