bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cefiderocol utilization in lung transplant recipients at a single center
Authors: Persaud Purnadeo N. , Xhemali Xhilda , Neuhaus Kristen , Budev Marie , Lum Jessica 
Published: June 2024

AbstractBackgroundMultidrug‐resistant organisms are increasing and are a significant cause of mortality among lung transplant recipients (LTRs). To assist with this issue, novel pharmacotherapies are being developed. This study describes the utilization of a novel antibiotic, cefiderocol (FDC), in LTRs where limited data exists in the current literature. We primarily assessed the clinical indications, duration of therapy, resistance, and adverse effects.MethodsConducted as a single‐center retrospective review, this study included adult LTRs who received FDC for at least 24 h. Data, extracted from electronic medical records, encompassed patient demographics, transplant history, antimicrobial dosing, adverse effects, bacterial cultures, and outcomes. The research protocol received institutional review board approval.ResultsFDC exhibited effectiveness against multidrug‐resistant Pseudomonas aeruginosa, with 26% 30‐day mortality and microbiological clearance observed in nine out of 13 cases. Notably, FDC was used in diverse clinical settings, including for prophylaxis, empiric, and targeted treatment.ConclusionFurther studies are needed to evaluate optimal clinical indications for FDC use in LTRs.
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Lower synaptic density and its association with cognitive dysfunction in patients with obsessive-compulsive disorder
Authors: Xiao Qian , Hou Jiale , Xiao Ling , Zhou Ming , He Zhiyou , Dong Huixi , Hu Shuo 
Published: June 2024

BackgroundUnderstanding synaptic alteration in obsessive-compulsive disorder (OCD) is crucial for elucidating its pathological mechanisms, butin vivoresearch on this topic remains limited.AimsThis study aimed to identify the synaptic density indicators in OCD and explore the relationship between cognitive dysfunction and synaptic density changes in OCD.MethodsThis study enrolled 28 drug-naive adults with OCD aged 18–40 years and 16 healthy controls (HCs). Three-dimensional T1-weighted structural magnetic resonance imaging and18F-SynVesT-1 positron emission tomography were conducted. Cognitive function was assessed using the Wisconsin Cart Sorting Test (WCST) in patients with OCD and HCs. Correlative analysis was performed to examine the association between synaptic density reduction and cognitive dysfunction.ResultsCompared with HCs, patients with OCD showed reduced synaptic density in regions of the cortico-striato-thalamo-cortical circuit such as the bilateral putamen, left caudate, left parahippocampal gyrus, left insula, left parahippocampal gyrus and left middle occipital lobe (voxel p<0.001, uncorrected, with cluster level above 50 contiguous voxels). The per cent conceptual-level responses of WCST were positively associated with the synaptic density reduction in the left middle occipital gyrus (R2=0.1690, p=0.030), left parahippocampal gyrus (R2=0.1464, p=0.045) and left putamen (R2=0.1967, p=0.018) in patients with OCD.ConclusionsAdults with OCD demonstrated lower18F-labelled difluoro analogue of18F-SynVesT-1 compared with HCs, indicating potentially lower synaptic density. This is the first study to explore the synaptic density in patients with OCD and provides insights into potential biological targets for cognitive dysfunctions in OCD.
Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China
Authors: Jiang Qirui , Lin Junyu , Wei Qianqian , Yang Tianmi , Hou Yanbing , Zhang Lingyu , Ou Ruwei , Xiao Yi , Wang Shichan , Zheng Xiaoting , Li Chunyu , Shang Huifang 
Published: June 2024

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.MethodsGenetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.ResultsA total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65;FUS, n=43;TARDBP, n=27;C9orf72, n=37).SOD1mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038).C9orf72expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008).SOD1andFUSmutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients withSOD1mutations,C9orf72expansions and those carrying pathogenicFUSmutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS withC9orf72expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).ConclusionOur study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease’s progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.
Effects of large-scale restoration on understory plant communities in an industrial landscape
Authors: Munford Kimber E. , Humphrey William , Levasseur Patrick A. , Beckett Peter , Watmough Shaun A. 
Published: June 2024

Starting in the mid 1970’s, researchers, industry leaders, and residents collaborated on one of the world’s largest regreening programs in the industrial region of Sudbury, Canada. The Sudbury Regreening Recipe included the application of crushed dolomitic limestone, nitrogen–phosphorus–potassium fertilizers, grass–legume seed mixtures across 8200 ha, and subsequent tree planting across 25 000 ha of acidic metal-contaminated land. The current study evaluated shifts in understory vegetation diversity and soil geochemistry on a chronosequence of sites treated the same way between 1982 and 2012. Fifty-six plant species were identified across the 24 sites, only four of which were planted in the initial remediation effort. Key factors influencing plant community composition and diversity were related to shifts in soil properties over time: bulk density, LFH layer depth, and mineral soil horizon pH. Plant communities differed with stand age and rocky sites had significantly different plant communities and lower canopy cover than less rocky sites. Mineral soil horizon pH increased with age, reflecting the movement of applied dolomite in soil. Despite high concentrations of total copper and nickel in soil, plant succession patterns were generally similar to those in naturally recovering forests demonstrating the overall success of the restoration program.
Properties of the ground and excited states of triply heavy spin-1/2 baryons
Authors: Rajabi Najjar Z. , Azizi K. , Moshfegh H. R. 
Published: June 2024

AbstractWe study the triply heavy spin-1/2 baryons with quark contents ccb and bbc, and calculate their mass and residue using QCD sum rules. In the calculations, we consider the ground (1 S), first orbitally excited (1P) and first radially excited (2 S) states. Aiming to achieve higher accuracies in the results, we perform the computations by taking into account the non-perturbative operators up to eight mass dimensions. We compare our results with the predictions of other theoretical studies existing in the literature. The obtained results may help experimental groups in their search for these yet unseen, but previously predicted by the quark model, interesting particles.
Comparison of the efficacy of dapagliflozin and linagliptin in the treatment of type 2 diabetes patients with normal body mass index and poor metformin monotherapy
Authors: He Mingli , Jiang Li , Zhang Su , Yang Xinrong 
Published: June 2024

Objective: To explore the efficacy and safety of dapagliflozin and linagliptin in the treatment of type 2 diabetes patients (T2DM) with normal body mass index (BMI) who have poor single drug efficacy of metformin. Method: 102 T2DM patients with normal BMI who visited our hospital from December 2021 to March 2023 were randomly divided into an observation group (51 cases) and a control group (51 cases) using a random number table method. The control group patients were treated with linagliptin in addition to metformin treatment, while the observation group was treated with dapagliflozin in addition to metformin treatment. The general indicators, blood glucose metabolism, biochemical indicators, and adverse reactions of the two groups of patients were compared. Result: After treatment, the body weight and BMI of both the observation group and the control group slightly decreased, while the systolic blood pressure of the observation group decreased. The changes in systolic blood pressure of the control group were not significant, and the differences were not statistically significant ([Formula: see text]); after treatment, the fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) of both groups of patients decreased, and the FPG and HbA1c of the control group were not significantly lower than those of the observation group ([Formula: see text]). After treatment, the values of blood creatinine, blood uric acid, urinary microalbumin (UAlb), and urinary microalbumin/creatinine (UACR) in both groups of patients decreased, and the decrease in various biochemical indicators in the control group was not as significant as that in the observation group. The comparison of blood uric acid, UAlb, and UACR between the two groups showed statistical significance ([Formula: see text]). The incidence of adverse reactions in the observation group and control group patients was 8.70% and 13.04%, respectively, and there was no statistically significant difference ([Formula: see text]) after comparison. Conclusion: Both dapagliflozin and linagliptin have shown good efficacy in the treatment of T2DM patients with normal BMI and poor efficacy in monotherapy with metformin. Compared to linagliptin, dapagliflozin can cause slight weight loss in patients, but its control effect on blood glucose and blood pressure is better than that of linagliptin. The risk of hypoglycemia is lower, and it has a protective effect on the kidneys. The disadvantage is that it slightly increases the risk of urogenital tract infections, Overall, it has high security and can be promoted for use.
Computational Exploration of Atriplex halimus Phytocompounds: A Targeted Approach Toward Inhibiting SARS-CoV-2
Authors: Roubi Mohammed , Dalli Mohammed , Azizi Salah-eddine , Mahdi Youness , Mothana Ramzi A. , Alanzi Abdullah R. , Conte Raffaele , Gseyra Nadia 
Published: June 2024

The primary aim of this investigation is to shed light on potential targets within the main protease Mpro, spike protein of SARS-CoV-2, and Angiotensine converting enzyme 2 (ACE2) for the exploration of novel inhibitors derived from therapeutic natural compounds originating from Atriplex halimus (AH). Many constituents were discerned within AH extracts through comprehensive gas chromatography/mass spectrometry (GC/MS). Notably, compounds, such as oleocanthal and methyl stearate, exhibited promising attributes across various biological activities, including inhibition of key proteins associated with SARS-CoV-2. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) settings were evaluated to explore the potential safety and viability of these compounds for pharmaceutical application, affirming their non-interference with human physiology and thus suggesting their suitability for pharmaceutical use. Catechin, epigallocatechin, and methyl stearate were discovered to be the compounds with the highest affinity to the studied protein showing a great potential to be inhibitors to COVID-19. Consequently, this discovery highlights Atriplex halimus as a promising candidate for utilization in combating the virus.
Integration of Extended Reality with a Cyber-Physical Factory Environment and its Digital Twins
Authors: Emporio Marco , Caputo Ariel , Pintani Deborah , Cheng Dong Seon , De Marchi Thomas , Forte Gianmaria , Fummi Franco , Giachetti Andrea 
Published: June 2024

In this paper, we present an example of complete integration of eXtended Reality technologies within a demonstration laboratory showcasing Industry 4.0/5.0 compliant machinery in realistic scenarios of use. We describe the design choices and the implementation of the augmented and virtual reality applications developed and potentially usable to support different real-world tasks, featuring advanced gesture-based interaction modes. We also describe the optimized communication architecture used to synchronize data between the cyber-physical factory environment with all its components, its industrial digital twin, and the augmented and virtual replica of the factory.
Example tasks supported with the tools in public demonstrations allow users wearing Microsoft HoloLens 2 or Meta Quest 2 headsets to monitor the status of the prototype production line and operate on it, locally or remotely.
An example video showing the applications is available in the supplementary material.
A Multimodal Drug–Diet–Immunotherapy Combination Restrains Melanoma Progression and Metastasis
Authors: Oatman Nicole , Gawali Mruniya V. , Congrove Sunny , Cáceres Román , Sukumaran Abitha , Gupta Nishtha , Murugesan Narmadha , Arora Priyanka , Subramanian Srividhya , Choi Kwangmin , Abdel-Malek Zalfa , Reisz Julie A. , Stephenson Daniel , Amaravadi Ravi , Desai Pankaj , D’Alessandro Angelo , Komurov Kakajan , Dasgupta Biplab 
Published: June 2024

Abstract
The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic codeletion along with PTEN on chromosome 10q in approximately 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low-SCD expression. Although this SCD-deficient subset was refractory to SCD inhibitors, the subset of PTEN wild-type melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low oleic acid custom diet was combined with an SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wild-type melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T-cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment.
Significance: Blockade of endogenous production of fatty acids essential for melanoma combined with restriction of dietary intake blocks tumor growth and enhances response to immunotherapy, providing a rational drug–diet treatment regimen for melanoma.
Single-Stranded DNA Gap Accumulation Is a Functional Biomarker for USP1 Inhibitor Sensitivity
Authors: da Costa Alexandre A. , Somuncu Ozge , Ravindranathan Ramya , Mukkavalli Sirisha , Martignetti David B. , Nguyen Huy , Jiao Yuqing , Lamarre Benjamin P. , Sadatrezaei Golbahar , Moreau Lisa , Liu Joyce , Iyer Divya R. , Lazaro Jean-Bernard , Shapiro Geoffrey I. , Parmar Kalindi , D’Andrea Alan D. 
Published: June 2024

Abstract
Recent studies suggest that PARP and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetically lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Herein, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with drug sensitivity. USP1 inhibition increased monoubiquitinated proliferating cell nuclear antigen at replication forks, mediated by the ubiquitin ligase RAD18, and knockdown of RAD18 caused USP1 inhibitor resistance and suppression of ssDNA gaps. USP1 inhibition overcame PARP inhibitor resistance in a BRCA1-mutated xenograft model and induced ssDNA gaps. Furthermore, USP1 inhibition was synergistic with PARP and POLQ inhibition in BRCA1-mutant cells, with enhanced ssDNA gap accumulation. Finally, in patient-derived ovarian tumor organoids, sensitivity to USP1 inhibition alone or in combination correlated with the accumulation of ssDNA gaps. Assessment of ssDNA gaps in ovarian tumor organoids represents a rapid approach for predicting response to USP1 inhibition in ongoing clinical trials.
Significance: USP1 inhibitors kill BRCA1-deficient cells and cause ssDNA gap accumulation, supporting the potential of using ssDNA gap detection as a functional biomarker for clinical trials on USP1 inhibitors.
An Evaluation of Novel Oncology Approvals with a PMR/C for Assessing Data in Racial and Ethnic Populations Underrepresented in Premarket Clinical Trials
Authors: Collins Grace , Andrews Hillary S. , McKelvey Brittany , Rice Carrigan , Allen Jeff D. , Stewart Mark D. 
Published: June 2024

Abstract
Clinical trials supporting oncology drug approvals frequently underrepresent diverse racial and ethnic populations. Recent policies have focused on ensuring premarket clinical trials are more inclusive and representative of racial and ethnic diversity in the general U.S. population or intended patient population; however, recent U.S. Food and Drug Administration (FDA) guidance on postmarketing approaches to collecting data in underrepresented populations demonstrates that, in certain circumstances, postmarketing requirements and/or commitments (PMR/Cs) may be issued to conduct more representative studies if there are remaining questions about safety or efficacy. This analysis demonstrates that prior to 2020, no drugs had PMR/Cs to further characterize use in a more representative population, and in the last 3 years, more than half of novel oncology approvals have had such a PMR/C (21/40, 53%). In addition, this analysis helps to identify characteristics, such as single-arm pivotal trial design, U.S. enrollment, and results of safety subgroup analyses based on race and ethnicity, that may contribute to decisions to issue a PMR/C to conduct a study that is more representative of the racial and ethnic diversity of the U.S. or intended patient population. These results can inform efforts to improve premarket clinical trials to ensure they are representative and able to characterize use in any patient who may need the drug.
Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models
Authors: Dong Lauren , Choi Hyejin , Budhu Sadna , Schulze Isabell , Verma Svena , Mangarin Levi M. , Estrada Nevarro Valeria , Mehanna Nezar , Khan Jonathan F. , Venkatesh Divya , Thach Daniel , Rosen Neal , Wolchok Jedd D. , Merghoub Taha 
Published: June 2024

Abstract
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway–dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell–mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.
Generation, Transcriptomic States, and Clinical Relevance of CX3CR1+ CD8 T Cells in Melanoma
Authors: Ishigaki Hirohito , Yamauchi Takayoshi , Long Mark D. , Hoki Toshifumi , Yamamoto Yuta , Oba Takaaki , Ito Fumito 
Published: June 2024

Abstract

Recent progress in single-cell profiling technologies has revealed significant phenotypic and transcriptional heterogeneity in tumor-infiltrating CD8+ T cells. However, the transition between the different states of intratumoral antigen-specific CD8+ T cells remains elusive. Here, we sought to examine the generation, transcriptomic states, and the clinical relevance of melanoma-infiltrating CD8+ T cells expressing a chemokine receptor and T-cell differentiation marker, CX3C chemokine receptor 1 (CX3CR1). Analysis of single-cell datasets revealed distinct human melanoma-infiltrating CD8+ T-cell clusters expressing genes associated with effector T-cell function but with distinguishing expression of CX3CR1 or PDCD1. No obvious impact of CX3CR1 expression in melanoma on the response to immune checkpoint inhibitor therapy was observed while increased pretreatment and on-treatment frequency of a CD8+ T-cell cluster expressing high levels of exhaustion markers was associated with poor response to the treatment. Adoptively transferred antigen-specific CX3CR1− CD8+ T cells differentiated into the CX3CR1+ subset in mice treated with FTY720, which inhibits lymphocyte egress from secondary lymphoid tissues, suggesting the intratumoral generation of CX3CR1+ CD8+ T cells rather than their trafficking from secondary lymphoid organs. Furthermore, analysis of adoptively transferred antigen-specific CD8+ T cells, in which the Cx3cr1 gene was replaced with a marker gene confirmed that CX3CR1+ CD8+ T cells could directly differentiate from the intratumoral CX3CR1− subset. These findings highlight that tumor antigen–specific CX3CR1− CD8+ T cells can fully differentiate outside the secondary lymphoid organs and generate CX3CR1+ CD8+ T cells in the tumor microenvironment, which are distinct from CD8+ T cells that express markers of exhaustion.

Significance:
Intratumoral T cells are composed of heterogeneous subpopulations with various phenotypic and transcriptional states. This study illustrates the intratumoral generation of antigen-specific CX3CR1+ CD8+ T cells that exhibit distinct transcriptomic signatures and clinical relevance from CD8+ T cells expressing markers of exhaustion.