bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas
Authors: Charalambous Antonia , Mpekris Fotios , Panagi Myrofora , Voutouri Chrysovalantis , Michael Christina , Gabizon Alberto A. , Stylianopoulos Triantafyllos 
Published: June 2024

Abstract
Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate–doxorubicin (PLAD) plus anti–programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti–programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.
A Phone in a Basket Looks Like a Knife in a Cup: Role-Filler Independence in Visual Processing
Authors: Hafri Alon , Bonner Michael F. , Landau Barbara , Firestone Chaz 
Published: June 2024

Abstract
When a piece of fruit is in a bowl, and the bowl is on a table, we appreciate not only the individual objects and their features, but also the relations containment and support, which abstract away from the particular objects involved. Independent representation of roles (e.g., containers vs. supporters) and “fillers” of those roles (e.g., bowls vs. cups, tables vs. chairs) is a core principle of language and higher-level reasoning. But does such role-filler independence also arise in automatic visual processing? Here, we show that it does, by exploring a surprising error that such independence can produce. In four experiments, participants saw a stream of images containing different objects arranged in force-dynamic relations—e.g., a phone contained in a basket, a marker resting on a garbage can, or a knife sitting in a cup. Participants had to respond to a single target image (e.g., a phone in a basket) within a stream of distractors presented under time constraints. Surprisingly, even though participants completed this task quickly and accurately, they false-alarmed more often to images matching the target’s relational category than to those that did not—even when those images involved completely different objects. In other words, participants searching for a phone in a basket were more likely to mistakenly respond to a knife in a cup than to a marker on a garbage can. Follow-up experiments ruled out strategic responses and also controlled for various confounding image features. We suggest that visual processing represents relations abstractly, in ways that separate roles from fillers.
Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses
Authors: von Jan Jana , Timonen Sanna , Braun Till , Jiang Qu , Ianevski Aleksandr , Peng Yayi , McConnell Kathleen , Sindaco Paola , Müller Tony Andreas , Pützer Sabine , Klepzig Hanna , Jungherz Dennis , Dechow Annika , Wahnschaffe Linus , Giri Anil K. , Kankainen Matti , Kuusanmäki Heikki , Neubauer Heidi A. , Moriggl Richard , Mazzeo Paolo , Schmidt Nicole , Koch Raphael , Hallek Michael , Chebel Amel , Armisen David , Genestier Laurent , Bachy Emmanuel , Mishra Anjali , Schrader Alexandra , Aittokallio Tero , Mustjoki Satu , Herling Marco 
Published: June 2024

Abstract
T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL’s pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK/STAT signaling. To further develop related preclinical therapeutic concepts, we studied inhibitors of histone deacetylases ([H]DACs), B-cell lymphoma 2 (BCL2), cyclin-dependent kinase (CDK), mouse double minute 2 (MDM2), and classical cytostatics, using (1) single-agent and combinatorial compound testing in 20 well-characterized and molecularly profiled primary T-PLL (validated by additional 42 cases) and (2) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single agents and combinations (in vitro and in mice) included cladribine, romidepsin ([H]DAC), venetoclax (BCL2), and/or idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance toward MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activation and downstream signals (including enhanced accessibility of target-gene chromatin regions), in particular synergy with insults by cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.
Immune modulation permits tolerance and engraftment in a murine model of late-gestation transplantation
Authors: Riley John S. , Berkowitz Cara L. , Luks Valerie L. , Dave Apeksha , Cyril-Olutayo Mojisola C. , Pogoriler Jennifer , Flake Alan W. , Abdulmalik Osheiza , Peranteau William H 
Published: June 2024

Abstract
In utero hematopoietic cell transplantation is an experimental nonmyeloablative therapy with potential applications in hematologic disorders, including sickle cell disease (SCD). Its clinical utility has been limited due to the early acquisition of T-cell immunity beginning at ∼14 weeks gestation, posing significant technical challenges and excluding treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days postcoitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable with that of the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T-cell depletion followed by central tolerance induction confirmed by donor–specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrated the successful application of this approach in the Townes mouse model of SCD. These findings confirm the developing fetal T-cell response as a barrier to LGT and support transient T-cell depletion as a safe and effective immunomodulatory strategy to overcome it.
Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML
Authors: Bewersdorf Jan Philipp , Shimony Shai , Shallis Rory M. , Liu Yiwen , Berton Guillaume , Schaefer Eva J. , Zeidan Amer M. , Goldberg Aaron D. , Stein Eytan M. , Marcucci Guido , Bystrom Rebecca P. , Lindsley R. Coleman , Chen Evan C. , Ramos Perez Jorge , Stein Anthony , Pullarkat Vinod , Aldoss Ibrahim , DeAngelo Daniel J. , Neuberg Donna S. , Stone Richard M. , Garciaz Sylvain , Ball Brian , Stahl Maximilian 
Published: June 2024

Abstract
Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).
Physical activity dynamically moderates the impact of multimorbidity on the trajectory of healthy aging over sixteen years
Authors: Ojijieme Nnaelue Godfrey , Feng Tieying , Chui Chin Man , Qi Xinzhu , Liu Yuan 
Published: June 2024

Abstract
Background
Research examining the healthy aging trajectory of retired older adults with multimorbidity is limited, leaving uncertainties regarding the optimal physical activity (PA) intensity and frequency necessary to sustain healthy aging during retirement.

Methods
Our study investigated the moderating effects of PA on the healthy aging trajectories of retired older adults living with multimorbidity in the United States (US). We utilized data from 1,238 retired individuals aged 50 to 102 who contributed 11,142 observations over 16 years from the Health and Retirement Study (HRS). We employed mixed effects modeling to assess the impact of various classes of multimorbidity on this group and examine how different PA, PA intensities, and PA frequencies influence the disability, physical, and cognitive functioning domains of healthy aging.

Results
The results reveal that while outcomes differed significantly, retired older adults in the US attained healthy aging at baseline. However, their ability to maintain healthy aging declined over time, with multimorbidity, especially musculoskeletal and neurological conditions, accelerating this decline. Fortunately, PA, especially light to moderate intensities, is associated with improving healthy aging and moderating the impact of multimorbidity on the disability and cognitive functioning domains of healthy aging. However, the specific moderating effects of PA depend on its frequency, intensity, and chronic conditions.

Conclusions
The significant variability in healthy aging attainment among retired older adults underlies the need to consider these differences when addressing healthy aging issues in the US. Accounting for these variations would aid in evaluating the potential impact of future interventions and contribute to achieving health equity. Fortunately, our dynamic findings facilitate this objective by identifying specific frequencies and intensities of PA tailored to different aspects of multimorbidity and healthy aging. This highlights PA, especially light-to-moderate intensity, as an essential, cost-effective, and amenable strategy for alleviating the impact of multimorbidity on healthy aging.
Factors influencing participation and regular attendance in a program combining physical activity and nutritional advice for overweight and obese pregnant women
Authors: Lelorain Sophie , Deruelle Philippe , Béhal Hélène , Machet Elise , Thiblet Marie , Lengagne-Piedbois Christelle , Deken-Delannoy Valerie , Pigeyre Marie 
Published: June 2024

Abstract
Background
Educational programs incorporating physical activity (PA) sessions and nutritional workshops have demonstrated potential benefits for overweight and obese pregnant women. However, participation in such programs remains challenging. This prospective study aimed to investigate the factors influencing participation and regular attendance, while examining changes in health behaviors, along with obstetric and neonatal outcomes.

Methods
Pregnant women with at 12–22 weeks’ gestation a BMI ≥ 25 kg/m2 were invited to join an educational program combining three nutritional workshops conducted in groups and 12 weekly PA sessions. They self-selected their participation into the program. Regardless of program uptake and regularity of attendance, the women’s PA levels, eating behaviors, and affectivity were assessed using validated questionnaires at 20–24 weeks, 32–34 weeks, and postpartum. A multivariable logistic regression model was used to determine the factors influencing participation.

Results
Of the 187 women enrolled in the study, 61.5% agreed to participate in the program. Of these, only 45% attended six or more sessions (regardless of the nature of sessions, i.e. nutritional workshops and/or PA sessions), while only 8.7% attended six or more PA sessions. Participation was associated with higher rates of problematic eating behaviors and lower PA levels at baseline, while regular attendance was mainly associated with higher household incomes. No significant difference was observed between participants and non-participants in terms of changes in eating behaviors, PA levels, or affectivity. However, at the 32–34 week visit, regular participants displayed a higher change in positive affectivity, but unexpectedly also in cognitive restraint, than non-regular participants, a difference that did not persist at postpartum.

Conclusion
The educational program combining nutrition and PA was shown to be safe. Women facing challenges related to health behavior displayed a willingness to sign up for the program, but tailored interventions addressing their individual challenges are needed to improve attendance. Accordingly, four recommendations are proposed for the design of future interventions.

Trial registration
ClinicalTrials.gov; Identifier: NCT02701426; date of first registration: 08/03/2016.
Association of effective dose to immune cells and vertebral marrow dose with hematologic toxicity during neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma
Authors: Zhang Meng , Li Zhenjiang , Yin Yong 
Published: June 2024

Abstract
Background
To explore the correlation between effective dose to immune cells (EDIC) and vertebral bone marrow dose and hematologic toxicity (HT) for esophageal squamous cell carcinoma (ESCC) during neoadjuvant chemoradiotherapy (nCRT).

Methods
The study included 106 ESCC patients treated with nCRT. We collected dosimetric parameters, including vertebral body volumes receiving 10–40 Gy (V10, V20, V30, V40) and EDIC and complete blood counts. Associations of the cell nadir and dosimetric parameters were examined by linear and logistic regression analysis. The receiver operating characteristic (ROC) curves were used to determine the cutoff values for the dosimetric parameters.

Results
During nCRT, the incidence of grade 3–4 lymphopenia, leukopenia, and neutropenia was 76.4%, 37.3%, and 37.3%, respectively. Patients with EDIC ≤ 4.63 Gy plus V10 ≤ 140.3 ml were strongly associated with lower risk of grade 3–4 lymphopenia (OR, 0.050; P < 0.001), and patients with EDIC ≤ 4.53 Gy plus V10 ≤ 100.9 ml were strongly associated with lower risk of grade 3–4 leukopenia (OR, 0.177; P = 0.011), and patients with EDIC ≤ 5.79 Gy were strongly associated with lower risk of grade 3–4 neutropenia (OR, 0.401; P = 0.031). Kaplan-Meier analysis showed that there was a significant difference among all groups for grade 3–4 lymphopenia, leukopenia, and neutropenia (P < 0.05).

Conclusion
The dose of vertebral bone marrow irradiation and EDIC were significantly correlated with grade 3–4 leukopenia and lymphopenia, and EDIC was significantly correlated with grade 3–4 neutropenia. Reducing vertebral bone marrow irradiation and EDIC effectively reduce the incidence of HT.
Association between dipeptidyl peptidase-4 inhibitor use and diabetic retinopathy: a systematic review and meta-analysis of real-world studies
Authors: Wang Minxi , Lu Jiali , Dong Jiyue 
Published: June 2024

Abstract
Background
The purpose of this review was to examine if dipeptidyl peptidase-4 inhibitor (DPP4i) use affects the risk of diabetic retinopathy (DR).

Methods
Cohort studies published up to 20th July 2023 in the databases of PubMed, CENTRAL, Embase, Scopus, and Web of Science were searched. The adjusted effect size was pooled to calculate the odds ratio (OR).

Results
Seven studies were included. Meta-analysis showed that the use of DPP4i was not associated with any significant change in the risk of DR (OR: 0.86 95% CI: 0.70, 1.06 I2 = 78%). The pooled analysis also found that DPP4i use was not associated with any significant risk of progression of DR (OR: 0.87 95% CI: 0.47, 1.59 I2 = 86%). The results did not change during sensitivity analysis.

Conclusion
Present evidence from a limited number of real-world studies shows that DPP4i may not affect the incidence and progression of DR. There is a need for further studies from different countries using accurate definitions of DR and its progression to validate the current results.
Decrease in pelvic incidence after adult spinal deformity surgery is a predictive factor for progression of hip joint osteoarthritis
Authors: Tomizawa Kazuo , Inami Satoshi , Moridaira Hiroshi , Ueda Haruki , Sekimoto Iwao , Kanto Tomoya , Taneichi Hiroshi 
Published: June 2024

Abstract
Background
This study aimed to evaluate the association between spinopelvic alignment parameters and hip osteoarthritis progression after spinal alignment correction surgery for adult spinal deformity, focusing on the preoperative to postoperative change in spinopelvic alignment.

Methods
This retrospective study enrolled 100 adult spinal deformity patients (196 hip joints) who underwent spinal fusion surgery, after excluding four joints with previous total hip arthroplasty. Acetabular roof obliquity (ARO), center edge angle (CE) and Kellgren and Lawrence (KL) grade were measured in the hip joint. Spinopelvic alignment parameters were measured preoperatively and 1-month postoperatively and the changes (Δ) during this period were calculated. Patients were followed-up for ≥ 5 years and factors associated with KL grade progression at 5-years postoperatively were determined by logistic regression analysis.

Results
In the analysis with all cases, KL grade progressed in 23 joints. Logistic regression analysis revealed age (OR: 1.098, 95% CI: 1.007–1.198, p = 0.019), ARO (OR: 1.176, 95% CI: 1.01–1.37, p = 0.026), and Δ PI (OR: 0.791, 95% CI: 0.688–0.997, p < 0.001) as parameters significantly associated with KL grade progression. On the other hand, in the analysis limited to 185 cases with 1-month postoperative KL grade of 0, KL grade progressed in 13 joints. Logistic regression analysis revealed PI-LL (OR: 1.058, 95% CI: 1.001–1.117, p = 0.04), ΔPI (OR: 0.785, 95% CI: 0.649–0.951, p < 0.001), and ΔCobb (OR: 1.127, 95% CI: 1.012–1.253, p = 0.009) as parameters significantly associated with progression.

Conclusions
Both the overall and limited analyzes of this study identified preoperative to postoperative change in PI as parameters affecting the hip osteoarthritis progression after spinal fusion surgery. Decrease in PI might represent preexisting sacroiliac joint laxity. Patients with this risk factor should be carefully followed for possible hip osteoarthritis progression.
Knowledge and practices of Iranian students (13–16 age) regarding the use of fluoride toothpaste
Authors: Hashemipour Maryam Alsadat , Zeyghami Zahra , Rajaee Halle 
Published: June 2024

Abstract
Introduction
Fluoride is the main factor in reducing the prevalence of caries worldwide. However, there is insufficient knowledge about whether people in different age groups are aware of the benefits of fluoride toothpaste, as well as about people’s daily oral care habits and whether they use fluoride. The purpose of this research is to investigate the knowledge and performance of Iranian students regarding the use of toothpaste containing fluoride.

Method
This study was conducted on the first- and second-year high school students of Kerman city. Questionnaires containing personal questions, general questions, and questions related to students’ knowledge and performance regarding the use of fluoride toothpaste were provided to them and then they were asked to complete and submit it. The results obtained from the survey were analyzed by T-test, Mann-Whitney test, and Chi-Square test in SPSS Version 24. The significance level in data analysis was P < 0.05.

Results
In this research, 681 forms including 252 boys and 429 girls were examined. The average age of the participants was 14.1 ± 0.4. 91.2% declared that they use toothpaste and 77.8% of them used toothpaste containing fluoride. 521 people stated that the price of toothpaste is important in using the type of toothpaste. 621 people used regular toothbrush and 609 people evaluated their oral health as good. 621 of the participants stated that toothpaste makes the mouth healthy. The average knowledge score was 16.7 ± 2.1 out of 24, which indicates the average knowledge of students in this field.

Conclusion
This study showed that students’ knowledge and performance about using fluoride-containing toothpaste is average. There was no significant relationship between performance and knowledge with age and gender. There was also a positive correlation between knowledge and performance indicating that increasing knowledge leads to an increase in behavioral changes. Also, there was a positive correlation between knowledge and performance, and a correlation coefficient of 0.731 was obtained between knowledge and performance. It shows that increasing knowledge leads to increasing behavioral changes.