bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III randomized trial comparing neoadjuvant paclitaxel plus platinum with 5-fluorouracil plus platinum in esophageal or gastroesophageal junction squamous cell carcinoma
Authors: Noronha Vanita , Patil Vijay Maruti , Menon Nandini , Joshi Amit , Shah Minit Jalan , Singh Ajaykumar , Goud Supriya , Shah Srushti , More Sucheta , Nawale Kavita , Nakti Dipti , Yadav Akanksha , Jogdhankar Shweta , Kaushal Rajiv Kumar , Tiwari Virendra Kumar , Niyogi Devayani , Purandare Nilendu , Janu Amit , Chakrabarty Nivedita , Mahajan Abhishek , Tibdewal Anil , Agarwal Jaiprakash , Pawar Akash , Chowdhury Oindrila Roy , Sharma Vibhor , Kapu Venkatesh , Trikha Mehak , Kumar Srigadha Vivek , Kolkur Manali , Bhagyavant Priyanka , Peelay Zoya , Khedkar Rutvij , Jain Medha , Badwe Rajendra Achyut , Prabhash Kumar 
Published: September 2024

Abstract

Background
Standard neoadjuvant chemotherapy for locally advanced esophageal or gastroesophageal junction squamous cancer, 5-fluorouracil plus platinum, is toxic and logistically challenging; alternative regimens are needed.

Methods
This was a phase III randomized open-label noninferiority trial at Tata Memorial Center, India, in resectable locally advanced esophageal or gastroesophageal junction squamous cancer. Patients were randomly assigned 1:1 to 3 cycles of 3-weekly platinum (cisplatin 75 mg/m2 or carboplatin area under the curve 6) with paclitaxel 175 mg/m2 (day 1) or 5-fluorouracil 1000 mg/m2 continuous infusion (days 1-4), followed by surgery.

Results
Between August 2014 and June 2022, we enrolled 420 patients; 210 to each arm. Statistically significantly more patients on paclitaxel plus platinum (n =194, 92.3%) received all 3 chemotherapy cycles than on 5-fluorouracil with platinum (n = 170, 85.9%; P = .009). 5-fluorouracil plus platinum caused more grade 3 or higher toxicities (n = 124, 69.7%) than paclitaxel plus platinum (n = 97, 51.9%; P = .001). Surgery was performed in 131 (62.4%) patients on 5-fluorouracil plus platinum vs 139 (66.2%) on paclitaxel plus platinum (P = .415). Paclitaxel plus platinum resulted in higher pathologic primary tumor clearance (n = 33, 25.8%, vs n = 17, 15%; P = .04) and pathologic complete responses in 21.9% compared with 12.4% from 5-fluorouracil plus platinum (P = .053). Median overall survival was 27.5 months (95% confidence interval [CI] = 18.6 to 43.5 months) from paclitaxel plus platinum, which was noninferior to 27.1 months (95% CI = 18.8 to 40.7 months) from 5-fluorouracil plus platinum (hazard ratio [HR] = 0.89, 95% CI = 0.72 to 1.09; P = .346).

Conclusion
Neoadjuvant paclitaxel plus platinum chemotherapy is safer and results in similar R0 resections, higher pathologic tumor clearance and noninferior survival compared with 5-fluorouracil plus platinum. Paclitaxel plus platinum should replace 5-fluorouracil plus platinum as neoadjuvant chemotherapy for resectable locally advanced esophagealor gastroesophageal junction squamous cancer.

Clinical Trials Registry India Number
CTRI/2014/04/004516.
Non-parametric Bayesian approach to multiple treatment comparisons in network meta-analysis with application to comparisons of anti-depressants
Authors: Barrientos Andrés F , Page Garritt L , Lin Lifeng 
Published: September 2024

Abstract
Network meta-analysis is a powerful tool to synthesize evidence from independent studies and compare multiple treatments simultaneously. A critical task of performing a network meta-analysis is to offer ranks of all available treatment options for a specific disease outcome. Frequently, the estimated treatment rankings are accompanied by a large amount of uncertainty, suffer from multiplicity issues, and rarely permit possible ties of treatments with similar performance. These issues make interpreting rankings problematic as they are often treated as absolute metrics. To address these shortcomings, we formulate a ranking strategy that adapts to scenarios with high-order uncertainty by producing more conservative results. This improves the interpretability while simultaneously accounting for multiple comparisons. To admit ties between treatment effects in cases where differences between treatment effects are negligible, we also develop a Bayesian non-parametric approach for network meta-analysis. The approach capitalizes on the induced clustering mechanism of Bayesian non-parametric methods, producing a positive probability that two treatment effects are equal. We demonstrate the utility of the procedure through numerical experiments and a network meta-analysis designed to study antidepressant treatments.
Promoters Constrain Evolution of Expression Levels of Essential Genes in Escherichia coli
Authors: Tsuru Saburo , Hatanaka Naoki , Furusawa Chikara 
Published: September 2024

Abstract
Variability in expression levels in response to random genomic mutations varies among genes, influencing both the facilitation and constraint of phenotypic evolution in organisms. Despite its importance, both the underlying mechanisms and evolutionary origins of this variability remain largely unknown due to the mixed contributions of cis- and trans-acting elements. To address this issue, we focused on the mutational variability of cis-acting elements, that is, promoter regions, in Escherichia coli. Random mutations were introduced into the natural and synthetic promoters to generate mutant promoter libraries. By comparing the variance in promoter activity of these mutant libraries, we found no significant difference in mutational variability in promoter activity between promoter groups, suggesting the absence of a signature of natural selection for mutational robustness. In contrast, the promoters controlling essential genes exhibited a remarkable bias in mutational variability, with mutants displaying higher activities than the wild types being relatively rare compared to those with lower activities. Our evolutionary simulation on a rugged fitness landscape provided a rationale for this vulnerability. These findings suggest that past selection created nonuniform mutational variability in promoters biased toward lower activities of random mutants, which now constrains the future evolution of downstream essential genes toward higher expression levels.
SIADH and mixed delirium following the abrupt cessation of long-acting benzodiazepines: a case report
Authors: Alenezi Ahmad F , Alnuaimi Ahmed , Liberman Dan 
Published: September 2024

Abstract
Benzodiazepines (BZDs) are among the most commonly used medications due to their efficacy and rapid onset of action. Although they offer significant therapeutic benefits in treating various psychiatric and neurological conditions, their clinical utility is limited by substantial risks, including dependency and withdrawal symptoms. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been linked to BZD withdrawal. In this case report, we examine the case of an elderly female presented with a mixed delirium and SIADH following the abrupt cessation of long-term clonazepam therapy. To our knowledge, this is the second case that documents a link between SIADH and BZD withdrawal.
Can mass media campaigns increase demand for renewable energy? Experimental evidence from Senegal
Authors: Coville Aidan , Orozco-Olvera Victor , Reichert Arndt 
Published: September 2024

Abstract
This paper examines public investment in mass media campaigns aimed at stimulating market-led growth within the renewable energy sector in a developing country setting. We run a randomized field experiment to estimate the impact of a large-scale information campaign on the adoption of renewable energy technology, which includes clips broadcasted on national radio and print materials distributed in rural villages in Senegal. While the radio campaign primarily influences the number of renewable energy products owned by existing users (intensive margin), the combination of radio and print significantly increases the number of new adopters (extensive margin). However, when scaled nationally, we calculate a meaningful advantage of the radio clips over the print materials in terms of the cost per additional sales of solar lamps. The study further introduces an innovative methodological approach for examining nationally broadcasted information campaigns, offering valuable insights for future research and policy evaluations.
Impacts of stellar wind and supernovae on star cluster formation: Origins of extremely high N/O ratios and multiple stellar populations
Authors: Fukushima Hajime , Yajima Hidenobu 
Published: September 2024

Abstract
We study metal enrichment originating from stellar wind and supernovae in low-metallicity clouds by performing three-dimensional radiation hydrodynamics simulations. We find that metals ejected from stellar wind are accumulated, leading to subsequent star formation in the nitrogen-enriched gas. During this early phase, the ${\rm N/O}$ ratios are similar to observed nitrogen-enriched galaxies (${\rm [N/O]}\gtrsim 0.5$). Then, once supernovae occur, the ${\rm N/O}$ ratios decrease significantly. If the duration of star formation is comparable to the time-scale of supernovae, the mass fraction of nitrogen-enriched stars reaches half the mass of star clusters. We suggest that the mass of the star cluster needs to exceed $\sim \!10^6$ M$_{\odot }$ to have multiple populations due to stellar wind, considering the condition for massive star cluster formation and the timescales of stellar evolution.
CPK10 regulates low light–induced tomato flower drop downstream of IDL6 in a calcium-dependent manner
Authors: Fu Xin , Li Ruizhen , Liu Xianfeng , Cheng Lina , Ge Siqi , Wang Sai , Cai Yue , Zhang Tong , Shi Chun-Lin , Meng Sida , Tan Changhua , Jiang Cai-Zhong , Li Tianlai , Qi Mingfang , Xu Tao 
Published: September 2024

Abstract
Flower drop is a major cause for yield loss in many crops. Previously, we found that the tomato (Solanum lycopersicum) INFLORESCENCE DEFICIENT IN ABSCISSION-Like (SlIDL6) gene contributes to flower drop induced by low light. However, the molecular mechanisms by which SlIDL6 acts as a signal to regulate low light–induced abscission remain unclear. In this study, SlIDL6 was found to elevate cytosolic Ca2+ concentrations ([Ca2+]cyt) in the abscission zone (AZ), which was required for SlIDL6-induced flower drop under low light. We further identified that 1 calcium-dependent protein kinase gene, SlCPK10, was highly expressed in the AZ and upregulated by SlIDL6-triggered [Ca2+]cyt. Overexpression and knockout of SlCPK10 in tomato resulted in accelerated and delayed abscission, respectively. Genetic evidence further indicated that knockout of SlCPK10 significantly impaired the function of SlIDL6 in accelerating abscission. Furthermore, Ser-371 phosphorylation in SlCPK10 dependent on SlIDL6 was necessary and sufficient for its function in regulating flower drop, probably by stabilizing the SlCPK10 proteins. Taken together, our findings reveal that SlCPK10, as a downstream component of the IDL6 signaling pathway, regulates flower drop in tomato under low-light stress.
In situ deposition of nanobodies by an engineered commensal microbe promotes survival in a mouse model of enterohemorrhagic E. coli
Authors: Srivastava Rajkamal , González-Prieto Coral , Lynch Jason P , Muscolo Michele E , Lin Catherine Y , Brown Markus A , Lemos Luisa , Shrestha Anishma , Osburne Marcia S , Leong John M , Lesser Cammie F 
Published: September 2024

Abstract
Engineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. Enterohemorrhagic Escherichia coli (EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization. Citrobacter rodentium (Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify the C. rodentium genome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse precolonization with HS-PROT3EcT-TD4, a human commensal E. coli strain (E. coli HS) engineered to efficiently secrete an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study suggests that commensal E. coli engineered to deliver payloads that block essential virulence determinants can be developed as a new means to prevent and potentially treat infections including those due to antibiotic resistant microbes.
Combined associations of obesity and physical activity with pain, fatigue, stiffness and anxiety in adults with spondyloarthropathies: UK Biobank study
Authors: Roberts Matthew J , Johnson William , Qooja Sepehr , Moorthy Arumugam , Bishop Nicolette C 
Published: September 2024

Abstract

Objective
Inflammatory spondyloarthropathies are associated with pain, fatigue, stiffness and anxiety. The National Institute for Health and Care Excellence and the EULAR provide limited lifestyle guidance for managing symptoms with inflammatory spondyloarthropathies. We investigated the combined associations of obesity and physical activity with symptom severity in inflammatory spondyloarthropathies.

Methods
The relationship between BMI, physical activity and symptom severity (spinal and general pain, fatigue, anxiety, mobility) was examined in people with ISpAs (n = 1577). BMI categories were normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (≥30 kg/m2). Physical activity was assessed via the International Physical Activity Questionnaire (low &lt; 600 metabolic equivalent of task (MET)-min/week, moderate ≥ 600 METs, high ≥ 3000 METs). Statistical models adjusted for confounders, including medication, estimated the likelihood (odds ratios, OR) of higher symptom severity across BMI and physical activity categories.

Results
Overweight and obesity, compared with normal weight, were linked to higher severity of all symptoms, with stronger associations for obesity (OR ≥ 2.34, P &lt; 0.001) than overweight (OR ≥ 1.37, P ≤ 0.032). Moderate activity, compared with low, was associated with lower severity of all symptoms (OR ≤ 0.77, P ≤ 0.032). High activity, compared with low, was associated with lower severity of fatigue, anxiety and mobility issues (OR ≤ 0.74, P ≤ 0.029), but associations with spinal and general pain were not significant (OR ≤ 0.80, P ≥ 0.056). No BMI-by-physical activity combinations were detected, indicating physical activity benefits all BMI groups to a similar extent.

Conclusion
National Institute for Health and Care Excellence and EULAR guidance for inflammatory spondyloarthropathies should emphasize maintaining a normal weight. Moderate physical activity is optimal for reducing symptom severity and should be promoted in lifestyle guidance.
Cross-linking manipulation of waterborne biodegradable polyurethane for constructing mechanically adaptable tissue engineering scaffolds
Authors: Sheng Nan , Lin Weiwei , Lin Jingjing , Feng Yuan , Wang Yanchao , He Xueling , He Yuanyuan , Liang Ruichao , Li Zhen , Li Jiehua , Luo Feng , Tan Hong 
Published: September 2024

Abstract
Mechanical adaptation of tissue engineering scaffolds is critically important since natural tissue regeneration is highly regulated by mechanical signals. Herein, we report a facile and convenient strategy to tune the modulus of waterborne biodegradable polyurethanes (WBPU) via cross-linking manipulation of phase separation and water infiltration for constructing mechanically adaptable tissue engineering scaffolds. Amorphous aliphatic polycarbonate and trifunctional trimethylolpropane were introduced to polycaprolactone-based WBPUs to interrupt interchain hydrogen bonds in the polymer segments and suppress microphase separation, inhibiting the crystallization process and enhancing covalent cross-linking. Intriguingly, as the crosslinking density of WBPU increases and the extent of microphase separation decreases, the material exhibits a surprisingly soft modulus and enhanced water infiltration. Based on this strategy, we constructed WBPU scaffolds with a tunable modulus to adapt various cells for tissue regeneration and regulate the immune response. As a representative application of brain tissue regeneration model in vivo, it was demonstrated that the mechanically adaptable WBPU scaffolds can guide the migration and differentiation of endogenous neural progenitor cells into mature neurons and neuronal neurites and regulate immunostimulation with low inflammation. Therefore, the proposed strategy of tuning the modulus of WBPU can inspire the development of novel mechanically adaptable biomaterials, which has very broad application value.
An objective diagnosis of gout and calcium pyrophosphate deposition disease with machine learning of Raman spectra acquired in a point-of-care setting
Authors: Niessink Tom , Jansen Tim L , Coumans Frank A W , Welting Tim J M , Janssen Matthijs , Otto Cees 
Published: September 2024

Abstract

Objective
Raman spectroscopy is proposed as a next-generation method for the identification of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluid. As the interpretation of Raman spectra requires specific expertise, the method is not directly applicable for clinicians. We developed an approach to demonstrate that the identification process can be automated with the use of machine learning techniques. The developed system is tested in a point-of-care-setting at our outpatient rheumatology department.

Methods
We collected synovial fluid samples from 446 patients with various rheumatic diseases from three centres. We analysed all samples with our Raman spectroscope and used 246 samples for training and 200 samples for validation. Trained observers classified every Raman spectrum as MSU, CPP or other. We designed two one-against-all classifiers, one for MSU and one for CPP. These classifiers consisted of a principal component analysis model followed by a support vector machine.

Results
The accuracy for classification of CPP using the 2023 ACR/EULAR CPPD classification criteria was 96.0% (95% CI: 92.3, 98.3), while the accuracy for classification of MSU using the 2015 ACR/EULAR gout classification criteria was 92.5% (95% CI: 87.9, 95.7). Overall, the accuracy for classification of pathological crystals was 88.0% (95% CI: 82.7, 92.2). The model was able to discriminate between pathological crystals, artifacts and other particles such as microplastics.

Conclusion
We here demonstrate that potentially complex Raman spectra from clinical patient samples can be successfully classified by a machine learning approach, resulting in an objective diagnosis independent of the opinion of the medical examiner.
Fine particulate matter and osteoporosis: evidence, mechanisms, and emerging perspectives
Authors: Zhang Jiyang , Chu Hanshu , Li Ran , Liu Cuiqing 
Published: September 2024

Abstract
Air pollution, particularly fine particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5), has been recognized for its adverse effects on multiple organs beyond the lungs. Among these, the bone began to garner significant attention. This review covers epidemiological, animal, and cell studies on PM2.5 exposure and bone health as well as studies on PM2.5-induced diseases with skeletal complications. Emerging evidence from epidemiological studies indicates a positive association between PM2.5 exposure and the incidence of osteoporosis and fractures, along with a negative association with bone mineral density. Experimental studies have demonstrated that PM2.5 can disrupt the metabolic balance between osteoclasts and osteoblasts through inflammatory responses, oxidative stress, and endocrine disruption, thereby triggering bone loss and osteoporosis. Additionally, this review proposes a secondary mechanism by which PM2.5 may impair bone homeostasis via pathological alterations in other organs, offering new perspectives on the complex interactions between environmental pollutants and bone health. In conclusion, this contemporary review underscores the often-overlooked risk factors of PM2.5 in terms of its adverse effects on bone and elucidates the mechanisms of both primary and secondary toxicity. Further attention should be given to exploring the molecular mechanisms of PM2.5-induced bone impairment and developing effective intervention strategies.
Accelerated maturation of ARPE‐19 cells for the translational assessment of gene therapy
Authors: Bernd Jonathan , Plastino Flavia , Karayannis Joanna Jackelin , Kvanta Anders , Locri Filippo , André Helder 
Published: September 2024

AbstractThe human retinal pigment epithelium (RPE) cell line ARPE‐19 is widely used as an alternative to primary RPE despite losing many features of primary RPE. We aimed to determine whether a combination of RPE‐specific laminin (LN) and nicotinamide (NAM) could improve ARPE‐19 redifferentiation to resemble mature RPE and improve the assessment of RPE‐specific gene therapy strategies. ARPE‐19 cells were propagated on tissue culture plastic supplemented with NAM and human recombinant LN521‐coating. RPE maturation was performed by immunocytochemistry and gene expression by qPCR. Viral transduction experiments with adeno‐associated virus (AAV)1 or AAV2, carrying a VMD2‐driven GFP, were assessed at 2‐ and 4‐weeks post‐plating in the different culturing conditions with a low multiplicity of infection. The combination of LN521 coating with NAM supplementation promoted cytoskeletal and tight junction protein reorganization. The expression of maturation markers bestrophin‐1 and RPE 65 was promoted concomitantly with a reduction of several epithelial‐mesenchymal transition markers, such as TNF‐α, TGF‐β, CDH2, and vimentin. Redifferentiated ARPE‐19 transduced at low multiplicity of infection of both AAV1‐ and AAV2‐VMD2‐GFP. Expression of GFP was detected at 2 weeks and increased at 4 weeks post‐plating. AAV1 exhibited a greater expression efficacy compared to AAV2 in maturated ARPE‐19 cells already after 2 weeks with increased efficiency after 4 weeks. Our study demonstrates an improved maturation protocol for ARPE‐19 cells in vitro, mimicking an in vivo phenotype with the expression of signature genes and improved morphology. Viral‐mediated RPE‐specific gene expression demonstrates that the combination cultures mimic in vivo AAV tropism essential to test new gene therapies for RPE‐centered diseases.