bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone Demethylase KDM6B Promotes Chondrogenic Differentiation Potential of Stem Cells from the Apical Papilla Via HES1
Authors: Zhang Chen , Lian Xiaomeng , Zhu Mengyuan , Hu Meijun , Xia Dengsheng , Jin Luyuan , Yu Riyue , Li Jun
Published: January 2025

Introduction: Mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for treating articular cartilage injuries. However, enhancing the chondrogenic differentiation potential of MSCs remains a significant challenge. KDM6B, a histone demethylase that specifically removes H3K27me3 marks, is essential in controlling the maturation of chondrocytes. In this study, we examined how KDM6B influences chondrogenic differentiation in SCAPs and investigated the underlying mechanisms involved.
Methods: SCAPs were utilized. Alcian Blue staining, pellet culture, and cell transplantation in rabbit knee cartilage defect models assessed MSC chondrogenic differentiation. Western blot, Real-time RT-PCR, and Microarray analysis examined the underlying molecular mechanisms.
Results: KDM6B promotes the expression of Aggrecan, COL2A1, COL5, glycosaminoglycans, and collagen fibers, while also increasing the COL2/COL1 ratio in SCAPs. In vivo, SCAPs overexpressing KDM6B significantly enhanced the repair and regeneration of knee cartilage and subchondral bone, with higher levels of glycosaminoglycan and COL5 expression observed within the tissue. KDM6B promotes the chondrogenic differentiation potential of SCAPs by repressing HES1. In addition, knock-down of HES1 enhanced the chondrogenic differentiation of SCAPs.
Conclusions: KDM6B enhances the differentiation of SCAPs into chondrocytes and demonstrated its effectiveness in the repair and regeneration of cartilage tissue and subchondral bone in vivo experiments. These findings provide an important foundation for future research on the use of dental tissue-derived stem cells to treat cartilage injuries.
DWI Positivity in Mild, Nondisabling Acute Cerebral Ischemia: Data From the PRISMS Trial
Authors: Wang Lily L. , Khatri Pooja , Prabhakaran Shyam , Sucharew Heidi , Tomsick Thomas A. , Carrozzella Janice A. , Stanton Robert J. , Broderick Joseph , Kleindorfer Dawn , Levine Steven R. , Romano Jose G. , Saver Jeffrey L. , Yeatts Sharon D. , Vagal Achala
Published: January 2025

Background

In patients with acute cerebral ischemia (ACI) and mild deficit, acute infarction on magnetic resonance imaging (diffusion‐weighted imaging [DWI]‐positivity) is inconsistently detected. Our objective was to characterize the rate of detection in the first dedicated trial of a population with mild, nondisabling stroke and assess the detection and its association with baseline clinical and imaging characteristics. We hypothesized that white matter hyperintensity (WMH) would independently predispose patients to DWI‐positivity.

Methods

The phase 3b, randomized, double‐blinded PRISMS (Potential of Alteplase for Ischemic Strokes with Mild Symptoms) trial compared administration of intravenous alteplase to aspirin for mild (National Institutes of Health Stroke Scale score 0–5), nondisabling stroke at ≤3 hours from onset. For the current, prespecified study, patients with a final diagnosis of neurovascular mimic were excluded. Central readers, blinded to the treatment arm, assessed day 2 magnetic resonance imaging for prior infarct, WMH burden (graded quantitatively [volume] and qualitatively [(Fazekas]), and presence of DWI‐positivity (primary outcome). Alteplase treatment, demographics, and clinical covariates were prespecified for adjustment in regression modeling.

Results

Of 313 patients enrolled, 273 (87%) had a final diagnosis of ACI. Of 212 (77%) cases of ACI with magnetic resonance imaging, 109 (51%) had DWI positivity (median lesion volume 1.20 cc, interquartile range 0.57–2.50 cc). Univariately, the proportion with higher Fazekas grade (grade 2–3: 27% vs 41%;
P
= 0.02) and prior infarct (45% vs 27%,
P
<0.01) were associated with DWI positivity. WMH was not associated with DWI positivity in adjusted analysis (adjusted odds ratio [aOR]: 1.01, 95% CI: 0.99–1.03). The multivariable model also showed alteplase treatment inversely associated with DWI‐positivity (aOR: 0.48, 95% CI: 0.25–0.93).

Conclusions

Among patients presenting with mild, nondisabling ACI, WMH is not associated with DWI‐positivity. A hypothesis emerges that alteplase treatment may reduce DWI positivity in mild, nondisabling ACI.
Sex‐Based Differences in Thrombus Composition in Acute Ischemic Stroke
Authors: Schwarz Ghil , Cascio Rizzo Angelo , Cervo Amedeo , Di Como Martina , Costanza Aquilano Maria , Valtorta Emanuele , Carlo Pero Guglielmo , Piano Mariangela , Sessa Maria
Published: January 2025

BACKGROUND

Endovascular thrombectomy allows for detailed study of thrombus composition in acute ischemic stroke. Differences in thrombus composition can affect outcomes, and the impact of sex on coagulation physiology is recognized. This study investigates whether thrombus composition in acute ischemic stroke varies between sexes.

METHODS

Retrospective study on consecutive endovascular thrombectomy‐treated patients with acute ischemic stroke at Niguarda Hospital in 2023. Thrombi were stained with hematoxylin and eosin, and the percentages of fibrin, red blood cells (RBCs), and white blood cells (WBCs) were quantified as proportions of the total thrombus area. Univariate and multivariate analyses were performed to identify histological differences between sexes—multivariate analysis adjusted for variables associated with each thrombus component with a
P
value <0.1.

RESULTS

Seventy‐three cases (50.7% female) were included in the study. Male patients exhibited a higher percentage of RBCs within the thrombus (median 51.5% versus 33.8%,
P
= 0.004), whereas female patients had a higher percentage of fibrin (median 58.3% versus 45.1%,
P
= 0.020) and WBCs (median 6.5% versus 4.4%,
P
= 0.045). Univariate analysis indicated that sex was associated with all 3 thrombus components: fibrin (β = 10.08 [95% CI, 1.29–18.87],
P
= 0.025), RBCs (β = −12.12 [95% CI, l−21.04 to −3.21],
P
= 0.008), and WBCs (β = 2.05 [95% CI, 0.23–3.86],
P
= 0.028). In the multivariate analysis, sex lost its association with both fibrin and RBC percentages, and only baseline RBC count maintained its independent association with these 2 components. For the percentage of WBCs in the thrombus, both sex (β = 2.13 [95% CI, 0.25–4.01],
P
= 0.027) and stroke etiology (β = 0.81 [95% CI, 0.03–1.58],
P
= 0.041) showed significant and independent associations.

CONCLUSION

Our exploratory study shows that sex independently affects the percentage of WBCs in thrombi. The percentage of fibrin and RBC does not have an independent association with sex and may be mediated by different RBC count. Future research in this field should consider sex and baseline laboratory values.
EXPRESS: Natural Affect DEtection (NADE): Using Emojis to Infer Emotions from Text
Authors: Hotz-Behofsits Christian , Wlömert Nils , Nabout Nadia Abou
Published: January 2025

Emotions are central to consumer communications, and extracting them from user-generated online content is crucial for marketers, considering that such consumer opinions significantly shape brand perceptions, influence purchase decisions, and provide essential insights for marketing analytics. To leverage vast user-generated data, marketers and researchers require advanced text-to-emotion converters. However, existing tools for fine-grained emotion extraction face several limitations: Lexica are constrained by their dictionaries, machine learning models by human-annotated training data, and large language models by insufficient validation. As a result, marketing research still tends to rely on mere sentiment detection instead of extracting more nuanced emotions from text. This paper introduces Nade (Natural Affect DEtection), a novel text-to-emoji-to-emotion converter that first “emojifies” language and then converts these emojis into intensity measures of well-established, theory-grounded emotions. This approach addresses the limitations of existing tools by leveraging the inherent emotional information in emojis. Using human raters and state-of-the-art converters as benchmarks, the authors establish the benefits of exploiting emojis, validate Nade, and demonstrate its use in several marketing applications using data from various social media platforms. Users can apply the proposed converter through an easy-to-use online app and programming packages for Python and R.
EXPRESS: Product Returns and Assortment Decisions: a Strategic Analysis of Online and Offline Competition
Authors: Li Yue , Rao Raghunath Singh , Mallucci Paola
Published: January 2025

We present a model of product returns and assortment decisions in the context of online-offline retail competition. In equilibrium, the online store optimally offers easy-to-fit products to reduce costly returns. The competing brick-and-mortar store faces a subtle trade-off between generating higher sales and attracting more foot traffic, and thus, it might use its limited store size to stock harder-to-fit products. Our model provides a rationale for the prevalence of relatively lower-quality products sold online and the steady growth of specialty stores within the changing footprint of traditional retailing. The model is extended to include possibilities such as a physical store opening an online channel to compete with the online store.

We apply this framework to investigate the possibility and consequences of retailers collaborating to handle returns. Specifically, a recent “buy online and return in store” (BORS) return policy allows consumers to return online purchases directly to a competing brick-and-mortar store. In the short run, BORS increases the BMR’s foot traffic and the returns volume. In the long run, BORS expands the OR’s assortment and increases BMR’s foot traffic. BORS can be sustained in the long run if the BMR is small or if its cost-saving effect is large.
What are patients asking and reading online? An analysis of online patient searches about treatments for developmental dysplasia of the hip
Authors: Balachandran Uma , Ren Renee , Vicioso Camila , Park Jiwoo , Nietsch Katrina S , Sacks Brittany , Busigo Torres Rodnell , Ranade Sheena C
Published: January 2025

Purpose:

We aimed to analyze frequently searched questions through Google’s “People Also Ask” feature related to four common treatments for developmental dysplasia of the hip (DDH): the Pavlik harness, rhino brace, closed reduction surgery and open reduction surgery.

Methods:

Search terms for each treatment were entered into Google Web Search using a clean-install Google Chrome browser. The top frequently asked questions and associated websites were extracted. Questions were categorized using the Rothwell classification model. Websites were evaluated using the JAMA Benchmark Criteria. Chi-square tests were performed.

Results:

The initial search yielded 828 questions. Of 479 included questions, the most popular topics were specific activities that patients with DDH can/cannot do (32.8%), technical details about treatments (30.9%) and indications for treatments (18.2%). Websites were commonly academic (59.3%), commercial (40.5%) and governmental (12.3%). There were statistically significant more specific activity questions about Pavlik harnesses than about rhino braces ( χ2 = 7.1, p = 0.008), closed reduction ( χ2 = 56.5, p < 0.001) and open reduction ( χ2 = 14.7, p < 0.001). There were statistically significant more technical details questions about Pavlik harnesses than about closed reduction ( χ2 = 4.1, p = 0.04).

Conclusions:

This study provides insights into common concerns that parents have about their children’s DDH treatment, enabling orthopaedic surgeons to provide more effective and targeted consultations. This is particularly important for DDH because affected patients are often diagnosed within the first few months of life, leaving parents overwhelmed by caring for a newborn child and simultaneously coping with this diagnosis.
Urban Air Mobility demand forecasting: modeling evidence from the case study of Milan (Italy)
Authors: Coppola Pierluigi , De Fabiis Francesco , Silvestri Fulvio
Published: January 2025

This paper presents the results of a demand forecasting study about the introduction of Urban Air Mobility (UAM) services in the metropolitan area of Milan (Italy). Demand forecasting is based on random utility mode choice models, which include factors related to the individuals’ perception of vertical take-off/landing and low altitude flying over urbanized areas. The use cases of UAM services include airport shuttles, intercity air connections, and “air-taxis”, i.e., UAM services for short-trips within the metropolitan area. Several scenarios have been considered based on the number of access points (“vertiports”) and UAM fare levels. The results indicate that airport shuttles have a modal share of trips to/from airports (for both business and leisure) in a range of 2-5%. They resulted to be more attractive than air-taxis, which have a modal share in a range of 1-3%. Furthermore, the probability of choosing UAM services for intercity travels decreases with the distance and the time required for access/egress to/from the vertiports, whose catchment areas are dependent on the level of service provided by competing modes (notably the presence of good railway and highway connections).
Effects of Enterobacter cloacae extract, selenium nanoparticles and methyl jasmonate on shoot liquid cultures of Sarcocornia fruticosa under salinity stress
Authors: Salem Fathia , Rahman Raoufa Abdel , Tammam Amel
Published: January 2025

Background

The in vitro propagation of halophytes is innovative perspective for sustainable agriculture, conservation of natural plants and essential raw materials for industry due to increasing soil salinization and decreasing freshwater availability. Sarcocornia fruticosa, a halophytic plant, may hold promise for biosaline production systems and achieve bioactive products. Understanding the salt tolerance mechanisms of halophytes through elicitors can enhance the production of secondary metabolites, such as phenolics and flavonoids, under saline environment. This study aimed to evaluate the effects of NaCl salinity (700 mM and 1000 mM) on Sarcocornia fruticosa shoot cultures and assess the influence of different elicitors-Enterobacter cloacae extract (BE), selenium nanoparticles (SeNPs) and methyl jasmonate (MeJA) -on the plants growth, physiological and biochemical responses, and isorhamnetin production.

Methodology

Shoot cultures were grown under controlled conditions with two concentrations of NaCl, alone and in combination with BE (0.5%), SeNPs (100 ppm), or MeJA (50 µM). Growth parameters, photosynthetic pigments, ion accumulation, osmolyte content, oxidative stress marker, enzyme activity, phenolic compound levels, and isorhamnetin production were analyzed to determine the impact of salinity and elicitor treatments on S. fruticosa for 14 days.

Results

Sarcorcocnia fruticosa exhibited better tolerance up to 700 mM than 1000 mM NaCl, as evidenced by higher dry weights, chlorophyll a/b ratios, and enhanced osmolyte and antioxidant contents. Elicitation both saline cultures with BE and SeNPs improved growth mostly by increasing biomass, pigment contents, K+/Na+ ratios, and reducing lipid peroxidation, however, MeJA reduced the biomass mainly by increasing MDA and Na+ ion accumulation. In contrast, application of all elicitors stimulated the production of phenolic compounds and isorhamnetin, as well as BE can contribute for increasing resistance of S. fruticosa to stressful conditions.

Conclusion

This study demonstrated that PTC techniques and appropriate elicitors can optimize halophyte propagation and secondary metabolite production under saline conditions. The findings suggest that BE and SeNPs significantly enhanced the growth and biochemical resilience of S. fruticosa under salinity stress, with a notable increase in isorhamnetin production. MEJA.
Nebulized dexmedetomidine in the treatment of obstetric post-dural puncture headache: two case reports
Authors: Thomas Jeffrey , Soloniuk Leonard J. , Mehdizadeh Chris , Cheng Peter , Sinha Ashish
Published: January 2025

Post-dural puncture headache (PDPH) is a debilitating complication of neuraxial anesthesia, particularly prevalent in obstetric patients, usually characterized by a postural headache. PDPH is hypothesized to result from cerebrospinal fluid leakage through a dural puncture, triggering symptoms like neck stiffness and subjective hearing changes. While conservative measures are common for treatment, more refractory cases may require invasive interventions such as an epidural blood patch (EBP). Recent studies have shown promise in using nebulized dexmedetomidine (nDEX) for PDPH, offering a non-invasive alternative to EBP. Two case presentations illustrate the efficacy of nDEX in resolving PDPH symptoms rapidly and completely. These cases underscore the need for exploring novel therapeutic options, especially in obstetric patients where safe and prompt relief is essential for maternal and newborn well-being. While the EBP remains the gold standard, its limitations of accessibility and invasiveness highlight the significance of investigating alternatives like nDEX.
Efficacy of Xpert MTB/RIF assay in detecting Mycobacterium tuberculosis in samples with different results by smear and culture in a coastal city with high incidence of tuberculosis
Authors: Feng Gang , Jiang Hongyu , Chen Ying
Published: January 2025

Background

Tuberculosis (TB) is a global problem that seriously jeopardizes human health. Among them, the diagnosis and treatment of smear- or culture-negative TB patients is a challenge. The Xpert MTB/RIF (Xpert) assay has been reported to be a novel molecular diagnostic tool for rapidly detecting TB. Still, there is limited data on this assay's performance in subgroups of TB patients. This study aimed to evaluate the diagnostic value of the Xpert method in patients with different smear and culture results and to assess its efficacy for rifampicin resistance (RR) detection.

Methods

We retrospectively collected data from 1,721 patients with a clinical diagnosis of tuberculosis. Smear, Xpert, and traditional solid culture methods were used to detect TB infection and explore the detection rate of Xpert in the grouping of results from different smear and culture methods. Information on RR detected by the Xpert method and proportional method of drug sensitivity test (DST) was also recorded and kappa values, sensitivity, and specificity were calculated.

Results

We observed that among the three methods, the Xpert method had the highest detection rate of 66.8%, followed by the culture method at 56.0% and the smear method had the lowest at 40.0%. The detection rate of Xpert was 98.3% (642/653) when both smear and culture were positive, 85.1% (296/348) when only one of the two methods, smear and culture, was positive, and 29.4% (212/720) when both smear and culture were negative. The Xpert method and DST showed a high agreement (κ = 0.92) for RR detection. The highest mutation rate was observed for probe E (64.7%), and the least number of probe C mutations occurred (1.5%).

Conclusion

The Xpert method has high detection efficiency. It has good diagnostic value in detecting MTB and RR, especially in cases where traditional culture and sputum smear results are negative, and significantly reduces the rate of missed diagnosis.
Prediction of oral diseases in care dependent older people
Authors: Andersen Christina , Jespersen Astrid Pernille , Ekstrand Kim , Øzhayat Esben Boeskov
Published: January 2025

Background

A large number of older people depend on others for help with their daily personal care, including oral health care. Nursing home and elder-care staff often face challenges identifying older people, who are exposed to or at an increased risk of oral diseases. Thus, the aim of this study was to identify risk factors that non-dental care staff can use to identify older people at risk of oral diseases and poor oral hygiene.

Methods

In this cross-sectional study, the oral health and risk factors for poor oral health were determined for 217 care dependent older people living in two nursing homes and a rehabilitation centre or receiving home care in two Danish municipalities. The outcome variables for oral disease i.e. caries, periodontitis, and gingivitis, and oral hygiene, i.e. plaque and calculus, were assessed using standardised oral examinations. Risk factors for oral diseases and poor oral hygiene were assessed based on a questionnaire concerning (1) background information, (2) health status, (3) social support, (4) oral health behaviours, and (5) self-reported oral health. The associations between oral health and risk factors were investigated using logistic regression analyses.

Results

In general, older people with different living arrangements had quite similarly distributed risk factors. The oral examinations showed that 54.5% had oral diseases, and 14.8% had poor oral hygiene. Not seeing a dentist regularly was significantly associated with having oral diseases (Odds Ratio, 2.87; CI, 1.53–5.39) and poor oral hygiene (OR, 4.50; CI, 1.83–11.05). A significant association was found between the presence of an oral disease and adversely affected quality of life (OR, 2.65; CI, 1.42–4.95), especially due to challenges eating (OR, 3.76; CI, 1.64–8.60) and/or smiling and showing teeth (OR, 3.64; CI, 1.27–10.42). A significant association was also found between poor oral hygiene and taking psychotropic drugs (OR, 2.61; CI, 1.08–6.30).

Conclusion

Questions regarding the use of the dental care system and oral health problems could be used by nondental care staff in conversations with older people to determine their risk of oral diseases and poor oral hygiene.
Fit accuracy and fracture resistance evaluation of advanced lithium disilicate crowns (in- vitro study)
Authors: Fayed Amro Khalil , Azer Amir Shoukry , AboElhassan Rewaa Gaber
Published: January 2025

Background

Increasing demand for durable and aesthetically pleasing dental restorations, including laminates, inlays, onlays, and crowns, has led to advancements in all-ceramic systems, particularly with the development of advanced lithium disilicate materials. However, limited data on the fit accuracy and fracture resistance of these materials restricts their wider application in clinical restorative practices.

Aim of the study

This in vitro study aims to compare the marginal and internal fit, assess the fracture resistance, and evaluate the failure modes of crowns fabricated from advanced and conventional lithium disilicate materials.

Materials and methods

Thirty two (n = 32) crowns were fabricated and categorized into two groups based on the material used: Group (CT), where crowns were milled from CEREC Tessera (n = 16), and Group (EM), where crowns were milled from IPS e.max CAD (n = 16) using a CAD/CAM system. The marginal and internal fit were assessed digitally via a triple scan protocol. All samples were subjected to a fracture resistance test with a universal testing machine, followed by an analysis of failure modes under a stereomicroscope.

Results

In the evaluation of marginal, internal and total gaps, CEREC Tessera (CT) showed slightly better fit with lower gap values compared to e.max CAD (EM). However, an independent samples t-test indicated no statistically significant differences between the two groups (p = 0.141, p = 0.471). For fracture resistance (N), the CT group demonstrated higher values than the EM group; however, the independent samples t-test indicated no statistically significant difference (p = 0.053). Additionally, the Chi-squared test with Monte Carlo correction revealed no statistically significant differences in the modes of fracture between the two groups (p = 0.484).

Conclusion

Considering the limitations of this study, advanced lithium disilicate crowns demonstrated better results in terms of marginal fit, internal adaptation, and fracture resistance compared to traditional lithium disilicate crowns; however, the differences were not statistically significant. Both materials exhibited comparable fracture patterns.
Commentary on “Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth”
Authors: Raitoharju Emma , Marttila Saara
Published: January 2025

VTRNA2-1 is a polymorphically imprinted locus. The proportion of individuals with a maternally imprinted VTRNA2-1 locus is consistently approximately 75% in populations of European origin, with the remaining circa 25% having a non-methylated VTRNA2-1 locus. Recently, VTRNA2-1 hypermethylation at birth was suggested to be a precursor of paediatric acute lymphoblastic leukaemia with biomarker potential. The results presented by Ghantous et al. [1] allow for an alternative interpretation to what the authors discussed, and we argue that the observed methylation difference at birth is due to an uneven distribution of imprinted and non-methylated individuals among the cases and controls, with all individuals presenting normative physiological VTRNA2-1 methylation levels. In addition, the notable interindividual variation arising from the polymorphic imprinting in VTRNA2-1 methylation levels calls into question the validity of VTRNA2-1 methylation as a biomarker.
Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach
Authors: Rujirachaivej Punchita , Siriboonpiputtana Teerapong , Choomee Kornkan , Supimon Kamonlapat , Sangsuwannukul Thanich , Songprakhon Pucharee , Natungnuy Krissada , Luangwattananun Piriya , Yuti Pornpimon , Junking Mutita , Yenchitsomanus Pa-thai
Published: January 2025

Background

Multiple myeloma (MM) is an incurable plasma cell malignancy with increasing global incidence. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown efficacy in relapsed or refractory MM, but it faces resistance due to antigen loss and the tumor microenvironment. Bispecific T-cell engaging (BITE) antibodies also encounter clinical challenges, including short half-lives requiring continuous infusion and potential toxicities.

Methods

To address these issues, we developed a lentiviral system to engineer T cells that secrete αB7-H3-αCD3 bispecific engager molecules (αB7-H3-αCD3 ENG-T cells). We evaluated their effectiveness against MM cells with varying B7-H3 expression levels, from B7-H3neg to B7-H3high.

Results

The αB7-H3-αCD3 ENG-T cells demonstrated significant anti-tumor activity against MM cell lines expressing B7-H3. SupT-1 cells (B7-H3neg) served as controls and exhibited minimal cytotoxicity from αB7-H3-αCD3 ENG T cells. In contrast, these engineered T cells showed dose-dependent killing of B7-H3-expressing MM cells: NCI-H929 (B7-H3low), L-363 (B7-H3medium), and KMS-12-PE (B7-H3high). For NCI-H929 cells, cytotoxicity reached 38.5 ± 7.4% (p = 0.0212) and 54.0 ± 9.2% (p = 0.0317) at effector-to-target (E:T) ratios of 5:1 and 10:1, respectively. Against L-363 cells, cytotoxicity was 56.6 ± 3.2% (p < 0.0001) and 71.4 ± 5.2% (p = 0.0002) at E:T ratios of 5:1 and 10:1, respectively. For KMS-12-PE cells, significant cytotoxic effects were observed even at an E:T ratio of 1:1, with 27.2 ± 3.7% (p = 0.0004), 44.4 ± 3.7% (p < 0.0001), and 68.6 ± 9.2% (p = 0.0004) cytotoxicity at E:T ratios of 1:1, 5:1, and 10:1, respectively.

Conclusions

These results indicate that αB7-H3-αCD3 ENG T cells could be a promising therapy for B7-H3-positive MM. They may enhance current MM treatments and improve overall outcomes. Additional preclinical and clinical research is required to fully assess their therapeutic potential.
Impacts of genomic alterations on the efficacy of HER2-targeted antibody–drug conjugates in patients with metastatic breast cancer
Authors: Huang Riqing , Hu Anqi , Rong Qixiang , Shu Ditian , Chen Meiting , Yang Wei , Zhang Yue , Zheng Qiufan , An Xin , Xue Cong , Li Haifeng , Shi Yanxia
Published: January 2025

Background

HER2-targeted antibody–drug conjugates (ADCs) have revolutionized the treatment landscape of metastatic breast cancer. However, the efficacy of these therapies may be compromised by genomic alterations. Hence, this study aims to identify factors predicting sensitivity to HER2 ADC in metastatic breast cancer.

Methods

This comprehensive real-world retrospective study collected clinical data from patients diagnosed with metastatic breast cancer and performed genomic profiling using targeted next-generation sequencing. The study analyzed the associations between genomic alterations and clinical outcomes of HER2 ADC treatment.

Results

Sixty-three patients were included in this study, 33 with HER2-low breast cancer and 30 with HER2-positive breast cancer, respectively. The most frequently altered genes were TP53 (69%), PIK3CA (45%), MYC (35%), and ERBB2 (35%). Patients with amplifications in cell cycle-related genes showed inferior median progression-free survival (PFS) than those without amplifications (2.07 months vs. 8.40 months; HR = 5.24; 95% CI 2.11–13.01; p < 0.001), particularly in HER2-low patients (2.07 months vs. 8.27 months; HR = 4.23; 95% CI 1.50–11.91; p = 0.004). Additionally, ERBB2/CDK12 co-amplification exhibited a superior median PFS in all patients (19.33 months vs. 5.43 months; HR = 0.13; 95% CI 0.04–0.45; p < 0.001) and in HER2-positive patients (19.33 months vs. 6.87 months; HR = 0.18; 95% CI 0.05–0.72; p = 0.007). Multivariate analysis indicated that amplification in cell cycle-related genes was an independent predictor of inferior PFS (HR = 4.46; 95% CI 1.08–18.40; p = 0.039), while the presence of ERBB2/CDK12 co-amplification was independently correlated with superior PFS (HR = 0.16; 95% CI 0.04–0.65; p = 0.010).

Conclusions

Amplification in cell cycle genes may contribute to primary resistance of HER2 ADC in HER2-low breast cancer. ERBB2/CDK12 co-amplification may be a potential biomarker for favorable responses in HER2-positive breast cancer.
Multi-disciplinary treatment of broncho-esophageal fistula in a high-risk single-lung patient
Authors: Haaverstad Rune , Ovrebo Kjell , Sandvik Lorentz , Seland Håvard , Husebø Gunnar Reksten , Ellensen Vegard Skalstad , Farstad Marit , Strandenes Eivind , Sharma Rajinder , Øksnes Marianne , Storesund Anders Kjellevold , Kolseth Solveig Moss
Published: January 2025

Background

A broncho-esophageal fistula (BEF) is a medical and surgical disaster. Treatment of BEF is often limited to palliative stent treatment that may migrate or cause erosions and tissue necrosis. Surgical repair of BEF is the only established definite treatment.

Case presentation

BEF presented in a 40-year-old female patient 8 years after curative treatment with pneumonectomy and radio-chemotherapy for advanced lung cancer. She had autoimmune comorbidity, a single lung, vocal cord paralysis and an extremely hostile thorax. Multi-disciplinary collaboration, close patient involvement and evaluation by the hospital medical ethics committee were key elements in the following treatment course. After temporary stent treatment, a carefully staged surgical marathon was performed: Veno-venous ECMO was established to secure oxygenation, and bilateral thoracotomy and laparotomy performed to access structures in the frozen mediastinum. After extensive thoracoplasty and high-risk dissection, esophagectomy was performed and the 20 × 35 mm bronchial defect repaired by bronchoplasty with a latissimus muscle flap. It was complicated by thrombotic occlusion of the upper venous system, repeated postoperative bleedings and critical illness neuropathy. The patient recovered and was discharged 150 days after surgery. Within 1–2 years bronchoscopy showed a smooth undiscernible bronchoplasty with a stable open left main bronchus. At 5 years the patient lives an independent life at home with her family.

Conclusions

Surgical treatment of BEF in an extremely complex patient may turn out successfully. It demands careful ethical considerations, comprehensive surgical strategy, multi-disciplinary teamwork, and shared decision making with the patient. The patient presented in this case report is closely followed up with good life quality after 5 years.
Specific plasma metabolite profile in intestinal Behçet’s syndrome
Authors: Hou Cheng-cheng , Bao Hua-fang , She Chun-hui , Chen Hua-yu , Pan Guan-xing , Chen Hua-ning , Rui Hong-bing
Published: January 2025

Background

Intestinal Behçet’s syndrome (IBS) has high morbidity and mortality rates with serious complications. However, there are few specific biomarkers for IBS. The purposes of this study were to investigate the distinctive metabolic changes in plasma samples between IBS patients and healthy people, active IBS and inactive IBS patients, and to identify candidate metabolic biomarkers which would be useful for diagnosing and predicting IBS.

Methods

In this study, we performed a global untargeted metabolomics approach in plasma samples from 30 IBS patients and 20 healthy subjects. P value < 0.05 and variable importance projection (VIP) values > 1 were considered to be statistically significant metabolites. Univariate receiver operating characteristic (ROC) curve analysis was plotted as a measure for assessing the clinical performance of metabolites, and area under curve (AUC) were assessed.

Results

A total of 147 differentially abundant metabolites (DAMs) were identified between IBS patients and normal control (NC) group. The potential pathways involved in the pathogenesis of IBS include linoleic acid metabolism; GABAergic synapse; biosynthesis of unsaturated fatty acids; valine, leucine and isoleucine biosynthesis; ovarian steroidogenesis; and others. In addition, a total of 103 significant metabolites were selected to distinguish active IBS from inactive IBS patients. Tyrosine metabolism, dopaminergic synapse and neuroactive ligand-receptor interaction were found to be closely related to the disease activity of IBS. Furthermore, three potential metabolites including quinate, stearidonic acid (SDA) and capric acid (CA) could significantly differ IBS patients from NC group. On the other hand, 1-methyladenosine (m1A), genipin, methylmalonic acid (MMA) and ascorbate could significantly differentiated active IBS from inactive IBS patients.

Conclusion

In conclusion, this study demonstrated the characteristic plasma metabolic profiles between IBS group and NC group, as well as between active and inactive IBS patients by using an untargeted LC/MS metabolomics profiling approach. In this study, quinate, SDA and CA were identified as potential diagnostic biomarkers for IBS. Additionally, m1A, genipin, MMA and ascorbate could serve as potential biomarkers for evaluating IBS activity. These findings might provide potential valuable insights for developing therapeutic strategies to manage IBS in the future.
Unraveling the genetic spectrum of inherited deaf-blindness in Portugal
Authors: Machado Telma , Cortinhal Telmo , Carvalho Ana Luísa , Teixeira-Marques Francisco , Silva Rufino , Murta Joaquim , Marques João Pedro
Published: January 2025

Background

Syndromic genetic disorders affecting vision can also cause hearing loss, and Usher syndrome is by far the most common etiology. However, many other conditions can present dual sensory impairment. Accurate diagnosis is essential for providing patients with genetic counseling, prognostic information, and appropriate resources. This study aimed to describe the genetic profile of combined inherited deaf-blindness in Portugal.

Methods

This was a cross-sectional study conducted at a tertiary hospital in Portugal. Patients were identified through the national, web-based inherited retinal dystrophies registry (IRD-PT, retina.com.pt). Demographics, clinical, and genetic data were retrieved from individual patient records. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for solved cases.

Results

Eighty-four patients (58.3% males; mean age 40.0 ± 17.9 years) from 71 families were included. Usher syndrome was the most frequent etiology (71.4%) followed by Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome (6.0%), Autosomal dominant optic atrophy plus (4.8%) and cone-rod dystrophy and hearing loss (4.8%). Other less frequent etiologies included Alport syndrome (2.4%), Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (2.4%), Heimler syndrome (2.4%), Senior-Loken syndrome (1.2%), Waardenburg syndrome (1.2%), Maternally inherited diabetes and deafness (1.2%), and Stickler syndrome (1.2%). The overall diagnostic yield of deleterious variants in our deaf–blind cohort was 73.2%. A total of 55 genetic variants were identified across 16 different genes; 11 of these variants are novel and herein reported for the first time.

Conclusions

This is the first study to describe the genetic profile of patients with dual sensory impairment in Portugal, highlighting the genetic heterogeneity associated with inherited deaf-blindness. Usher syndrome was the most prevalent cause in this cohort. Nevertheless, several other less frequent causes must also be considered. This study showed a high diagnostic yield and reported 11 novel genetic variants, thereby contributing to expand the mutational spectrum of these conditions.
RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models
Authors: Lin Yingqi , Li Caijuan , Chen Yizhi , Gao Jiale , Li Jiawei , Huang Chunhui , Liu Zhaoming , Wang Wei , Zheng Xiao , Song Xichen , Wu Jianhao , Wu Jiaxi , Luo Oscar Junhong , Tu Zhuchi , Li Shihua , Li Xiao-Jiang , Lai Liangxue , Yan Sen
Published: January 2025

Background

HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention.

Methods

The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness.

Results

CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs.

Conclusions

These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.
Automatic segmentation model and machine learning model grounded in ultrasound radiomics for distinguishing between low malignant risk and intermediate-high malignant risk of adnexal masses
Authors: Liu Lu , Cai Wenjun , Zheng Feibo , Tian Hongyan , Li Yanping , Wang Ting , Chen Xiaonan , Zhu Wenjing
Published: January 2025

Objective

To develop an automatic segmentation model to delineate the adnexal masses and construct a machine learning model to differentiate between low malignant risk and intermediate-high malignant risk of adnexal masses based on ovarian-adnexal reporting and data system (O-RADS).

Methods

A total of 663 ultrasound images of adnexal mass were collected and divided into two sets according to experienced radiologists: a low malignant risk set (n = 446) and an intermediate-high malignant risk set (n = 217). Deep learning segmentation models were trained and selected to automatically segment adnexal masses. Radiomics features were extracted utilizing a feature analysis system in Pyradiomics. Feature selection was conducted using the Spearman correlation analysis, Mann–Whitney U-test, and least absolute shrinkage and selection operator (LASSO) regression. A nomogram integrating radiomic and clinical features using a machine learning model was established and evaluated. The SHapley Additive exPlanations were used for model interpretability and visualization.

Results

The FCN ResNet101 demonstrated the highest segmentation performance for adnexal masses (Dice similarity coefficient: 89.1%). Support vector machine achieved the best AUC (0.961, 95% CI: 0.925–0.996). The nomogram using the LightGBM algorithm reached the best AUC (0.966, 95% CI: 0.927–1.000). The diagnostic performance of the nomogram was comparable to that of experienced radiologists (p > 0.05) and outperformed that of less-experienced radiologists (p < 0.05). The model significantly improved the diagnostic accuracy of less-experienced radiologists.

Conclusions

The segmentation model serves as a valuable tool for the automated delineation of adnexal lesions. The machine learning model exhibited commendable classification capability and outperformed the diagnostic performance of less-experienced radiologists.

Critical relevance statement

The ultrasound radiomics-based machine learning model holds the potential to elevate the professional ability of less-experienced radiologists and can be used to assist in the clinical screening of ovarian cancer.

Key Points

We developed an image segmentation model to automatically delineate adnexal masses.

We developed a model to classify adnexal masses based on O-RADS.

The machine learning model has achieved commendable classification performance.

The machine learning model possesses the capability to enhance the proficiency of less-experienced radiologists.

We used SHapley Additive exPlanations to interpret and visualize the model.

Graphical Abstract
Decoding the future: a bibliometric exploration of blockchain in logistics
Authors: Fernández Moreno Mª Del Valle , Alcántara-Pilar Juan Miguel , Tolentino Marta
Published: January 2025

This paper presents the results of a bibliometric analysis concerning the application of blockchain technology to logistics. It aims to discern the relational structure among past and current topics, predict emerging trends, and provide a longitudinal perspective on this research domain. Using co-word analysis techniques, we employ SciMAT software to analyze over 800 papers from 2016 to March 2023. The investigation enhances the understanding of blockchain technology, revealing that scientific production in this area revolves around eight primary thematic clusters. Visual representations of the results are provided through longitudinal maps and strategic diagrams, illustrating pivotal themes across the three study periods: blockchain and sustainability. Smart contracts emerge as a focal topic in the final period under consideration.
Civil society organisations and the local politics of migration: how funding contexts matter
Authors: Lang Christine , Badenhoop Elisabeth
Published: January 2025

Migration studies have highlighted the crucial role of civil society organisations (CSOs) in the local politics of migration. Less explored is the impact of the material conditions under which CSOs operate. And yet CSOs delivering public services to migrant and racialised populations often rely on public funding which has been significantly restructured since neoliberal welfare reforms in many Western countries in the 1990s. This article examines how funding contexts shape the opportunities of CSOs to influence local policymaking on migration and migration-related change from a cross-country and cross-city comparative perspective. Based on the empirical analysis of four cities in France and Germany and a comprehensive dataset comprising interviews, observations and documents, we argue that funding contexts significantly impact on CSOs’ potential to shape local policymaking. They do so by enhancing and restricting (1) CSOs’ access to spaces of policymaking as well as (2) CSOs’ capacities for political engagement. We demonstrate the mediating importance of specific funding structures and politics at both national and local scales as well as the role of state-CSO relations in manifesting and reproducing these funding contexts.
‘This settlement is just a launch pad to move to better city spaces’: radical sense of place and migration aspirations among youth migrants in the diaspora
Authors: Bhanye Johannes , Matamanda Abraham , Shayamunda Ruvimbo
Published: January 2025

This ethnographic study investigates the perceptions of place and migration aspirations among young migrants within the Malawian diaspora in Lydiate, an informal settlement in Zimbabwe. Unlike traditional conceptions of diaspora that emphasize long-term settlement and place attachment, this study introduces the concept of a ‘radical sense of place,’ where the settlement is viewed not as a permanent home but as a temporary staging ground for future aspirations. Through qualitative data collected between 2018 and 2020, including participant observations and in-depth interviews with young migrants aged 15 to 35, this research explores how these youths strategically navigate their socio-economic marginalization. The findings reveal that young migrants perceive their settlement as a launch pad to better opportunities in more affluent urban areas, driven by a combination of harsh living conditions and the allure of urban life. This perspective challenges existing migration theories by highlighting the temporary and strategic relationships with place among diaspora youths. The study also highlights the interplay between age, identity, and aspirations, showcasing the pivotal role these factors play in shaping the radical decisions of young migrants. While young migrants exhibit resilience in the migration process, they also face social exclusion, lack of social protection, and the risk of abuse and discrimination. The study advocates for policies tailored to address the specific conditions and vulnerabilities faced by youths in diaspora ethnic enclaves, promoting avenues for meaningful employment and advocating for youth migration based on informed choices rather than forced migration.