bluuebunny/crossref_metadata_2025_split huggingface dataset:
GARP-mediated active TGF-β1 induces bone marrow NK cell dysfunction in AML patients with early relapse post–allo-HSCT
Authors: Wang Dongyao , Sun Zimin , Zhu Xiaoyu , Zheng Xiaohu , Zhou Yonggang , Lu Yichen , Yan Peidong , Wang Huiru , Liu Huilan , Jin Jing , Zhu Huaiping , Sun Rui , Wang Yi , Fu Binqing , Tian Zhigang , Wei Haiming 
Published: August 2022

Abstract
Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow−derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor β1 (TGF-β1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-β1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-β1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-β1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-β1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-β1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell−based immunotherapy.
A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis
Authors: Dampier Carlton D. , Telen Marilyn Jo , Wun Ted , Brown R. Clark , Desai Payal , El Rassi Fuad , Fuh Beng , Kanter Julie , Pastore Yves , Rothman Jennifer , Taylor James G. , Readett David , Sivamurthy Krupa M. , Tammara Brinda , Tseng Li-Jung , Lozier Jay Nelson , Thackray Helen , Magnani John L. , Hassell Kathryn L. 
Published: August 2022

Abstract
The efficacy and safety of rivipansel, a predominantly E-selectin antagonist, were studied in a phase 3, randomized, controlled trial for vaso-occlusive crisis (VOC) requiring hospitalization (RESET). A total of 345 subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an IV loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in the Open-label Extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary end point, was not different between rivipansel and placebo (−5.7 hours, P = .79; hazard ratio, 0.97), nor were differences seen in secondary end points of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use. Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a post hoc analysis, early rivipansel treatment within 26.4 hours of VOC pain onset (earliest quartile of time from VOC onset to treatment) reduced median TTRFD by 56.3 hours, reduced median TTD by 41.5 hours, and reduced median TTDIVO by 50.5 hours, compared with placebo (all P &lt; .05). A similar subgroup analysis comparing OLE early-treatment with early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P = .062) and in TTDIVO of 30.1 hours (P = .087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).
A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL
Authors: Zhao Lijun , Li Shuhong , Wei Xiaoyi , Qi Xuexiu , Liu Dong , Liu Lei , Wen Feiqiu , Zhang Ji-shuai , Wang Feng , Liu Ze-lin , Cao Yu J. 
Published: August 2022

Abstract
The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell−specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell−redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.
The diagnostic challenge of a tuberculous cold abscess of the epididymis: a case report
Authors: Undie Celsus Ukelina , Jibrin Paul , Nnana Ewomazino Ibanga , Torporo Kalenebari Raymond 
Published: August 2022

Abstract
Background
While genitourinary tuberculosis is a common form of extra-pulmonary tuberculosis, cold abscess of the epididymis is rare with our literature search finding no reports from the West African subregion. Where the index of suspicion is low, diagnosis is missed and unnecessary surgery may be performed on suspicion of a tumour. The aim of this case report is to highlight the diagnostic challenges of this condition in resource-limited settings in order to create awareness within the health community, increase the chance of appropriate diagnosis, thereby facilitating early commencement of treatment so as to avoid needless testicular loss or complications, such as infertility.

Case presentation
A 33-year-old Black African College-educated public service employee resident in Abuja, Nigeria, presented with a one-week history of right scrotal pain and swelling. Genital examination revealed a firm, non-tender epididymal mass which was initially mistaken for a malignancy. There were no constitutional symptoms, and the contralateral testis was normal. The swelling involved only the epididymis. The testis was distinctly palpable but not oedematous. There was some hemi-scrotal oedema. Blood count and urine cultures were normal. Ultrasound scan showed a hypoechogenic, uniformly enlarged epididymis. Testicular tumour markers were negative. However, CT-abdomen showed enlarged para-caval and pelvic nodes which were thought to be due to secondary deposits from a testicular tumour. Scrotal swelling was later found to be due to an abscess of the epididymis at surgery. Histology showed caseous granulomas typical of Mycobacterium tuberculosis. Gene-Xpert, a cartridge-based nucleic acid amplification test, later confirmed that patient had tuberculosis, for which he is being treated.

Conclusion
The differential diagnosis of an epididymal cold abscess from testicular tumour or chronic epididymitis can be challenging. Therefore, a high index of suspicion as well as a complete tuberculosis screen is essential in an apparently healthy patient presenting with a chronic epididymal swelling.
PhUGT78A22, a novel glycosyltransferase in Paeonia ‘He Xie’, can catalyze the transfer of glucose to glucosylated anthocyanins during petal blotch formation
Authors: Li Yang , Kong Fan , Liu Zheng’an , Peng Liping , Shu Qingyan 
Published: August 2022

Abstract
Background
Flower color patterns play an important role in the evolution and subsequent diversification of flowers by attracting animal pollinators. This interaction can drive the diversity observed in angiosperms today in many plant families such as Liliaceae, Paeoniaceae, and Orchidaceae, and increased their ornamental values. However, the molecular mechanism underlying the differential distribution of anthocyanins within petals remains unclear in Paeonia.

Results
In this study, we used an intersectional hybrid between the section Moutan and Paeonia, hereafter named Paeonia ‘He Xie’, which has purple flowers with dark purple blotches. After Ultra-high performance liquid chromatography-diode array detector (UPLC-DAD) analysis of blotched and non-blotched parts of petals, we found the anthocyanin content in the blotched part was always higher than that in the non-blotched part. Four kinds of anthocyanins, namely cyanidin-3-O-glucoside (Cy3G), cyanidin-3,5-O-glucoside (Cy3G5G), peonidin-3-O-glucoside (Pn3G), and peonidin-3,5-O-glucoside (Pn3G5G) were detected in the blotched parts, while only Cy3G5G and Pn3G5G were detected in the non-blotched parts. This suggests that glucosyltransferases may play a vital role in the four kinds of glucosylated anthocyanins in the blotched parts. Moreover, 2433 differentially expressed genes (DEGs) were obtained from transcriptome analysis of blotched and non-blotched parts, and a key UDP-glycosyltransferase named PhUGT78A22 was identified, which could use Cy3G and Pn3G as substrates to produce Cy3G5G and Pn3G5G, respectively, in vitro. Furthermore, silencing of PhUGT78A22 reduced the content of anthocyanidin 3,5-O-diglucoside in P. ‘He Xie’.

Conclusions
A UDP-glycosyltransferase, PhUGT78A22, was identified in P. ‘He Xie’, and the molecular mechanism underlying differential distribution of anthocyanins within petals was elucidated. This study provides new insights on the biosynthesis of different kinds of anthocyanins within colorful petals, and helps to explain petal blotch formation, which will facilitate the cultivar breeding with respect to increasing ornamental value. Additionally, it provides a reference for understanding the molecular mechanisms responsible for precise regulation of anthocyanin biosynthesis and distribution patterns.
Fetal echocardiographic parameters in pregnancies complicated by diabetes: a case control study
Authors: Darwish Amal , Abdel-Raouf Maged , Kamel Rasha , Salah Emad , Salah Mai , Okasha Ahmed 
Published: August 2022

Abstract

Background
At present, the prevalence of pregestational diabetes is 2.2% with an overall prevalence of hyperglycaemia in pregnancy of about 16.2%. Fetuses of diabetic mothers are at risk of functional cardiac abnormalities without structural cardiac anomalies especially in the third trimester. The main aim of this study was to assess the association of diabetes with different fetal echocardiographic parameters.

Methods
A case control study comprising a total of 120 pregnant women (60 cases and 60 controls). The cases group included fetuses of mothers known to have pre-gestational type 2 diabetes (DM group) while the control group included fetuses of euglycaemic healthy pregnant women. They were examined twice at 23–24 weeks' gestation (visit 1) and followed up at 27–28 weeks’ gestation (visit 2). The Modified Myocardial Performance Index (Mod MPI) was obtained in all fetuses. Also, M-mode echocardiography was used to measure the interventricular septum thickness at diastole in a transverse four chamber view.

Results
There was a significant increase in Iso-volumetric contraction time (ICT) (45.4 ms ± 8.9), Iso-volumetric relaxation time (IRT) (54.7 ms ± 11.22), Interventricular septal thickness (IVST) (4.08 mm ± 0.8), aortic acceleration time (AAT) (54.16 ms ± 12.77) and MPI (0.64 ± 0.09) in the diabetic group compared to the normal control group ICT (38.5 ms ± 9.59), IRT (46.13 ms ± 10.29), IVST (3.17 mm ± 0.6), AAT (49.73 ms ± 10.68) and MPI (0.5 ± 0.1) (all P values were < 0.001).
When comparing parameters assessed at both visits among diabetic patients, there was a significant increase in IVST in the second visit (4.74 ± 0.78 mm) compared to the first visit (4.08 ± 0.8 mm) (P value < 0.05).
The incidence of hypertrophic cardiomyopathy (HCM) was significantly higher in diabetic patients than in the control group. This is was observed in both first and second visit (33.4% and 56.7%) (P value < 0.001).

Conclusions
Fetuses of diabetic pregnant females show a significant increase in MPI, decrease in E\A ratio and HCM. These alterations in cardiac functions and structure were found to be continuous throughout the period of time between the two visits.
Longitudinal comparison of direct medical cost, radiological and health-related quality of life treatment outcomes between traditional growing rods and magnetically controlled growing rods from preoperative to maturity
Authors: Cheung Prudence Wing Hang , Wong Carlos King Ho , Sadiang-abay Jewel T. , Lau Sin Ting , Cheung Jason Pui Yin 
Published: August 2022

Abstract
Background
Magnetically controlled growing rods (MCGR) have replaced traditional growing rods (TGR) in the past decade, however, a comparison of their direct costs and treatment outcomes based on real longitudinal data is lacking. This study aims to compare the direct cost and treatment outcomes between TGR and MCGR, whilst incorporating complications, reoperations and changes in health-related quality of life (HRQoL) throughout the entire treatment course.

Methods
Patients with early onset scoliosis (EOS) who underwent initial growing rod surgery between 2003 and 2016 at a tertiary scoliosis clinic were studied with longitudinal data. Accumulated direct medical costs were calculated based on the unit cost of surgeries of each TGR and MCGR, costs incurred for any rod exchange or remedial surgery for post-operative complication. Treatment outcomes were evaluated via: Patient’s HRQoL using SRS-22r questionnaire, and radiological parameters (including major curve correction, spine length gains, spinal balance) throughout the treatment until maturity.

Results
A total of 27 EOS patients (16 MCGR, 11 TGR) were studied. Total direct cost of index surgery for MCGR was HKD$223,108 versus lower cost of HKD$135,184 for TGR (p < 0.001). At 2–3 years post-index surgery, accumulative total direct medical cost of MCGR and TGR became most comparable (TGR:MCGR ratio = 1.010) and had reached neutrality between the two groups since. Radiological parameters had no intergroup differences at maturity. For HRQoL, TGR group had shown the trend of less pain (domain score mean difference: 0.53, p = 0.024) post-index surgery and better self-appearance (domain score mean difference: 1.08, p = 0.017) before fusion. Higher satisfaction with treatment (domain score mean difference: 0.76, p = 0.029) was demonstrated by TGR patients at fusion/maturity. MCGR had negative (rs = -0.693) versus TGR’s positive (rs = 0.989) correlations (p < 0.05) of cost and SRS-22r total scores at 2–3 years post-index surgery.

Conclusions
From index surgery to maturity, TGR demonstrated better satisfaction with treatment by patients and comparable overall HRQoL with MCGR during the treatment course, as MCGR did not show apparent benefit despite less surgeries and cost neutrality between the two groups at 2–3 years post-index surgery.
Caregiver satisfaction and its associated factors in pediatric wards of Jimma University Medical Center, Southwest Ethiopia
Authors: Beshir Mohammed , Tilahun Tsion , Hordofa Diriba Fufa , Abera Gersam , Tesfaye Workineh , Daba Kumale Tolesa , Workineh Netsanet , Woldeyesus Samson Nadew , Debela Tilahun Fufa , Yesuf Elias Ali 
Published: August 2022

Abstract
Background
Measuring the caregivers' satisfaction is vital for the effectiveness of childcare. Children admitted to pediatric wards require special hospital situations, a bespoke approach from the medical team, and the participation of caregivers. It is important to give attention to the caregivers while planning for child services. The purpose of this study was to assess the caregiver’s satisfaction with the services provided in pediatric wards of Jimma University Medical Center and identify its associated factors.

Methods
Facility-based cross-sectional study design was done at Jimma University Medical Center. Participants in the study were primary caregivers who spent two or more days in the pediatric ward with their admitted children. Data were collected from 400 selected caregivers. A consecutive sampling method was employed. Principal component analysis was done for all Likert scale instruments to extract factor (s) representing each of the scales and to have factor scores. Variables with the Likert scale were treated as continuous after principal component analysis was employed. Using these factor scores, a multiple linear regression analysis was carried out to identify factors associated with caregivers' satisfaction with service in pediatric wards. A significance level of less than 0.05 was used in the final model to determine statistical significance.

Result
This study showed that caregivers' satisfaction with the services in the pediatric ward was 68%. Level of education (β = -0.24, (95% CI; -.411, -.070)), availability of basic facilities (β = 0.163, (95% CI; .063, .263)), patience to listen to patients' problem (β = 0.431, (95% CI; .324, .537, staff communication with client (β = 0.163, (95% CI; -4.839, -1.610)), availability of laboratory tests and its service (β = -0.964, (95% CI; -1.435, -.493)), availability of drug, imaging and service at radiology (β = 2.907, (95% CI; 1.470, 4.344)) and availability of pathology and its service (β = 1.869, (95% CI; .993, 2.746)) were significant factors associated with caregivers satisfaction with health service in pediatrics ward.

Conclusion
Caregivers were moderately satisfied. Education level, availability of basic facilities communication with client, and the availability of laboratory tests and drugs were factors that significantly associated with caregiver satisfaction. Hospital should avail laboratory tests and drugs in order to maintain high levels of caregiver satisfaction.
Changes in health-related quality of life in adolescents and the impact of gender and selected variables: a two-year longitudinal study
Authors: Mikkelsen Hilde Timenes , Småstuen Milada Cvancarova , Haraldstad Kristin , Helseth Sølvi , Skarstein Siv , Rohde Gudrun 
Published: August 2022

Abstract
Background
Increased knowledge about factors that can impact changes in adolescents’ health-related quality of life (HRQOL) is needed. The present study aimed to investigate possible HRQOL changes in adolescents at 14 and 16 years, and assess the impact of sociodemographic factors, gender, pain, self-esteem, self-efficacy, loneliness, and stress on HRQOL changes over time. Further, to assess HRQOL stratified by gender.

Methods
A longitudinal study involving 211 adolescents was conducted. Sociodemographic variables, pain, self-esteem, self-efficacy, loneliness, and stress were all assessed with well-validated instruments. KIDSCREEN-27 was used to measure HRQOL. Data were analyzed using independent t-tests, paired samples t-tests, and linear mixed models for repeated measures.

Results
When all variables were added to the linear mixed models, stress, loneliness, and pain were significantly, independently associated with a reduction in HRQOL change scores for four of the five KIDSCREEN subscales. Time was significantly associated with a reduction in physical and psychological well-being. Self-efficacy and self-esteem were significantly associated with an increase in HRQOL change scores for four and two subscales, respectively. Male gender was significantly negatively associated with changes in social support and peers compared to female gender.

Conclusion
Our results demonstrated a significant decline in adolescents’ HRQOL regarding physical and psychological well-being for the age range 14–16 years. Furthermore, we found that stress, loneliness, and pain have a significant negative impact on HRQOL changes, whereas self-esteem and self-efficacy have a significant positive impact. Our results highlight the importance of increased understanding regarding factors associated with changes in adolescents’ HRQOL to enable accurate and strategic interventions.
Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial
Authors: Jiang Qian , Li Zongru , Qin Yazhen , Li Weiming , Xu Na , Liu Bingcheng , Zhang Yanli , Meng Li , Zhu Huanling , Du Xin , Chen Suning , Liang Yang , Hu Yu , Liu Xiaoli , Song Yongping , Men Lichuang , Chen Zi , Niu Qian , Wang Hengbang , Lu Ming , Yang Dajun , Zhai Yifan , Huang Xiaojun 
Published: August 2022

Abstract
Background
BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP).

Methods
In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses.

Results
A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia.

Conclusions
Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation.
Trial registration: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).