bluuebunny/crossref_metadata_2025_split huggingface dataset:
INTEGRATED BIOINFORMATIC ANALYSIS TO EVALUATE TARGET GENES AND PATHWAYS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: ALTINOK GÜNEŞ Buket 
Published: January 2023

Objective: The most common type of leukemia, chronic lymphocytic leukemia (CLL), is characterized by progressive accumulation of monoclonal B cells with a specific immunophenotype in the blood, bone marrow, and lymphoid organ. The goal of this research was to use bioinformatic analysis to comprehend the molecular mechanisms causing CLL and to investigate potential targets for the diagnosis and therapy of CLL.
Material and Method: Expression data from CLL patients with accession numbers GSE22529 and GSE26725 were downloaded from the GEO database for bioinformatic analysis. GSE22529 data was studied with samples from 41 CLL patients and 11 healthy groups, while GSE26725 data was studied with blood samples from 12 CLL patients and 5 healthy groups. GEO2R was used to find differentially expressed genes (DEGs) in CLL patient samples and healthy control samples. The DAVID program was used to perform GO and KEGG enrichment analyses on DEGs. Using the Cytoscape software, a protein-protein interaction (PPI) network was created, and hub genes associated with CLL were identified.
Result and Discussion: DEGs with p 0.05 and log2FC 0, log2FC>0 were chosen after analysis with GEO2R. In the GSE22529 dataset, 942 genes had higher expression levels in CLL patients compared with controls, while the expression of 1007 genes decreased. In the GSE26725 dataset, CLL patients had lower expression levels for 916 genes compared with controls, while 939 genes showed an increase in expression. 229 DEGs with higher expression levels and 308 DEGs with lower expression levels were found in both sets of data. It has been observed that these common genes, whose expression has changed, are enriched in protein processing in the ER, Chemokine, B-cell receptor, T-cell receptor, protein export pathways. Additionally, DDOST, RPL18, RPL18A, RPL19, RPL31, GNB3, GNB4, GNG11, GNGT1, NEDD8, UBE2M RBX1, FBXO21, SKP1, KLHL9 and CAND1 were identified as the most important genes. Our study's findings demonstrated that newly discovered genes and pathways may be candidates for CLL biomarkers that can be used for both the diagnosis and drug treatment of the disease.
Effects of cervical rotatory manipulation on the cervical spinal cord complex with ossification of the posterior longitudinal ligament in the vertebral canal: A finite element study
Authors: Xue Fan , Deng Hao , Chen Zujiang , Yang Han , Li Yikai , Yuan Shiguo , Zheng Nansheng , Chen Meixiong 
Published: January 2023

Background: There are few studies focusing on biomechanism of spinal cord injury according to the ossification of the posterior longitudinal ligament (OPLL) during cervical rotatory manipulation (CRM). This study aimed to explore the biomechanical effects of CRM on the spinal cord, dura matter and nerve roots with OPLL in the cervical vertebral canal.Methods: Three validated FE models of the craniocervical spine and spinal cord complex were constructed by adding mild, moderate, and severe OPLL to the healthy FE model, respectively. We simulated the static compression of the spinal cord by OPLL and the dynamic compression during CRM in the flexion position. The stress distribution of the spinal cord complex was investigated.Results: The cervical spinal cord experienced higher von Mises stress under static compression by the severe OPLL. A higher von Mises stress was observed on the spinal cord in the moderate and severe OPLL models during CRM. The dura matter and nerve roots had a higher von Mises stress in all three models during CRM.Conclusion: The results show a high risk in performing CRM in the flexion position on patients with OPLL, in that different occupying ratios in the vertebral canal due to OPLL could significantly increase the stress on the spinal cord complex.
Knocking out central metabolism genes to identify new targets and alternating substrates to improve lipid synthesis in Y. lipolytica
Authors: Zhu Jiang , Gu Yang , Yan Yijing , Ma Jingbo , Sun Xiaoman , Xu Peng 
Published: January 2023

Introduction: Systematic gene knockout studies may offer us novel insights on cell metabolism and physiology. Specifically, the lipid accumulation mechanism at the molecular or cellular level is yet to be determined in the oleaginous yeast Y. lipolytica.Methods: Herein, we established ten engineered strains with the knockout of important genes involving in central carbon metabolism, NADPH generation, and fatty acid biosynthetic pathways.Results: Our result showed that NADPH sources for lipogenesis include the OxPP pathway, POM cycle, and a trans-mitochondrial isocitrate-α-oxoglutarate NADPH shuttle in Y. lipolytica. Moreover, we found that knockout of mitochondrial NAD+ isocitrate dehydrogenase IDH2 and overexpression of cytosolic NADP+ isocitrate dehydrogenase IDP2 could facilitate lipid synthesis. Besides, we also demonstrated that acetate is a more favorable carbon source for lipid synthesis when glycolysis step is impaired, indicating the evolutionary robustness of Y. lipolytica.Discussion: This systematic investigation of gene deletions and overexpression across various lipogenic pathways would help us better understand lipogenesis and engineer yeast factories to upgrade the lipid biomanufacturing platform.
Identification of compounds with activity against Trypanosoma cruzi within a collection of synthetic nucleoside analogs
Authors: Barnadas-Carceller Berta , Martinez-Peinado Nieves , Gómez Laura Córdoba , Ros-Lucas Albert , Gabaldón-Figueira Juan Carlos , Diaz-Mochon Juan J. , Gascon Joaquim , Molina Ignacio J. , Pineda de las Infantas y Villatoro María José , Alonso-Padilla Julio 
Published: January 2023

IntroductionChagas disease is caused by the protozoan parasite Trypanosoma cruzi, and it is the most important neglected tropical disease in the Americas. Two drugs are available to treat the infection, but their efficacy in the chronic stage of the disease, when most cases are diagnosed, is reduced. Their tolerability is also hindered by common adverse effects, making the development of safer and efficacious alternatives a pressing need. T. cruzi is unable to synthesize purines de novo, relying on a purine salvage pathway to acquire these from its host, making it an attractive target for the development of new drugs. MethodsWe evaluated the anti-parasitic activity of 23 purine analogs with different substitutions in the complementary chains of their purine rings. We sequentially screened the compounds' capacity to inhibit parasite growth, their toxicity in Vero and HepG2 cells, and their specific capacity to inhibit the development of amastigotes. We then used in-silico docking to identify their likely targets.ResultsEight compounds showed specific anti-parasitic activity, with IC50 values ranging from 2.42 to 8.16 μM. Adenine phosphoribosyl transferase, and hypoxanthine-guanine phosphoribosyl transferase, are their most likely targets. DiscussionOur results illustrate the potential role of the purine salvage pathway as a target route for the development of alternative treatments against T. cruzi infection, highlithing the apparent importance of specific substitutions, like the presence of benzene groups in the C8 position of the purine ring, consistently associated with a high and specific anti-parasitic activity.
Molecular distribution in intradermal injection for transfer and delivery of therapeutics
Authors: Lallow Emran O. , Busha Kishankumar J. , Park Sarah H. , Atzampou Maria , Jhumur Nandita C. , Demiryurek Yasir , Roberts Christine C. , Shan Jerry W. , Zahn Jeffrey D. , Shreiber David I. , Park Young K. , Singer Jonathan P. , Maslow Joel N. , Lin Hao 
Published: January 2023

Intradermal (ID) injection is a technique widely used in laboratorial and clinical applications. The boundary of the dome-like bleb formed during injection is assumed to represent the lateral extent of the injected material. This work systematically characterizes cargo molecule distribution (puddle) as a function of injection volume and molecular/particle size in rat skin post ID injection. In general, results indicate that the puddle forms a subdomain laterally contained within the bleb, with an area inversely correlating to the molecular size of the injected material. For 50 μL and 100 µL injections, the average area of the bleb was 40.97 ± 6.30 mm2 and 55.64 ± 8.20 mm2, respectively, regardless of the molecular/particle size. On the other hand, the area of the puddle was dependent on the molecular size and ranged between 45.38 ± 8.29 mm2 and 6.14 ± 4.50 mm2 for 50 µL injections, and 66.64 ± 11.22 mm2 and 11.50 ± 9.67 mm2 for 100 µL injections. The lateral distribution appears to have no time-dependency up to 10 min post injection. The trend in the depth of cargo penetration is also similar, with smaller particles extending deeper into the dermis and subcutaneous fat layers. Because the area of puddle can be significantly less than that of the bleb, establishing base characterization is essential to understand cellular interactions with the injected biological substances.
Growth differentiation factor 10 induces angiogenesis to promote wound healing in rats with diabetic foot ulcers by activating TGF-β1/Smad3 signaling pathway
Authors: Zhao Qingsong , Xu Jinmei , Han Xu , Zhang Zheqi , Qu Jiahui , Cheng Zhifeng 
Published: January 2023

BackgroundDiabetic foot ulcer (DFU) represents a highly-prevalent complication of diabetes mellitus (DM). Herein, the current study sought to identify the role of growth differentiation factor 10 (GDF-10) in wound healing in DFU via regulation of the transforming growth factor-beta 1 (TGF-β1)/Smad3 pathway.MethodsDM- and DFU-related microarray datasets GSE29221 and GSE134431 were firstly retrieved, and weighted gene co-expression network analysis (WGCNA) was carried out to construct a co-expression network affecting wound healing in DFU, followed by differential analysis. A protein-protein interaction (PPI) network of the DFU-related genes was subsequently constructed, and the core genes and signaling pathways in DFU were screened with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analyses. A DFU rat model was constructed for mechanism verification of the effect of GDF-10 on wound healing in DFU.ResultsWGCNA screened five co-expression modules, and the brown module was most closely-related to DM. Clustering analysis screened 4417 candidate genes, of which 175 differential genes were associated with wound healing, further involved in TGF-β1/Smad3 signaling pathway regulation of wound healing in DFU. The PPI network analysis predicted that GDF-10 might regulate the TGF-β1/Smad3 signaling pathway to participate in DFU development. Results of animal experimentation showed that the wound healing rates of NFU, DFU, DFU + GDF and GDF + SIS3 groups on the 22nd day were (87.66 ± 6.80)%, (56.31 ± 7.29)%, (71.64 ± 9.43)% and (55.09 ± 7.13)%, respectively. Besides, the expression of TGF-β1 in NFU, DFU, DFU + GDF and GDF + SIS3 groups was 0.988 ± 0.086, 0.297 ± 0.036, 0.447 ± 0.044, and 0.240 ± 0.050, respectively, and that of Smad3 was 1.009 ± 0.137, 0.145 ± 0.017, 0.368 ± 0.048, and 0.200 ± 0.028, respectively. Specifically, GDF-10 exerted a significant diminishing effect on fasting blood glucose level, and promoted wound healing in DFU rats, in addition to up-regulation of VEGF, FGF, Ang-1, TGF-β1, Smad3 and enhancement of IL-1b, IL-6, TNF-a and MMP-9, thereby promoting fibroblast proliferation, collagen deposition and angiogenesis.ConclusionsOur findings highlight that GDF-10 may promote angiogenesis by activating TGF-β1/Smad3 signaling, thereby promoting wound healing in DFU rats.
Applying a hybrid model to support management of the endangered Topeka shiner in oxbow habitats
Authors: Galic Nika , Schmolke Amelie , Bartell Steven , Roy Colleen , Brain Richard 
Published: January 2023

IntroductionHabitat restoration aims at reinstating abiotic and biotic habitat conditions to support long-term species persistence and viability. This management practice is commonly part of recovery plans developed for species listed as threatened or endangered under the Endangered Species Act. The endangered Topeka shiner (Notropis topeka) inhabits off-channel habitats, such as oxbow lakes which are increasingly the focus of restoration, but the exact abiotic conditions conducive to its persistence in this habitat are not fully understood. In this study, a hybrid model consisting of an individual-based model of the Topeka shiner and an aquatic ecosystem model representing the oxbow habitat was applied to identify optimal environmental conditions for the persistence of Topeka shiner populations.Materials and methodsEnvironmental conditions that correlated with Topeka shiner presence were gathered from published studies and included water temperature, turbidity, oxbow depth, light intensity (as a function of riparian vegetation presence), dissolved nitrogen, and dissolved phosphorus. Selected conditions were systematically varied in simulations and results were analyzed with a partial rank correlation method that quantifies the relative influence on model output from multiple factors.ResultsConducted simulations identified water temperature, depth, and dissolved inorganic nitrogen to be the most influential for Topeka shiner population biomass and additional simulations were conducted exploring the magnitudes and directions of effects of these three factors. Water temperature had the largest positive impact on population biomass followed by oxbow depth and nitrogen reduction.DiscussionWe recommend that the three identified factors be further explored in a combination of empirical and modeling approaches to advise management for the endangered Topeka shiner. This study demonstrated how ecological models could inform recovery plans by identifying factors that enhance species persistence. Ultimately, models should support management practices that result in long-term population viability of listed species and could facilitate their timely delisting.
High-risk patients with locally advanced non-small cell lung cancer treated with stereotactic body radiation therapy to the peripheral primary combined with conventionally fractionated volumetric arc therapy to the mediastinal lymph nodes
Authors: Eichkorn Tanja , Lischalk Jonathan W. , Stüwe Cedric , Tonndorf-Martini Eric , Schubert Kai , Dinges Lisa-Antonia , Regnery Sebastian , Bozorgmehr Farastuk , König Laila , Christopoulos Petros , Hörner-Rieber Juliane , Adeberg Sebastian , Herfarth Klaus , Winter Hauke , Thomas Michael , Rieken Stefan , Debus Jürgen , El Shafie Rami A. 
Published: January 2023

IntroductionA very narrow therapeutic window exists when delivering curative chemoradiotherapy for inoperable locally advanced non-small cell lung cancer (NSCLC), particularly when large distances exist between areas of gross disease in the thorax. In the present study, we hypothesize that a novel technique of stereotactic body radiation therapy (SBRT) to the primary tumor in combination with volumetric arc therapy (VMAT) to the mediastinal lymph nodes (MLN) is a suitable approach for high-risk patients with large volume geographically distant locally advanced NSCLC.Patients and methodsIn this single institutional review, we identified high-risk patients treated between 2014 and 2017 with SBRT to the parenchymal lung primary as well as VMAT to the involved MLN using conventional fractionation. Dosimetrically, comparative plans utilizing VMAT conventionally fractionated delivered to both the primary and MLN were analyzed. Clinically, toxicity (CTCAE version 5.0) and oncologic outcomes were analyzed in detail.ResultsA total of 21 patients were identified, 86% (n=18) of which received chemotherapy as a portion of their treatment. As treatment phase was between 2014 and 2017, none of the patients received consolidation immunotherapy. Target volume (PTV) dose coverage (99 vs. 87%) and CTV volume (307 vs. 441 ml) were significantly improved with SBRT+MLN vs. for VMAT alone (p&lt;0.0001). Moreover, low-dose lung (median V5Gy [%]: 71 vs. 77, p&lt;0.0001), heart (median V5Gy [%]: 41 vs. 49, p&lt;0.0001) and esophagus (median V30Gy [%]: 54 vs. 55, p=0.03) dose exposure were all significantly reduced with SBRT+MLN. In contrast, there was no difference observed in high-dose exposure of lungs, heart, and spinal cord. Following SBRT+MLN treatment, we identified only one case of high-grade pneumonitis. As expected, we observed a higher rate of esophagitis with a total of seven patients experience grade 2+ toxicity. Overall, there were no grade 4+ toxicities identified. After a median 3 years follow up, disease progression was observed in 70% of patients irradiated using SBRT+MLN, but never in the spared ‘bridging’ tissue between pulmonary SBRT and mediastinal VMAT.ConclusionFor high risk patients, SBRT+MLN is dosimetrically feasible and can provide an alternative to dose reductions necessitated by otherwise very large target volumes.
A retrospective study to evaluate the effect of preoperative hormonal therapy on continence recovery
Authors: Wang Yuwen , Zhang Shun , Huang Haifeng , Qiu Xuefeng , Fu Yao , Lyu Xiaoyu , Xu Linfeng , Zhuang Junlong , Guo Hongqian 
Published: January 2023

ObjectiveTo evaluate whether different preoperative hormonal therapy options affect postoperative continence and to identify risk/protective factors for continence recovery.MethodsThis is a retrospective analysis of several clinical trials (NCT04356430, NCT04869371, NCT04992026 and NCT05406999). Data from patients treated with hormonal therapy followed by RARP were collected and analyzed. Continence was defined as 0 pad/day or one safety pad.ResultsThe study included 230 patients with adequate information. The median time to continence recovery is 8 weeks. A total of 216 (93.9%) participants recovered to urinary continence within 12 months after surgery. 21 (9.1%) participants achieved immediate continence. 69, 85, 27 and 14 participants restored continence at 1 month, 1-3 month, 3-6 month, 6-12 month, accounting for 30.0%, 40.0%, 11.7% and 6.1% accordingly. No difference in continence recovery was found among different preoperative hormonal treatment options (p=0.821). Cox regression showed that membranous urethral length (MUL) was the only independent factor influencing urinary continence recovery either in the univariate analysis (OR=1.13, 95%CI: 1.04-1.22, p=0.002) or in the multivariate analysis (OR=1.12, 95%CI: 1.04-1.20, p=0.002). Different preoperative treatment options were not associated with urinary recovery. More advanced preoperative T stage (OR=0.46, 95%CI: 0.24-0.85, p=0.014) delayed the recovery of immediate continence. MUL was associated with continence restoring at 1 month (OR=1.20, 95%CI: 1.03-1.39, p=0.017), 3 month (OR=1.27, 95%CI: 1.07-1.51, p=0.006), 6 month (OR=1.34, 95%CI: 1.07-1.67, p=0.011) and 12 month (OR=1.36, 95%CI: 1.01-1.84, p=0.044).ConclusionThere is no difference in postoperative continence recovery among ADT, ADT+Docetaxel and ADT+Abiraterone preoperative treatment options. More advanced T stage indicated poor immediate continence recovery. Longer membranous urethral length was a promotional factor for both short-time and long-time continence recovery.
Cost-effectiveness analysis of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer
Authors: He Jiaoxue , Wang Qingfeng , Hu Qiancheng , Li Changlin 
Published: January 2023

BackgroundRadiotherapy is an effective curative treatment option for intermediate- to high-risk localized prostate cancer. According to the HYPO-RT-PC trial (ISRCTN45905321), there was no significant difference in 5 years of follow-up in terms of failure-free survival, overall survival, urinary toxicity, and bowel toxicity, while erectile function decreased between ultra-hypofractionated radiotherapy with conventionally fractionated radiotherapy, except that the incidence of urinary toxicity in ultra-hypofractionated radiotherapy was higher at 1 year of follow-up. We evaluated the cost-effectiveness of ultra-hypofractionated radiotherapy and conventionally fractionated radiotherapy for intermediate- to high-risk localized prostate cancer from the Chinese payer’s perspective.MethodsWe developed a Markov model with a 15-year time horizon to compare the cost and effectiveness of ultra-hypofractionated radiotherapy with those of conventionally fractionated radiotherapy for localized intermediate- to high-risk prostate cancer. The outcomes were measured in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and willingness-to-pay (WTP). Univariable and probability sensitivity analyses were performed to evaluate the robustness of the Markov model.ResultsBased on the Markov model, conventionally fractionated radiotherapy yielded 2.32 QALYs compared with 2.14 QALYs in ultra-hypofractionated radiotherapy in China. The cost of ultra-hypofractionated radiotherapy was found to be decreased by about 14% folds ($4,251.04) in comparison with that of conventionally fractionated radiotherapy. The ICER of conventionally fractionated radiotherapy versus that of ultra-hypofractionated radiotherapy was $23,616.89 per QALY in China. The failure-free survival with grade 2 or worse urinary toxicity and the discount rate per annum were the most sensitive parameters utilized in ultra-hypofractionated radiotherapy. The cost-effectiveness acceptability curve showed that conventionally fractionated radiotherapy had 57.7% probability of being cost-effective under the Chinese WTP threshold.ConclusionFrom the perspective of Chinese payers, ultra-hypofractionated radiotherapy was not a cost-effective strategy compared with conventionally fractionated radiotherapy for patients with localized intermediate- to high-risk prostate cancer. Nevertheless, reduction of the grade 2 or worse urinary toxicity of ultra-hypofractionated radiotherapy could alter the results.