bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients
Authors: Ruschil Christoph , Gabernet Gisela , Kemmerer Constanze Louisa , Jarboui Mohamed Ali , Klose Franziska , Poli Sven , Ziemann Ulf , Nahnsen Sven , Kowarik Markus Christian 
Published: March 2023

IntroductionB cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level.MethodsWe performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level.ResultsThe analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment.DiscussionOur findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.
Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
Authors: Cruz Cruz Joselyn , Allison Kristen C. , Page Lauren S. , Jenkins Alexis J. , Wang Xiaodong , Earp H. Shelton , Frye Stephen V. , Graham Douglas K. , Verneris Michael R. , Lee-Sherick Alisa B. 
Published: March 2023

BackgroundPrevious studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation.MethodsSince MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells.ResultsWe found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-β, IL-18, and IL-1β through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1+Tim-3+ and LAG3+ checkpoint expression, and increased CD69+CD107a+ expression.DiscussionThese results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.
Biophysical contexture of coastal biofilm-sediments varies heterogeneously and seasonally at the centimeter scale across the bed-water interface
Authors: Chen Xindi , Kang Yanyan , Zhang Qian , Jin Chuang , Zhao Kun 
Published: March 2023

Coastal sediments filter and accumulate organic and inorganic materials from the terrestrial and marine environment, and thus provide a high diversity of microbial niches. However, sediment-based analyses typically examine bulk samples and seldom consider variation at a scale relevant to changes in environmental conditions, due to the lack of mid-long term field data which can cover both the seasonal and sediment depth variations. In this study, microbial production and bacterial community structure were determined together with grain parameters over 10 months of intertidal silty sands on Jiangsu Coast, China. We demonstrated that the microbiological effects did not merely present on the surface, but greatly varied and stratified in both physical and biological contexture within the top 4 cm layer. Bacterial community structure showed a clear vertical variation with higher operational taxonomic unit (OTU) numbers at 1~2 cm depth than in the top 2 mm, probably because of the decreasing disturbance by hydrodynamic forces. However, the microbial production rates and metabolic activities, represented by the production of extracellular polymeric substances (EPS), were always higher in the top. Seasonal changes were strongly reflected in the vertical patterns of EPS but could not explain the variation across sites. The overall EPS secretion in spring and summer was generally at high level than that in autumn and winter, with the maximum value of 5~6 times higher. Interestingly, the stratification of biological and physical properties followed a fixed relationship, where with the decrease of the grain size D50, the EPS content increased exponentially, and this relationship was independent of temporal or spatial variation. Despite the significant seasonal variation of microbial activity and sedimentary grain size individually, the basic function between EPS content and D50 however did not alter. Filling these knowledge gaps will not only help to decipher the fate of grain-biofilm aggregates and organic matter burial under global changes, but also provide field evidence for the development of sediment transport models as well as blue carbon models incorporating microbial processes.
Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience
Authors: Gascón-Giménez Francisco , Alcalá Carmen , Ramió-Torrentà Lluís , Montero Paloma , Matías-Guiu Jorge , Gómez-Estevez Irene , Oreja-Guevara Celia , Gil-Perotín Sara , Blanco Yolanda , Carcelén María , Quintanilla-Bordás Carlos , Costa Lucienne , Villar Luisa Maria , Martínez-Rodriguez Jose Enrique , Domínguez José Andrés , Calles Carmen , González Inés , Sotoca Javier , Oterino Agustin , Lucas-Jimenez Celia , Pérez-Miralles Francisco , Casanova Bonaventura 
Published: March 2023

IntroductionRituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS.Patients and methodsObservational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS.ResultsA total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5–27.2), ARR decreased by 85.7% (p &lt; 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p &lt; 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy).ConclusionRituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.
Case report: Cerebrotendinous xanthomatosis with a novel mutation in the CYP27A1 gene mimicking behavioral variant frontotemporal dementia
Authors: Chun Min Young , Heo Nam Jin , Seo Sang Won , Jang Hyemin , Suh Yeon-Lim , Jang Ja-Hyun , Kim Young-Eun , Kim Eun-Joo , Moon So Young , Jung Na-Yeon , Lee Sun Min , Kim Hee Jin 
Published: March 2023

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by a mutation in the CYP27A1 gene. Due to the disruption of bile acid synthesis leading to cholesterol and cholestanol accumulation, CTX manifests as premature cataracts, chronic diarrhea, and intellectual disability in childhood and adolescence. This report presents a case of CTX with an unusual phenotype of behavioral variant frontotemporal dementia (bvFTD) in middle age.Case presentationA 60-year-old woman presented with behavioral and personality changes. She showed disinhibition, such as hoarding and becoming aggressive over trifles; compulsive behavior, such as closing doors; apathy; and dietary change. The patient showed a progressive cognitive decline and relatively sparing memory and visuospatial function. She had hyperlipidemia but no family history of neurodegenerative disorders. Initial fluid-attenuated inversion recovery (FLAIR) images showed a high signal in the periventricular area, and brain spectroscopy showed hypoperfusion in the frontal and temporal lobes, mimicking bvFTD. However, on physical examination, xanthomas were found on both the dorsum of the hands and the Achilles tendons. Hyperactive deep tendon reflexes in the bilateral biceps, brachioradialis, and knee and positive Chaddock signs on both sides were observed. Four years later, FLAIR images showed symmetrical high signals in the bilateral dentate nuclei of the cerebellum. Her serum cholestanol (12.4 mg/L; normal value ≤6.0) and 7α,12α-dihydroxycholest-4-en-3-one (0.485 nmol/mL; normal value ≤0.100) levels were elevated. A novel likely pathogenic variant (c.1001T&gt;A, p.Met334Lys) and a known pathogenic variant (c.1420C&gt;T, p.Arg474Trp) of the CYP27A1 gene were found in trans-location. The patient was diagnosed with CTX and prescribed chenodeoxycholic acid (750 mg/day).ConclusionsThis report discusses the case of a middle-aged CTX patient with an unusual phenotype of bvFTD. A novel likely pathogenic variant (c.1001T&gt;A, p.Met334Lys) was identified in the CYP27A1 gene. Early diagnosis is important because supplying chenodeoxycholic acid can prevent CTX progression.
Active monitoring improves radiopharmaceutical administration quality
Authors: Crowley James R. , Barvi Iryna , Kiser Jackson W. 
Published: March 2023

IntroductionIn 2016, our center adopted technology to routinely monitor 18F-FDG radiopharmaceutical administrations. Within six months of following basic quality improvement methodology, our technologists reduced extravasation rates from 13.3% to 2.9% (p &lt; 0.0001). These same technologists administer other radiopharmaceuticals (without monitoring technology) for general nuclear medicine procedures in a separate facility at the clinic. Our hypothesis was that they would apply 18F-FDG lessons-learned to 99mTc-MDP administrations and that 99mTc-MDP manual injection extravasation rate would be consistent with the ongoing 18F-FDG manual injection extravasation rate (3.4%). We tested our hypothesis by following the same quality improvement methodology and added monitoring equipment to measure extravasation rates for 99mTc-MDP administrations.Results816 99mTc-MDP administrations were monitored during 16-month period (four 4-month periods: A, B, C, D). Period A (first four months of active monitoring) extravasation rate was not statistically different from the Measure Phase extravasation rate of the previously completed PET/CT QI Project: 12.75% compared to 13.3% (p-0.7925). Period A extravasation rate was statistically different from Period C (months 9–12) extravasation rate and Period D (months 13–16) extravasation rate: 12.75% compared to 2.94% and to 3.43% (p &lt; 0.0001). During Period C and D technologists achieved extravasation rates comparable to the longstanding manual 18F-FDG injection extravasation rate (3.4%).ConclusionOur initial hypothesis, that awareness of a problem and the steps need to correct it would result in process improvement, was not accurate. While those factors are important, they are not sufficient. Our findings suggest that active monitoring and the associated display of results are critical to quality improvement efforts to reduce and sustain radiopharmaceutical extravasation rates.
Decreased transthyretin predicts a poor prognosis in primary myelodysplastic syndrome
Authors: Chen Ying , Niu Tingting , Chen Ting , Wu Yue , Zou Duobing , Shi Cong , Wu Ying , Zhang Zhaoyi , Wu Ningning , Zhang Yi , Yan Xiao , Sheng Lixia , Lv Dingfeng , Ouyang Guifang , Chen Xueqin , Mu Qitian 
Published: March 2023

BackgroundThis study aims to investigate the prognostic significance of transthyretin in newly diagnosed myelodysplastic syndromes (MDS).MethodsThe clinical, laboratory, and follow-up data of 280 newly diagnosed patients with MDS were collected. The relationship between serum transthyretin levels and overall survival (OS) and leukemia-free survival (LFS) were analyzed by Kaplan–Meier analysis and Cox Regression Model.ResultIn the MDS cohort, there were 121 cases in the low transthyretin group and 159 cases in the normal transthyretin group. MDS patients with decreased transthyretin had a higher risk score on the Revised International Prognostic Scoring System (IPSS-R) (p = 0.004) and on the molecular IPSS (IPSS-M) (p = 0.005), a higher frequency of TP53 mutation (p &lt; 0.0001), a shorter OS (p &lt; 0.0001) and LFS (p &lt; 0.0001). Multivariate analyses showed that higher IPSS-R and IPSS-M score were adverse factors for OS (p = 0.008 and p = 0.015, respectively) and LFS (p = 0.024 and p = 0.005, respectively). Mutations of TP53 and NRAS were also poor factors for LFS (p = 0.034 and p = 0.018, respectively). Notably, decreased transthyretin was an independent adverse predictor for OS (p = 0.009, HR = 0.097, 95%CI, 0.017–0.561) but not for LFS (p = 0.167) when IPSS-R was included in the Cox regression model and an independent poor one for OS (p = 0.033, HR = 0.267, 95%CI, 0.080–0.898) and LFS (p = 0.024, HR = 0.290, 95%CI, 0.099–0.848) while IPSS-M involved.ConclusionThe results indicate that decreased transthyretin could be an independent adverse prognostic factor in patients with MDS and may provide a supplement to IPSS-R and IPSS-M.
Plasma-only circulating tumor DNA analysis detects minimal residual disease and predicts early relapse in hepatocellular carcinoma patients undergoing curative resection
Authors: Xu Yuyan , Cai Jianpeng , Zhong Kaihang , Wen Yaohong , Cai Lei , He Guolin , Liao Hangyu , Zhang Cheng , Fu Shunjun , Chen Tingting , Cai Jinping , Zhong Xuefeng , Chen Chunzhu , Huang Mengli , Cheng Yuan , Pan Mingxin 
Published: March 2023

BackgroundMinimal residual disease (MRD) is considered an essential factor leading to relapse within 2 years (early relapse) after radical surgery, which is challenging to be detected by conventional imaging. Circulating tumor DNA (ctDNA) provides a novel approach for detecting MRD and predicting clinical outcomes. Here, we tried to construct a fixed panel for plasma-only ctDNA NGS to enable tumor-uninformed MRD detection in hepatocellular carcinoma (HCC).MethodsHere, we performed the followings: (i) profiling genomic alteration spectrum of ctDNA from the Chinese HCC cohort consisting of 493 individuals by NGS; (ii) screening of MRD monitoring genes; and (iii) performance evaluation of MRD monitoring genes in predicting early relapse in the ZJZS2020 cohort comprising 20 HCC patients who underwent curative resection.ResultsA total of 493 plasma samples from the Chinese HCC cohort were detected using a 381/733-gene NGS panel to characterize the mutational spectrum of ctDNA. Most patients (94.1%, 464/493) had at least one mutation in ctDNA. The variants fell most frequently in TP53 (45.1%), LRP1B (20.2%), TERT (20.2%), FAT1 (16.2%), and CTNNB1 (13.4%). By customized filtering strategy, 13 MRD monitoring genes were identified, and any plasma sample with one or more MRD monitoring gene mutations was considered MRD-positive. In the ZJZS2020 cohort, MRD positivity presented a sensitivity of 75% (6/8) and a specificity of 100% (6/6) in identifying early postoperative relapse. The Kaplan-Meier analysis revealed a significantly short relapse-free survival (RFS; median RFS, 4.2 months vs. NR, P=0.002) in the MRD-positive patients versus those with MRD negativity. Cox regression analyses revealed MRD positivity as an independent predictor of poor RFS (HR 13.00, 95% CI 2.60-69.00, P=0.002).ConclusionsWe successfully developed a 13-gene panel for plasma-only MRD detection, which was effective and convenient for predicting the risk of early postoperative relapse in HCC.
Identification and verification of the temozolomide resistance feature gene DACH1 in gliomas
Authors: Gu Qiang , Li Lang , Yao Jiahao , Dong Fa-yan , Gan Yifan , Zhou Shuhuai , Wang Xinyu , Wang Xue-feng 
Published: March 2023

IntroductionThe most important chemotherapy treatment for glioma patients is temozolomide. However, the development of drug resistance severely restricts the use of temozolomide. Therefore, elucidating the mechanism of temozolomide resistance, enhancing temozolomide sensitivity, and extending patient survival are urgent tasks for researchers.MethodsTemozolomide resistance hub differential genes were identified using differential analysis and protein interaction analysis from the GEO datasets (GSE100736 and GSE113510). These genes were further studied in glioma patients treated with temozolomide in the TCGA and CGGA databases. Patients from the mRNAseq_325 dataset (CGGA) were considered as the training set to construct a risk model for predicting glioma sensitivity to temozolomide, while patients from the mRNAseq_693 dataset (CGGA) and TCGA-GBM dataset were considered as the validation set to evaluate the performance of models. PCR and western blot were performed to determine the difference in expression of the feature gene DACH1 between glioma cells and temozolomide-resistant glioma cells. The alterations in the sensitivity of tumor cells to temozolomide were also observed after DACH1 was silenced. The patients were then divided into two groups based on the expression of DACH1, and the differences in patient survival rates, molecular pathway activation, and level of immune infiltration were compared.ResultsBased on four signature genes (AHR, DACH1, MGMT, and YAP1), a risk model for predicting glioma sensitivity to temozolomide was constructed, and the results of timeROC in both the training and validation sets showed that the model had good predictive performance. The expression of the signature gene DACH1 was significantly downregulated in temozolomide-resistant cells, according to the results of the PCR and western blot experiments. The sensitivity of tumor cells to temozolomide was significantly reduced after DACH1 was silenced. DACH1 probably regulates temozolomide resistance in glioblastoma through the transcriptional dysregulation in cancer and ECM.DiscussionThis study constructs a risk model that can predict glioma susceptibility to temozolomide and validates the function of the feature gene DACH1, which provides a promising target for the research of temozolomide resistance.
JNJ-64619178 radiosensitizes and suppresses fractionated ionizing radiation-induced neuroendocrine differentiation (NED) in prostate cancer
Authors: Pawar Jogendra Singh , Al-Amin Md. Yusuf , Hu Chang-Deng 
Published: March 2023

BackgroundRadiation therapy (RT) is a standard treatment regimen for locally advanced prostate cancer; however, its failure results in tumor recurrence, metastasis, and cancer-related death. The recurrence of cancer after radiotherapy is one of the major challenges in prostate cancer treatment. Despite overall cure rate of 93.3% initially, prostate cancer relapse in 20-30% patients after radiation therapy. Cancer cells acquire radioresistance upon fractionated ionizing radiation (FIR) treatment, eventually undergo neuroendocrine differentiation (NED) and transform into neuroendocrine-like cells, a mechanism involved in acquiring resistance to radiation therapy. Radiosensitizers are agents that inhibit the repair of radiation-induced DNA damage. Protein arginine methyltransferase 5 (PRMT5) gets upregulated upon ionizing radiation treatment and epigenetically activates DNA damage repair genes in prostate cancer cells. In this study, we targeted PRMT5 with JNJ-64619178 and assessed its effect on DNA damage repair gene activation, radiosensitization, and FIR-induced NED in prostate cancer.MethodsγH2AX foci analysis was performed to evaluate the DNA damage repair after radiation therapy. RT-qPCR and western blot were carried out to analyze the expression of DNA damage repair genes. Clonogenic assay was conducted to find out the surviving fraction after radiation therapy. NED was targeted with JNJ-64619178 in androgen receptor (AR) positive and negative prostate cancer cells undergoing FIR treatment.ResultsJNJ-64619178 inhibits DNA damage repair in prostate cancer cells independent of their AR status. JNJ-64619178 impairs the repair of ionizing radiation-induced damaged DNA by transcriptionally inhibiting the DNA damage repair gene expression and radiosensitizes prostate, glioblastoma and lung cancer cell line. It targets NED induced by FIR in prostate cancer cells.ConclusionJNJ-64619178 can radiosensitize and suppress NED induced by FIR in prostate cancer cells and can be a potential radiosensitizer for prostate cancer treatment.