bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model
Authors: Ng Brandon D. , Rajagopalan Adhithi , Kousa Anastasia I. , Fischman Jacob S. , Chen Sophia , Massa Alyssa , Elias Harold K. , Manuele Dylan , Galiano Michael , Lemarquis Andri L. , Boardman Alexander P. , DeWolf Susan , Pierce Jonah , Bogen Bjarne , James Scott E. , van den Brink Marcel R. M. 
Published: April 2024

Abstract
Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
Advancing colorectal cancer therapy with biosynthesized cobalt oxide nanoparticles: a study on their antioxidant, antibacterial, and anticancer efficacy
Authors: Momen Eslamiehei Fateme , Mashreghi Mansour , Matin Maryam M. 
Published: April 2024

Abstract
Background
Colorectal cancer (CRC) ranks as the third most common cancer globally and the second leading cause of cancer-related mortality. Traditional chemotherapy, while effective, often results in significant side effects, highlighting the need for more efficient cancer therapies. Recent advancements in nanotechnology have led to the development of strategies that aim to minimize toxicity to normal cells by more precise targeting of cancer cells. In this context, cobalt oxide nanoparticles (Co3O4 NPs) have shown promising anticancer potential. Our study focuses on evaluating the antioxidant, antibacterial, and anticancer properties of Co3O4 NPs synthesized using Vibrio sp. VLC, a bioluminescent bacterium.

Results
XRD and FTIR analyses confirmed the successful synthesis of Co3O4 NPs, which displayed spherical morphology with an average diameter of 60 nm. The nanoparticles demonstrated significant antioxidant and antibacterial activities. The MTT assay indicated that the NPs caused dose- and time-dependent toxicity against CT26 cells, while exhibiting relatively lower toxicity towards normal cells. In vivo experiments further confirmed the significant tumor suppressive effects in BALB/c mice, with minimal side effects on the liver, spleen, and kidney tissues compared to the widespread toxicity of cisplatin.

Conclusion
This study verifies the successful synthesis of Co3O4 NPs and their potent antioxidant, antibacterial, and anticancer activities. The biosynthesized Co3O4 NPs represent a promising targeted method for CRC therapy. However, further research is needed to elucidate their mechanism of action and also their application in the clinical phase.

Graphical Abstract
DPI_CDF: druggable protein identifier using cascade deep forest
Authors: Arif Muhammad , Fang Ge , Ghulam Ali , Musleh Saleh , Alam Tanvir 
Published: April 2024

Abstract
Background
Drug targets in living beings perform pivotal roles in the discovery of potential drugs. Conventional wet-lab characterization of drug targets is although accurate but generally expensive, slow, and resource intensive. Therefore, computational methods are highly desirable as an alternative to expedite the large-scale identification of druggable proteins (DPs); however, the existing in silico predictor’s performance is still not satisfactory.

Methods
In this study, we developed a novel deep learning-based model DPI_CDF for predicting DPs based on protein sequence only. DPI_CDF utilizes evolutionary-based (i.e., histograms of oriented gradients for position-specific scoring matrix), physiochemical-based (i.e., component protein sequence representation), and compositional-based (i.e., normalized qualitative characteristic) properties of protein sequence to generate features. Then a hierarchical deep forest model fuses these three encoding schemes to build the proposed model DPI_CDF.

Results
The empirical outcomes on 10-fold cross-validation demonstrate that the proposed model achieved 99.13 % accuracy and 0.982 of Matthew’s-correlation-coefficient (MCC) on the training dataset. The generalization power of the trained model is further examined on an independent dataset and achieved 95.01% of maximum accuracy and 0.900 MCC. When compared to current state-of-the-art methods, DPI_CDF improves in terms of accuracy by 4.27% and 4.31% on training and testing datasets, respectively. We believe, DPI_CDF will support the research community to identify druggable proteins and escalate the drug discovery process.

Availability
The benchmark datasets and source codes are available in GitHub: http://github.com/Muhammad-Arif-NUST/DPI_CDF.
Maize ZmLAZ1-3 gene negatively regulates drought tolerance in transgenic Arabidopsis
Authors: Yu Haoqiang , Liu Bingliang , Yang Qinyu , Yang Qingqing , Li Wanchen , Fu Fengling 
Published: April 2024

Abstract
Background
Molecular mechanisms in response to drought stress are important for the genetic improvement of maize. In our previous study, nine ZmLAZ1 members were identified in the maize genome, but the function of ZmLAZ1 was largely unknown.

Results
The ZmLAZ1-3 gene was cloned from B73, and its drought-tolerant function was elucidated by expression analysis in transgenic Arabidopsis. The expression of ZmLAZ1-3 was upregulated by drought stress in different maize inbred lines. The driving activity of the ZmLAZ1-3 promoter was induced by drought stress and related to the abiotic stress-responsive elements such as MYB, MBS, and MYC. The results of subcellular localization indicated that the ZmLAZ1-3 protein localized on the plasma membrane and chloroplast. The ectopic expression of the ZmLAZ1-3 gene in Arabidopsis significantly reduced germination ratio and root length, decreased biomass, and relative water content, but increased relative electrical conductivity and malondialdehyde content under drought stress. Moreover, transcriptomics analysis showed that the differentially expressed genes between the transgenic lines and wild-type were mainly associated with response to abiotic stress and biotic stimulus, and related to pathways of hormone signal transduction, phenylpropanoid biosynthesis, mitogen-activated protein kinase signaling, and plant-pathogen interaction.

Conclusion
The study suggests that the ZmLAZ1-3 gene is a negative regulator in regulating drought tolerance and can be used to improve maize drought tolerance via its silencing or knockout.
Exogenous ascorbic acid as a potent regulator of antioxidants, osmo-protectants, and lipid peroxidation in pea under salt stress
Authors: Kanwal Rehana , Maqsood Muhammad Faisal , Shahbaz Muhammad , Naz Nargis , Zulfiqar Usman , Ali Muhammad Fraz , Jamil Muhammad , Khalid Faizan , Ali Qasim , Sabir Muhammad Azeem , Chaudhary Talha , Ali Hayssam M. , Alsakkaf Waleed A. A. 
Published: April 2024

AbstractPea (Pisum sativum L.), a globally cultivated leguminous crop valued for its nutritional and economic significance, faces a critical challenge of soil salinity, which significantly hampers crop growth and production worldwide. A pot experiment was carried out in the Botanical Garden, The Islamia University of Bahawalpur to alleviate the negative impacts of sodium chloride (NaCl) on pea through foliar application of ascorbic acid (AsA). Two pea varieties Meteor (V1) and Sarsabz (V2) were tested against salinity, i.e. 0 mM NaCl (Control) and 100 mM NaCl. Three levels of ascorbic acid 0 (Control), 5 and 10 mM were applied through foliar spray. The experimental design was completely randomized (CRD) with three replicates. Salt stress resulted in the suppression of growth, photosynthetic activity, and yield attributes in pea plants. However, the application of AsA treatments effectively alleviated these inhibitory effects. Under stress conditions, the application of AsA treatment led to a substantial increase in chlorophyll a (41.1%), chl. b (56.1%), total chl. contents (44.6%) and carotenoids (58.4%). Under salt stress, there was an increase in Na+ accumulation, lipid peroxidation, and the generation of reactive oxygen species (ROS). However, the application of AsA increased the contents of proline (26.9%), endogenous AsA (23.1%), total soluble sugars (17.1%), total phenolics (29.7%), and enzymatic antioxidants i.e. SOD (22.3%), POD (34.1%) and CAT (39%) in both varieties under stress. Salinity reduced the yield attributes while foliarly applied AsA increased the pod length (38.7%), number of pods per plant (40%) and 100 seed weight (45.2%). To sum up, the application of AsA alleviated salt-induced damage in pea plants by enhancing photosynthetic pigments, both enzymatic and non-enzymatic activities, maintaining ion homeostasis, and reducing excessive ROS accumulation through the limitation of lipid peroxidation. Overall, V2 (Sarsabz) performed better as compared to the V1 (Meteor).
Heart surgery over two decades: what we have learned about results and changing risks
Authors: Tajdini Masih , Behnoush Amir Hossein , Pashang Mina , Jameie Mana , Khalaji Amirmohammad , Sadeghian Saeed , Vasheghani-Farahani Ali , Poorhosseini Hamidreza , Masoudkabir Farzad , Hosseini Kaveh , Davoodi Saeed , Sahebjam Mohammad , Barkhordari Khosro , Ashraf Haleh , Shafiei Akbar , Karimi Abbasali ,   T. H. C. Surgery Databank Collaborators, Ahmadi Tafti Seyed Hossein , Mansourian Soheil , Shirzad Mahmood , Bagheri Jamshid , Jalali Arash , Abbasi Kiomars , Zoroufian Arezou , Hosseinsabet Ali , Davarpasand Tahereh , Mohseni-Badalabadi Reza , Hali Reza , Mehrabanian Mohammadjavad , Dehghani Firoozabadi Mehdi , Nooralishahi Behrang , Mortazavi Seyedeh Hamideh , Lotfi-Tokaldany Masoumeh , Rostami Elham , Karimi Mahdieh 
Published: April 2024

Abstract
Objectives
Using the cardiac surgery database is of high importance in referral centers and can lead to a better quality of care for patients. Tehran Heart Center (THC) is a cardiovascular referral center that was inaugurated in 2001. In this report, we aimed to present the third report of trends in patients' cardiovascular risk factors and surgical procedures from 2002 to 2021 that have been gathered for all THC patients.

Methods
This serial cross-sectional study was conducted at Tehran Heart Center from 2002 to 2021. All patients undergoing cardiac surgeries were eligible to enter the study (N = 63,974). Those with miscellaneous types of surgeries were excluded (N = 9556). The distribution of cardiac surgeries (including isolated coronary artery bypass graft (CABG), isolated valve, and CABG + valve surgeries) and their respective in-hospital mortality were recorded. Furthermore, 20-year trends in the prevalence of various cardiovascular risk factors (CVRFs) among the following groups were evaluated: a) isolated CABG, b) aortic valve replacement/repair for aortic stenosis (AS/AVR/r), and c) isolated other valve surgeries (IVS).

Results
A total of 54,418 patients (male: 70.7%, age: 62.7 ± 10.8 years) comprised the final study population, with 84.5% prevalence of isolated CABG. Overall, the AS/AVR/r group was in between the CABG and IVS groups concerning CVRFs distribution. Excluding some exceptions for the AS/AVR/r group (in which the small sample size (N = 909) precluded observing a clear trend), all studied CVRFs demonstrated an overall rising trend from 2002 to 2021 in all three groups. Regarding in-hospital mortality, the highest rate was recorded as 4.0% in 2020, while the lowest rate was 2.0% in 2001.

Conclusions
Isolated CABG remained the most frequent procedure in THC. Notable, increasing trends in CVRFs were observed during this 20-year period and across various types of cardiac surgeries, which highlights the clinical and policy-making implications of our findings.

Graphical Abstract
HAPLN1 knockdown inhibits heart failure development via activating the PKA signaling pathway
Authors: Yan Tao , Song Shushuai , Sun Wendong , Ge Yiping 
Published: April 2024

Abstract
Background
Heart failure (HF) is a heterogeneous syndrome that affects millions worldwide, resulting in substantial health and economic burdens. However, the molecular mechanism of HF pathogenesis remains unclear.

Methods
HF-related key genes were screened by a bioinformatics approach.The impacts of HAPLN1 knockdown on Angiotensin II (Ang II)-induced AC16 cells were assessed through a series of cell function experiments. Enzyme-linked immunosorbent assay (ELISA) was used to measure levels of oxidative stress and apoptosis-related factors. The HF rat model was induced by subcutaneous injection isoprenaline and histopathologic changes in the cardiac tissue were assessed by hematoxylin and eosin (HE) staining and echocardiographic index. Downstream pathways regulated by HAPLN1 was predicted through bioinformatics and then confirmed in vivo and in vitro by western blot.

Results
Six hub genes were screened, of which HAPLN1, FMOD, NPPB, NPPA, and COMP were overexpressed, whereas NPPC was downregulated in HF. Further research found that silencing HAPLN1 promoted cell viability and reduced apoptosis in Ang II-induced AC16 cells. HAPLN1 knockdown promoted left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS), while decreasing left ventricular end-systolic volume (LVESV) in the HF rat model. HAPLN1 knockdown promoted the levels of GSH and suppressed the levels of MDA, LDH, TNF-α, and IL-6. Mechanistically, silencing HAPLN1 activated the PKA pathway, which were confirmed both in vivo and in vitro.

Conclusion
HAPLN1 knockdown inhibited the progression of HF by activating the PKA pathway, which may provide novel perspectives on the management of HF.
Barriers and facilitators of the reporting by family doctors of cases of domestic violence – a qualitative study across Portugal
Authors: Moreira Diana Nadine , Pinto da Costa Mariana 
Published: April 2024

Abstract
Background
Domestic violence (DV) is a serious and prevalent public health problem with devastating consequences for the victims and their families. Whilst the number of cases reported to the authorities has risen in recent years, many victims still chose not to present a complaint. In Portugal, to address this, DV became a public crime. As victims of DV present multiple health problems and frequently seek professional help, family doctors are in a privileged position to detect and report cases of DV to the authorities. However, little is known about what motivates these professionals to report or not the DV cases they encounter in their practice to the authorities.

Methods
We conducted semi-structured interviews with family doctors from all regional health administrations of continental Portugal. Interviews occurred between July 2020 and September 2022, were conducted in person or remotely, audio recorded, transcribed, and analysed using thematic analysis. Content analysis was conducted to assess the agreement or disagreement regarding mandatory reporting in each of the themes and subthemes.

Results
Fifty-four family doctors took part in this study (n = 39 women, n = 15 men). The main themes that arose from the analysis were: “Barriers related to the physician’s activity,” “Barriers related to the victim or aggressor,” “Facilitators related to the physician’s activity,” “Facilitators related to the victim or aggressor.” Although different barriers were described, most doctors agreed with the mandatory reporting of DV cases.

Conclusions
Family doctors encounter multiple barriers and facilitators when considering reporting a DV case to the authorities. The results of this study can help develop new interventions to address the barriers described by the doctors, increasing their compliance with mandatory reporting, the protection of victims and the just persecution of the aggressor.
Trajectories of depressive symptom and its association with air pollution: evidence from the Mr. OS and Ms. OS Hong Kong cohort study
Authors: Zhao Yinan , Liu Qingcai , Chen Yifei , Kwok Timothy C. Y. , Leung Jason C. S. , Feng Hui , Wong Samuel Yeung Shan 
Published: April 2024

Abstract
Background
Depression is a global health priority. Maintaining and delaying depressive symptoms in older adults is a key to healthy aging. This study aimed to identify depressive symptom trajectories, predictors and mortality, while also exploring the relationship between air quality and depressive symptoms in older adults in the Hong Kong community over 14 years.

Methods
This study is a longitudinal study in Hong Kong. The target population was community-dwelling older adults over age 65. Depressive symptoms were measured by the Geriatric Depression Scale (GDS-15). Group-based trajectory model was used to identify heterogeneity in longitudinal changes over 14 years and examine the associations between baseline variables and trajectories for different cohort members using multinomial logistic regression. The Kaplan–Meier method was employed to conduct survival analysis and explore the variations in survival probabilities over time among different trajectory group. Linear mixed model was used to explore the relationship between air quality and depressive symptoms.

Results
A total of 2828 older adults were included. Three different trajectories of depressive symptoms in older people were identified: relatively stable (15.4%), late increase (67.1%) and increase (17.5%). Female, more number of chronic diseases, poor cognitive function, and poor health-related quality of life (HRQOL) were significantly associated with other less favorable trajectories compared with participants with stable levels of depressive symptoms. The late increase group had a lower mortality rate than the relatively stable and increased groups. Lower baseline ambient air pollutant exposure to NO2 over 14 years was significantly associated with fewer depressive symptoms.

Conclusions
In this study, we found that a late increase in depressive symptoms was the predominant trend in older Chinese people in Hong Kong. Poorer HRQOL was predictive of less favorable trajectories of depressive symptoms. Ambient air pollution was associated with depressive symptoms. This novel observation strengthens the epidemiological evidence of longitudinal changes in depressive symptoms and associations with late-life exposure to air pollution.
Comparative safety of tramadol and other opioids following total hip and knee arthroplasty
Authors: Bosco Elliott , Riester Melissa R. , Beaudoin Francesca L. , Schoenfeld Andrew J. , Gravenstein Stefan , Mor Vincent , Zullo Andrew R. 
Published: April 2024

Abstract
Background
Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA.

Methods
This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models.

Results
The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons.

Conclusions
Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.
Fabry disease in W162C mutation: a case report of two patients and a review of literature
Authors: Furia Alessandro , Ditaranto Raffaello , Biagini Elena , Parisi Vanda , Incensi Alex , Parisini Sara , Liguori Rocco , Donadio Vincenzo 
Published: April 2024

Abstract
Background
Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement.

Case presentation
The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases.

Conclusions
Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.