bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells
Authors: Pan Wentao , Luo Qiuyun , Liang Eric , Shi Mude , Sun Jian , Shen Huimin , Lu Zhenhai , Zhang Lin , Yan Xianglei , Yuan Luping , Zhou Suna , Yi Hanjie , Zhai Yifan , Qiu Miao-zhen , Yang Dajun 
Published: May 2024

Abstract
Background
Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting.

Methods
We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release.

Results
In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models.

Conclusions
APG-1387 has the potential to turn “cold tumors” into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).

Graphic abstract
Emergence of extensive drug resistance and high prevalence of multidrug resistance among clinical Proteus mirabilis isolates in Egypt
Authors: ElTaweel Maggi , Said Heba Shehta , Barwa Rasha 
Published: May 2024

Abstract
Background
Proteus mirabilis is an opportunistic pathogen that has been held responsible for numerous nosocomial and community-acquired infections which are difficult to be controlled because of its diverse antimicrobial resistance mechanisms.

Methods
Antimicrobial susceptibility patterns of P. mirabilis isolates collected from different clinical sources in Mansoura University Hospitals, Egypt was determined. Moreover, the underlying resistance mechanisms and genetic relatedness between isolates were investigated.

Results
Antimicrobial susceptibility testing indicated elevated levels of resistance to different classes of antimicrobials among the tested P. mirabilis clinical isolates (n = 66). ERIC-PCR showed great diversity among the tested isolates. Six isolates (9.1%) were XDR while all the remaining isolates were MDR. ESBLs and AmpCs were detected in 57.6% and 21.2% of the isolates, respectively, where blaTEM, blaSHV, blaCTX−M, blaCIT−M and blaAmpC were detected. Carbapenemases and MBLs were detected in 10.6 and 9.1% of the isolates, respectively, where blaOXA−48 and blaNDM−1 genes were detected. Quinolone resistant isolates (75.8%) harbored acc(6')-Ib-cr, qnrD, qnrA, and qnrS genes. Resistance to aminoglycosides, trimethoprim-sulfamethoxazole and chloramphenicol exceeded 80%. Fosfomycin was the most active drug against the tested isolates as only 22.7% were resistant. Class I or II integrons were detected in 86.4% of the isolates. Among class I integron positive isolates, four different gene cassette arrays (dfrA17- aadA5, aadB-aadA2, aadA2-lnuF, and dfrA14-arr-3-blaOXA−10-aadA15) and two gene cassettes (dfrA7 and aadA1) were detected. While class II integron positive isolates carried four different gene cassette arrays (dfrA1-sat1-aadA1, estXVr-sat2-aadA1, lnuF- dfrA1-aadA1, and dfrA1-sat2).

Conclusion
P. Mirabilis ability to acquire resistance determinants via integrons may be held responsible for the elevated rates of antimicrobial resistance and emergence of XDR or even PDR strains limiting the available therapeutic options for management of infections caused by those strains.
Enhancing intraneural revascularization following peripheral nerve injury through hypoxic Schwann-cell-derived exosomes: an insight into endothelial glycolysis
Authors: Sun Jun , Zeng Qiuhua , Wu Zhimin , Li Zhangyu , Gao Qun , Liao Zhi , Li Hao , Ling Cong , Chen Chuan , Wang Hui , Zhang Baoyu 
Published: May 2024

Abstract
Background
Endothelial cell (EC)-driven intraneural revascularization (INRV) and Schwann cells-derived exosomes (SCs-Exos) both play crucial roles in peripheral nerve injury (PNI). However, the interplay between them remains unclear. We aimed to elucidate the effects and underlying mechanisms of SCs-Exos on INRV following PNI.

Results
We found that GW4869 inhibited INRV, as well as that normoxic SCs-Exos (N-SCs-Exos) exhibited significant pro-INRV effects in vivo and in vitro that were potentiated by hypoxic SCs-Exos (H-SCs-Exos). Upregulation of glycolysis emerged as a pivotal factor for INRV after PNI, as evidenced by the observation that 3PO administration, a glycolytic inhibitor, inhibited the INRV process in vivo and in vitro. H-SCs-Exos more significantly enhanced extracellular acidification rate/oxygen consumption rate ratio, lactate production, and glycolytic gene expression while simultaneously suppressing acetyl-CoA production and pyruvate dehydrogenase E1 subunit alpha (PDH-E1α) expression than N-SCs-Exos both in vivo and in vitro. Furthermore, we determined that H-SCs-Exos were more enriched with miR-21-5p than N-SCs-Exos. Knockdown of miR-21-5p significantly attenuated the pro-glycolysis and pro-INRV effects of H-SCs-Exos. Mechanistically, miR-21-5p orchestrated EC metabolism in favor of glycolysis by targeting von Hippel-Lindau/hypoxia-inducible factor-1α and PDH-E1α, thereby enhancing hypoxia-inducible factor-1α-mediated glycolysis and inhibiting PDH-E1α-mediated oxidative phosphorylation.

Conclusion
This study unveiled a novel intrinsic mechanism of pro-INRV after PNI, providing a promising therapeutic target for post-injury peripheral nerve regeneration and repair.

Graphical Abstract
Efficacy and safety of autologous or allogeneic mesenchymal stromal cells from adult adipose tissue expanded and combined with tricalcium phosphate biomaterial for the surgical treatment of atrophic nonunion of long bones: a phase II clinical trial
Authors: Orozco Delclós Lluís , Soler Rich Robert , Arriaza Loureda Rafael , Moreno García Alonso , Gómez Barrena Enrique 
Published: May 2024

Abstract
Background
Autologous bone grafting is the standard treatment for the surgical management of atrophic nonunion of long bones. Other solutions, such as bone marrow mesenchymal stem cells (BM-MSC) combined with phospho-calcium material, have also been used. Here we evaluate the safety and early efficacy of a novel procedure using autologous or allogenic adipose tissue mesenchymal stromal cells (AT-MSC) seeded in a patented tricalcium phosphate-based biomaterial for the treatment of bone regeneration in cases of atrophic nonunion.

Methods
This was a prospective, multicentric, open-label, phase 2 clinical trial of patients with atrophic nonunion of long bones. Biografts of autologous or allogenic AT-MSC combined with a phosphate substrate were manufactured prior to the surgical procedures. The primary efficacy was measured 6 months after surgery, but patients were followed for 12 months after surgery and a further year out of the scope of the study. All adverse events were recorded. This cohort was compared with a historical cohort of 14 cases treated by the same research team with autologous BM-MSC.

Results
A total of 12 patients with atrophic nonunion of long bones were included. The mean (SD) age was 41.2 (12.1) years and 66.7% were men. Bone healing was achieved in 10 of the 12 cases (83%) treated with the AT-MSC biografts, a percentage of healing similar (11 of the 14 cases, 79%) to that achieved in patients treated with autologous BM-MSC. Overall, two adverse events, in the same patient, were considered related to the procedure.

Conclusions
The results of this study suggest that AT-MSC biografts are safe for the treatment of bone regeneration in cases of atrophic nonunion and reach high healing rates.

Trial registration
Study registered with EUDRA-CT (2013-000930-37) and ClinicalTrials.gov (NCT02483364).
The biological function of the N6-Methyladenosine reader YTHDC2 and its role in diseases
Authors: Wu Xudong , Chen Hui , Li Kai , Zhang Hong , Li Kai , Tan Haoyu 
Published: May 2024

AbstractN6-methyladenosine (m6A) stands as the most prevalent modified form of RNA in eukaryotes, pivotal in various biological processes such as regulating RNA stability, translation, and transcription. All members within the YT521-B homology (YTH) gene family are categorized as m6A reading proteins, capable of identifying and binding m6A modifications on RNA, thereby regulating RNA metabolism and functioning across diverse physiological processes. YTH domain-containing 2 (YTHDC2), identified as the latest member of the YTH family, has only recently started to emerge for its biological function. Numerous studies have underscored the significance of YTHDC2 in human physiology, highlighting its involvement in both tumor progression and non-tumor diseases. Consequently, this review aims to further elucidate the pathological mechanisms of YTHDC2 by summarizing its functions and roles in tumors and other diseases, with a particular focus on its downstream molecular targets and signaling pathways.
The effect of audit and feedback and implementation support on guideline adherence and patient outcomes in cardiac rehabilitation: a study protocol for an open-label cluster-randomized effectiveness-implementation hybrid trial
Authors: Michelsen Halldóra Ögmundsdóttir , Lidin Matthias , Bäck Maria , Duncan Therese Scott , Ekman Björn , Hagström Emil , Hägglund Maria , Lindahl Bertil , Schlyter Mona , Leósdóttir Margrét 
Published: May 2024

Abstract
Background
Providing secondary prevention through structured and comprehensive cardiac rehabilitation programmes to patients after a myocardial infarction (MI) reduces mortality and morbidity and improves health-related quality of life. Cardiac rehabilitation has the highest recommendation in current guidelines. While treatment target attainment rates at Swedish cardiac rehabilitation centres is among the highest in Europe, there are considerable differences in service delivery and variations in patient-level outcomes between centres. In this trial, we aim to study whether centre-level guideline adherence and patient-level outcomes across Swedish cardiac rehabilitation centres can be improved through a) regular audit and feedback of cardiac rehabilitation structure and processes through a national quality registry and b) supporting cardiac rehabilitation centres in implementing guidelines on secondary prevention. Furthermore, we aim to evaluate the implementation process and costs.

Methods
The study is an open-label cluster-randomized effectiveness-implementation hybrid trial including all 78 cardiac rehabilitation centres (attending to approximately 10 000 MI patients/year) that report to the SWEDEHEART registry. The centres will be randomized 1:1:1 to three clusters: 1) reporting cardiac rehabilitation structure and process variables to SWEDEHEART every six months (audit intervention) and being offered implementation support to implement guidelines on secondary prevention (implementation support intervention); 2) audit intervention only; or 3) no intervention offered. Baseline cardiac rehabilitation structure and process variables will be collected. The primary outcome is an adherence score measuring centre-level adherence to secondary prevention guidelines. Secondary outcomes include patient-level secondary prevention risk factor goal attainment at one-year after MI and major adverse coronary outcomes for up to five-years post-MI. Implementation outcomes include barriers and facilitators to guideline adherence evaluated using semi-structured focus-group interviews and relevant questionnaires, as well as costs and cost-effectiveness assessed by a comparative health economic evaluation.

Discussion
Optimizing cardiac rehabilitation centres’ delivery of services to meet standards set in guidelines may lead to improvement in cardiovascular risk factors, including lifestyle factors, and ultimately a decrease in morbidity and mortality after MI.

Trial registration
ClinicalTrials.gov. Identifier: NCT05889416. Registered 2023-03-23.
Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases
Authors: Wilke Matheus V. M. B. , Klee Eric W. , Dhamija Radhika , Fervenza Fernando C. , Thomas Brittany , Leung Nelson , Hogan Marie C. , Hager Megan M. , Kolbert Kayla J. , Kemppainen Jennifer L. , Loftus Elle C. , Leitzen Katie M. , Vitek Carolyn R. , McAllister Tammy , Lazaridis Konstantinos N. , Pinto e Vairo Filippo 
Published: May 2024

Abstract
Background
Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics. Results: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A). Conclusion: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.
Cartoon copyright recognition method based on character personality action
Authors: Li De , Wang Lingyu , Jin Xun 
Published: May 2024

AbstractAiming at the problem of cartoon piracy and plagiarism, this paper proposes a method of cartoon copyright recognition based on character personality actions. This method can be used to compare the original cartoon actions with the action characteristics of pirated or copied cartoons to identify whether there is piracy or plagiarism. Firstly, an image preprocessing scheme for character extraction is designed. GrabCut interactive image segmentation algorithm was used to obtain cartoon characters, and then binarization and morphological processing were performed on the results. Secondly, a feature extraction scheme based on character profile, moving character and character pose is designed. By extracting the perimeter and area of the character contour, the length-to-width ratio of the smallest rectangle and the inclination angle of the contour, the character contour features are obtained. The three-dimensional coordinates are established by the central point position of the cartoon character in the two-dimensional image and the change of the character's zoom in and out, and the character's motion angle characteristics are calculated. By skeletonizing a character to obtain the pose characteristics, and using deburring operation to remove redundant branches, then extract the skeleton joint angle information. Finally, feature fusion is performed on the extracted features. The experimental results show that the proposed method breaks the limitation of the conventional single feature based recognition, and can better extract the character features including contour feature, motion feature and pose feature through multi-feature based extraction, so as to protect the cartoon copyright.
SOFA in sepsis: with or without GCS
Authors: Wang Lu , Ma Xudong , Zhou Guanghua , Gao Sifa , Pan Wei , Chen Jieqing , Su Longxiang , He Huaiwu , Long Yun , Yin Zhi , Shu Ting , Zhou Xiang ,   China National Critical Care Quality Control Centre Group (China-NCCQC), Liu Yongjun , Kang Yan , Yan Jing , Chen Erzhen , Xiong Bin , Qin Bingyu , Qian Kejian , Fang Wei , Zhao Mingyan , Ma Xiaochun , Yu Xiangyou , Lin Jiandong , Yang Yi , Shen Feng , Li Shusheng , Zhang Lina , Wu Weidong , Duan Meili , Wan Linjun , Yang Xiaojun , Liu Jian , Wang Zhen , Xu Lei , Hu Zhenjie , Yang Congshan 
Published: May 2024

Abstract
Purpose
Sepsis is a global public health burden. The sequential organ failure assessment (SOFA) is the most commonly used scoring system for diagnosing sepsis and assessing severity. Due to the widespread use of endotracheal intubation and sedative medications in sepsis, the accuracy of the Glasgow Coma Score (GCS) is the lowest in SOFA. We designed this multicenter, cross-sectional study to investigate the predictive efficiency of SOFA with or without GCS on ICU mortality in patients with sepsis.

Methods
First, 3048 patients with sepsis admitted to Peking Union Medical College Hospital (PUMCH) were enrolled in this survey. The data were collected from June 8, 2013 to October 12, 2022. Second, 18,108 patients with sepsis in the eICU database were enrolled. Third, 2397 septic patients with respiratory system ≥ 3 points in SOFA in the eICU database were included. We investigated the predictive efficiency of SOFA with or without GCS on ICU mortality in patients with sepsis in various ICUs of PUMCH, and then we validated the results in the eICU database.

Main results
In data of ICUs in PUMCH, the predictive efficiency of SOFA without GCS (AUROC [95% CI], 24 h, 0.724 [0.688, 0.760], 48 h, 0.734 [0.699, 0.769], 72 h, 0.748 [0.713, 0.783], 168 h, 0.781 [0.747, 0.815]) was higher than that of SOFA with GCS (AUROC [95% CI], 24 h, 0.708 [0.672, 0.744], 48 h, 0.721 [0.685, 0.757], 72 h, 0.735 [0.700, 0.757], 168 h, 0.770 [0.736, 0.804]) on ICU mortality in patients with sepsis, and the difference was statistically significant (P value, 24 h, 0.001, 48 h, 0.003, 72 h, 0.004, 168 h, 0.005). In septic patients with respiratory system ≥ 3 points in SOFA in the eICU database, although the difference was not statistically significant (P value, 24 h, 0.148, 48 h, 0.178, 72 h, 0.132, 168 h, 0.790), SOFA without GCS (AUROC [95% CI], 24 h, 0.601 [0.576, 0.626], 48 h, 0.625 [0.601, 0.649], 72 h, 0.639 [0.615, 0.663], 168 h, 0.653 [0.629, 0.677]) had a higher predictive efficiency on ICU mortality than SOFA with GCS (AUROC [95% CI], 24 h, 0.591 [0.566, 0.616], 48 h, 0.616 [0.592, 0.640], 72 h, 0.628 [0.604, 0.652], 168 h, 0.651 [0.627, 0.675]).

Conclusions
In severe sepsis, it is realistic and feasible to discontinue the routine GCS for SOFA in patients with a respiratory system ≥ 3 points, and even better predict ICU mortality.
Tibiofemoral articulation and axial tibial rotation of the knee after a cruciate retaining total knee arthroplasty
Authors: Li Guoan , Zhou Chaochao , Li Sophia , Yu Jia , Foster Timothy , Bedair Hany 
Published: May 2024

Abstract
Purpose
Numerous research has reported that total knee arthroplasty (TKA) cannot reproduce axial tibial rotations of normal knees. The objective of this study was to measure the tibiofemoral articular contact motions and axial tibial rotations of TKA knees to investigate the mechanism causing the knee kinematics change of after TKAs.

Methods
Eleven patients with unilateral cruciate retaining (CR) TKA were tested for measurements of knee motion during a weight-bearing flexion from 0° to 105° using an imaging technique. The tibiofemoral contact kinematics were determined using the contact points on medial and lateral surfaces of the tibia and femoral condyles. Axial tibial rotations were calculated using the differences between the medial and lateral articulation distances on the femoral condyles and tibial surfaces at each flexion interval of 15°.

Results
On femoral condyles, articular contact distances are consistently longer on the medial than on the lateral sides (p < 0.05) up to 60° of flexion, corresponding to internal tibial rotations (e.g., 1.3° ± 1.0° at 15–30° interval). On tibial surfaces, the articular contact point on the medial side moved more posteriorly than on the lateral side at low flexion angles, corresponding to external tibial rotations (e.g., −1.4° ± 1.8° at 15–30° interval); and more anteriorly than on the lateral sides at mid-range flexion, corresponding to internal tibial rotations (e.g., 0.8° ± 1.7° at 45–60° interval). At higher flexion, articular motions on both femoral condyles and tibial surfaces caused minimal changes in tibial rotations.

Conclusions
These results indicate that the axial tibial rotations of these TKA knees were mainly attributed to asymmetric articulations on the medial and lateral femoral condyles and tibial surfaces. The data can help understand the mechanisms causing axial tibial rotations of TKA knees and help improve implant designs for restoration of normal knee kinematics.
Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test
Authors: Mather Kieren J , Mari Andrea , Heise Tim , DeVries J Hans , Hua Ming , Urva Shweta , Coskun Tamer , Haupt Axel , Heine Robert J , Pratt Edward , Thomas Melissa K , Milicevic Zvonko 
Published: May 2024

Abstract

Context
In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood.

Objective
This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data.

Methods
A 28-week double–blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2–mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio.

Results
Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P &lt; .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P &lt; .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P &lt; .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P &lt; .05), showing improved β-CGS. MMTT-derived β-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P &lt; .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment.

Conclusion
These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.