bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural compounds target the M23B zinc metallopeptidase Mpg to modulate
Neisseria gonorrhoeae
Type IV pilus expression
Authors: Nicholson Kathleen R. , Yin Shaohui , Edwards Jennifer L. , Luan Chi-Hao , Seifert H Steven
Published: February 2025

Neisseria gonorrhoeae
uses the Type IV pilus (T4p) to colonize several sites within humans by adhering to host cells and tissues. Previously, we identified a periplasmic M23B zinc metallopeptidase, Mpg, that is necessary to protect from oxidative and nonoxidative killing and these phenotypes are mediated by Mpg activities on T4p expression. Here, we use a high-throughput, target-based screening approach to identify novel inhibitors of Mpg’s enzymatic activity. We identified two natural compounds, punicalagin and chebulinic acid, which inhibit the peptidoglycan-hydrolyzing activity of Mpg in a dose-dependent manner. Moreover, treatment of
N. gonorrhoeae
with these compounds leads to a concomitant decrease in the number of T4p, similar to an
mpg
mutant. However, these compounds are not toxic to
N. gonorrhoeae
. These compounds exhibit activity against Mpg orthologs from other bacterial species. Notably, these natural compounds inhibit
N. gonorrhoeae
colonization and survival in cell culture models of infection. This work provides the characterization of two natural compounds with activity against
N. gonorrhoeae
T4p through the Mpg M23B class zinc metallopeptidase.

IMPORTANCE

Neisseria gonorrhoeae
is a global health burden with high transmission rates and multidrug resistance.
N. gonorrhoeae
encodes a Type IV pilus (T4p), which is a major colonization and virulence factor. The importance of the T4p in multiple stages of infection makes it an attractive drug target. Previously, we identified an M23B zinc metallopeptidase, Mpg, important for T4p production and T4p-mediated resistance to neutrophil killing. In this study, we identified two natural compounds, punicalagin and chebulinic acid, as novel inhibitors of Mpg’s enzymatic activity that thus inhibit T4p expression. These findings identify two potential anti-colonization and anti-virulence compounds and provide a framework to target T4p components for future screens, poising the field to potentially discover additional compounds to combat
N. gonorrhoeae
infection.
A novel function of short cationic peptide FP-CATH9 without antimicrobial activity reverses resistance to minocycline in common multidrug-resistant gram-negative bacteria
Authors: Tang Yingqi , Liu Jiye , Yan Jiani , Xie Zhixiong , Zhong Lipeng
Published: February 2025

The increase in bacterial resistance to minocycline and other tetracyclines poses a serious threat to global public health. Because the development of new antibiotics has proven problematic, antibiotic sensitization therapy is now an effective coping strategy. While antimicrobial peptides generally exhibit broad-spectrum antibacterial activity and good biocompatibility, naturally truncated portions of antimicrobial peptides (such as snake cathelicidin) often do not exhibit antimicrobial activity, and their function remains unknown. FP-CATH9 is a short cationic peptide derived from FP-CATH (snake cathelicidin antimicrobial peptide) with an amphiphilic α-helical structure and no discernible antibacterial activity. However, FP-CATH9 was previously found to significantly enhance the activity of minocycline against gram-negative bacteria. In the present paper, clinically relevant minocycline-resistant gram-negative bacteria (
Escherichia coli
,
Klebsiella pneumoniae
,
Acinetobacter baumannii
, and
Pseudomonas aeruginosa
) were used as test bacteria for antibiotic sensitization screening. The sensitization activity of FP-CATH9 was found to be dose dependent in a double-dilution assay. The synergistic activity of FP-CATH9 on minocycline was subsequently determined using the checkerboard method. An ethidium bromide efflux test revealed that FP-CATH9 caused an accumulation of minocycline in bacteria. Additionally, FP-CATH9 exhibited low hemolytic activity on red blood cells and low cytotoxicity on Raw264.7 cells. In an
in vivo
model of bacterial infection, FP-CATH9 combined with minocycline exhibited an 80% protective effect on
Galleria mellonella
larvae infected with multidrug-resistant
K. pneumoniae
. In summary, FP-CATH9 is a new antibiotic adjuvant that reverses the resistance of gram-negative bacteria to minocycline by increasing intracellular accumulation of minocycline. This finding has broad application potential.

IMPORTANCE

The existence of the efflux pump system enables bacteria to expel antibiotics, reduce the concentration of antibiotics in cells, and make antibiotics unable to effectively inhibit or kill bacteria, which is one of the main mechanisms of bacterial resistance to antibiotics. However, some efflux pumps are substrate specific, while others are with a wide range of substrates. In this study, FP-CATH9 as a new antibiotic adjuvant can specifically reverse the resistance of gram-negative bacteria to minocycline by increasing the intracellular accumulation of minocycline in bacteria and provides a new way to solve the increasing problem of bacterial drug resistance.
Supplemental Material: Tracking ancient unconformity development with martite (U-Th)/He thermochronometry
Authors: Jensen Jordan , Ault Alexis
Published: February 2025

Sampling and analytical methods information, including data files for (U-Th)/He, electron backscatter diffraction, and Raman analyses. 
Supplemental Material: Tracking a common mantle source: From southwest Iberia to the Madeira-Canarias Islands
Authors: Pereira Ricardo , al. et
Published: February 2025

(1) Detailed methodology used in this work; (2) a summary table with the magmatic occurrences within the Central-East Atlantic Alkaline Province, showing the geochronological data used in this work, along with its references; (3) supplemental figures that show the different paleogeographic reconstructions; and (4) a video showing the tectonic plates moving over a fixed mantle upwelling, from which the multiple magmatic manifestations were derived. 
A Study of the Influence of Packaging Material on the Development of a Pattern in Semi-hard Cheeses Produced Using Propionic Acid Bacteria
Authors: Rogov G. N. , Smirnova T. S. , Kartashov S. I. , Kovalishina D. A. , Kalmykova M. V. , Namsaraev Z. B.
Published: February 2025

Propionic acid bacteria play an important role in the formation of a pattern on cheese produced using them. In recent years, cheese producers have actively used the rindless technology for its ripening, which has made it difficult to obtain a pre-defined cheese pattern. The influence of the type of packaging material, the ripening temperature in the main chamber, and the salting technology on the process of pattern formation in semi-hard cheese with the involvement of propionic acid bacteria has been studied. The pattern in cheese was analyzed using the non-destructive method of magnetic resonance imaging. Our studies have shown that, the pattern formation during the production of semi-hard cheeses using propionic acid bacteria weighing 5–7 kg and a mass moisture fraction of 44–45% depends on the gas permeability of the polymer material used for cheese ripening and on the temperature in the main ripening chamber. The lowest amount of gas was formed when using a polymer material with a carbon dioxide permeability of 50 cm3/(m2 day). The best result was observed when cheese was ripened in packages with CO2 permeability above 1750 cm3/(m2 day) at a temperature of 24°C in the main ripening chamber. The lowering of the temperature in the main chamber to 18°C reduces the volume of formed gas by 5 times. It has also been established that the decrease in the permeability of the polymer material for carbon dioxide from 1750 to 750 cm3/(m2 day) has little effect on the development of a pattern in cheese. Increasing the salt concentration gradient in the surface layer of cheese reduces the volume of eyes formed in the subrind layer, thereby reducing the potential for defects in the finished product.
Metastatic breast cancer diagnosed on upper gastrointestinal endoscopy
Authors: LIM Annabelle Xiao Hui , Ellis-Owen Rwth , Morgan Meleri , Abdalla Badr
Published: February 2025

A woman in her late 60s was referred with a positive faecal immunochemical test and change in bowel habit; a suspicion of gastrointestinal (GI) cancer led to straight-to-test vetting for colonoscopy, which was unsuccessful due to a nontraversable, fixed sigmoid colon, secondary to prior hysterectomy and adhesions.

Radiological evaluation with CT scanning revealed an abnormally thickened stomach, with subsequent upper GI endoscopy and biopsy findings confirming the presence of invasive poorly differentiated carcinoma consistent with metastatic invasive lobular carcinoma originating from the breast. Immunohistochemistry testing for gross cystic disease fluid protein was positive, and the tumour demonstrated positive oestrogen receptor status, while human epidermal growth factor receptor 2 status was negative. The immunohistochemical profile of this carcinoma was identical to that observed in synchronous breast cores, indicating metastatic invasive lobular carcinoma of the breast.

This unusual presentation of breast cancer metastasis is not well recognised.
Dry and dusty outback: infant botulism
Authors: Grant Patricia , Legge Alexandra A , Gonzalez Aranzazu , Carmo Kathryn Browning
Published: February 2025

Infant botulism is a rare but life-threatening neuroparalytic syndrome caused by intestinal colonisation ofClostridium botulinumresulting in a symmetrical descending flaccid paralysis. This gram-positive, rod-shaped anaerobic bacillus is universally found in soil with previous links to ingestion of honey and dust contaminated withC. botulinumspores. We present a case of a baby boy with this rare condition eventually linked to dust on a rural outback property. This young patient was ventilated for 90 days. Initial serology for botulism toxin was negative, althoughC. botulinumspores were eventually grown in the stool. The patient did not receive early treatment with Human Botulism Immune Globulin Intravenous (BIG-IV) as there was a low index of suspicion and a delay in obtaining a stool sample for nearly 6 weeks due to constipation. This case highlights the importance of early treatment with BIG-IV when clinical features and environmental conditions in the remote Australian outback favour persistence ofC. botulinumspores in soil without awaiting confirmatory tests.
Young child with MuSK myasthenia gravis: treatment and remission with rituximab
Authors: Santarosa Julia , Cartwright Michael
Published: February 2025

Myasthenia gravis is an autoimmune disorder characterised by autoantibodies directed against postsynaptic receptors of the neuromuscular junction. Muscle-specific tyrosine kinase (MuSK) myasthenia gravis is a subtype of myasthenia gravis containing antibodies specific to the MuSK subunit of the motor endplate. MuSK myasthenia gravis tends to display a severe clinical course, and most patients are refractory to treatment. Paediatric MuSK myasthenia gravis is exceedingly rare and is typically managed with pyridostigmine, corticosteroids and intravenous immunoglobulin or plasmapheresis for acute crisis control. This report discusses a case of a 4-year-old girl diagnosed with MuSK myasthenia gravis who was treated with rituximab. She is one of the youngest children in the literature to receive rituximab for this condition, and she continues to show favourable outcomes. This case demonstrates the safety and efficacy of this treatment in paediatric patients diagnosed with MuSK myasthenia gravis.
Integrative anticoagulation of nafamostat mesylate in double plasma molecular adsorption system plus sequential half-dose plasmapheresis for patients with liver failure: a randomised controlled trial protocol
Authors: Sun Xiankun , Wang Fang , Chen Zhiwen , Liao Juan , Yang Yingying , Bai Lang , Zhang Ling
Published: February 2025

Introduction

Nafamostat mesylate (NM) is widely recognised as a premier anticoagulant, especially in Japan and Korea. However, it has not yet been used as an anticoagulant in double plasma molecular adsorption system (DPMAS) plus sequential half-dose plasmapheresis (PE) therapy. This study aims to comprehensively evaluate the safety and efficacy of NM-integrated anticoagulation during DPMAS plus sequential half-dose PE therapy for patients with liver failure.

Methods and analysis

A two-arm, open-label, parallel, randomised controlled trial involving 132 patients with liver failure will be conducted in China. Eligible participants will be randomly allocated to either the nafamostat mesylate integrative anticoagulation group or the heparin integrative anticoagulation group, employing a central randomisation system at a 1:1 ratio throughout the course of DPMAS plus sequential half-dose PE therapy. The primary outcome includes the number of successfully completed DPMAS plus sequential half-dose PE therapy. The secondary outcomes include liver function indicators, extracorporeal circulation pressures, coagulation function parameters, all-cause mortality rates and survival rates. Clinical safety will be assessed by analysis of the number of bleeding events, the number of clotting events and adverse events. Outcome analyses will be performed on both the intention-to-treat population, which includes all patients randomised, and the per-protocol population, which includes eligible patients who adhere to the planned treatment and follow-ups.

Ethics and dissemination

The trial protocol was approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (approval number (2022)860). During the protocol revision process, all changes were reexamined and reapproved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University. The results will be presented at national and international conferences and published in peer-reviewed journals.

Trial registration number

ChiCTR2200064725.
Non-malignant gynaecological disease and risk of cardiovascular or cerebrovascular disease: a systematic review and meta-analysis
Authors: Colombo Giorgia Elisabeth , Mahamat-Saleh Yahya , Armour Mike , Madan Kedar , Sabag Angelo , Kvaskoff Marina , Missmer Stacey A , Condous George , Pathan Faraz , Leonardi Mathew
Published: February 2025

Background

Cardiovascular disease is the leading cause of death globally. Non-malignant gynaecological diseases (NMGD) significantly affect patient health and well-being and may be associated with cardiovascular or cerebrovascular disease (C/CVD).

Methods

Seven databases were searched for relevant studies up to 21 April 2024. Observational studies reporting risk estimates and 95% CIs for the association between NMGD and C/CVD were included. Data were extracted by two independent reviewers. Random effects models were used to calculate summary relative risk (SRR) with 95% CI. Composite C/CVD outcome was defined as a combination of ischaemic heart disease, cerebrovascular disease, heart failure, and peripheral vascular disease. The ROBINS-I tool defined study quality and risk of bias.

Results

We screened 6639 studies, of which 59 were eligible for full-text review and 28 were included in our analysis, comprising a total of 3 271 242 individuals. The majority (53.5%) of the studies were scored as having a ‘serious’/‘critical’ risk of bias. Overall, individuals with an NMGD had a significantly greater risk of composite C/CVD with low heterogeneity among contributing studies (SRR 1.28, 95% CI 1.20 to 1.37; n=16 studies, I2=65.3%), ischaemic heart disease (SRR 1.41, 95% CI 1.31 to 1.51; n=21 studies, I2=73.7%), and cerebrovascular disease (SRR 1.33, 95% CI 1.18 to 1.51; n=16 studies, I2=91.5%). In NMGD-specific analyses, the risk of C/CVD and its components was greater among those with a history of endometriosis or polycystic ovary syndrome.

Conclusions

We found an overall association between NMGD and C/CVD across all studies. However, estimates from individual studies varied substantially.
Developing and testing the predictive validity of household firearm storage measures: insights from rural Alaska
Authors: Sokol Rebeccah , Mueller-Williams Amelia , Porter Kelsey , Leys Megan , Apala Flaherty Aneliese , Wexler Lisa
Published: February 2025

Introduction

Measuring change in firearm storage is paramount to evaluating if interventions influence storage. Yet, there is little empirical basis for how to measure this change. This methodology study compared three different firearm storage measures using data from the Family Safety Net trial (n=46), a randomised controlled trial among firearm-owning adults in a rural Alaska Native community to encourage unloaded and locked firearm storage.

Methods

The team compared baseline and 1-month follow-up measures of household firearm storage: (1) cumulative firearm accessibility, (2) average firearm accessibility, and (3) number of unlocked firearms. All measures included information about locking status; the cumulative and average firearm accessibility measures incorporated additional information about ammunition. Unadjusted and adjusted generalised estimating equations evaluated the associations of the storage measures with adult perceptions of youth firearm access. Receiver operating characteristic curves from unadjusted models compared the measures’ abilities to predict adult perceptions of youth firearm access.

Results

All household firearm storage measures were sensitive to change between baseline and 1 month follow-up (ps<0.05). These measures demonstrated a similar and moderate ability to predict adult perceptions of youth access (area under the curve range: 0.68–0.76).

Conclusion

The number of unlocked firearms is an easily interpretable outcome when evaluating the effect of firearm storage interventions on storage practices, and it performed similarly well in predicting adults’ perceptions of youth firearm access as compared with more complex measures. Research that evaluates the ability of firearm storage measures to predict actual youth access will inform interventions to prevent youth firearm access.
Do scoring systems help us to estimate prognosis after mechanical thrombectomy? Data from the German Stroke Registry
Authors: Hahn Marianne , Gröschel Sonja , Paul Roman , Weitbrecht Luis , Protopapa Maria , Reder Sebastian , Othman Ahmed E , Gröschel Klaus , Uphaus Timo
Published: February 2025

Background

Numerous scoring systems have been developed to individualize estimation of functional outcome after endovascular thrombectomy (EVT) of acute ischemic stroke. The aim of our study was to assess their utility for clinical practice based on a large cohort from real-world care of EVT.

Methods

For 13 082 patients included in the German Stroke Registry Endovascular Treatment (GSR-ET) (July 2015 to December 2021), we calculated the following prognostic tools: pre-interventional PRE-, Totaled Health Risks in Vascular Events – Endovascular therapy (THRIVE-EVT)- and Computed Tomography for Late Endovascular Reperfusion (CLEAR) scores and post-interventional MR PREDICTS@24 hours and BET-score. Area under the receiver operating characteristic curve (AUC) analyses in the total cohort and pre-defined subgroups were performed to determine each tool’s prognostic value for good functional outcome (modified Rankin Scale (mRS) 0–2) and mortality at 90-day follow-up.

Results

All pre-interventional tools achieved a moderate prognostic value for predicting good functional outcome (PRE: AUC (95% confidence interval): 0.757 (0.747–0.768), THRIVE-EVT: 0.751 (0.740–0.761), CLEAR: 0.731 (0.72–0.742)), had a higher predictive value than the admission National Institute of Health Stroke Scale ((NIHSS); 0.705 (0.694–0.716), all P<0.001), but were inferior to the NIHSS 24 hours after EVT (0.864 (0.855–0.872), all P<0.001). Predictive capacity for mortality was less accurate (AUC range: 0.697–0.729). Subgroup analyses revealed that the PRE-score was most robust at predicting good functional outcome, whereas the THRIVE-EVT score was superior in predicting mortality. Post-interventionally, MR PREDICTS@24 hours yielded high predictive accuracy for good functional outcome and mortality (both AUC >0.85), superior to 24-hour NIHSS for all subgroups, except patients <50 years of age.

Conclusion

Pre-interventional scoring tools predict functional outcome after EVT better than stroke severity alone. Post-interventionally, the MR PREDICTS@24 hours tool adds predictive value to the 24-hour NIHSS as a single prognostic feature. Multivariate prognostic tools incorporating (post-)procedural information enable individualization of prognosis assessment after EVT under routine-care conditions.
Safety and efficacy of tirofiban versus traditionaldualantiplatelettherapy in endovasculartreatment of intracranialaneurysms: asystematicreview and meta-analysis
Authors: Xiao ZhenKun , Hu XuYi , Deng LiangJie , Liu JianHua , Liu Aihua
Published: February 2025

Background

The selection of antiplatelet agents plays a crucial role in ensuring the safety and efficacy of endovascular treatment for intracranial aneurysms (IA). Currently, the primary agents used include tirofiban and traditional dual antiplatelet therapy (DAPT). Due to the lack of high-level consolidated evidence in this field, we conducted the first systematic review and meta-analysis aimed at comparing the safety and efficacy of tirofiban vs traditional DAPT in the endovascular treatment of IA.

Methods

Studies published before November 1, 2024, were searched in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials. The primary outcome was thrombosis, and secondary outcomes included intracranial hemorrhage (ICH), non-intracranial bleeding events (NoICH-BE), ischemic stroke (IS), and follow-up prognosis. Relative risks (RRs) were synthesized for comparison between tirofiban and DAPT groups.

Results

Nine studies involving 2481 patients were included. Tirofiban significantly reduced the risk of thrombosis compared with DAPT (RR, 0.292; 95% CI, 0.174 to 0.492; P<0.001). It did not increase risks of ICH (RR, 0.633; P=0.125), NoICH-BE (RR, 0.253; P=0.259), IS (RR, 0.730; P=0.172), or poor prognosis (RR, 0.981; P=0.896).

Conclusion

Tirofiban effectively lowers the risk of thrombosis without increasing bleeding or adverse prognosis risks compared with DAPT. It shows promise as an alternative antiplatelet therapy for IA treatment, but further large-scale studies are needed to confirm these findings.
Examining tissue-level changes in Doxorubicin accumulation and Nitric Oxide formation in skeletal muscle and tumours in a mouse model of breast cancer
Authors: McCue Meghan Victoria , Rebalka Irena A. , Hawke Tom , MacLean David A
Published: February 2025

Introduction: Doxorubicin is a commonly used chemotherapy that rapidly accumulates in skeletal muscle and disrupts nitric oxide (NO) formation. However, studies investigating these effects have largely been performed in tumour-free models, therefore it remains unknown whether intramuscular accumulation and disruptions to nitric oxide content persist during tumour growth.

Methodology: Female C57bl/6 mice (n = 8/group) were randomly assigned to true control, Doxorubicin control, tumour only, or tumour plus Doxorubicin groups. Tumours were grown for 21, 24, or 28 days using E0771 cells. Doxorubicin was administered as a single 10 mg/kg intraperitoneal dose on day 21.

Results: Doxorubicin accumulation was similar in muscle with and without tumours present. Doxorubicinol, a metabolite of Doxorubicin, was elevated (p<0.05) in 24-day tumour+Doxorubicin compared to Doxorubicin alone. NO was similar across all groups in muscle; however, tumour NO was 15-fold higher at day 21 compared to 24, or 28 days (p<0.05).

Conclusion: The results confirm that Doxorubicin is sequestered in skeletal muscle when a tumour is present, which may impact bioavailability. Tumour growth transiently increased intramuscular Doxorubicinol, potentially exacerbating the toxicity of the drug. Earlier stage tumour growth appeared to profoundly elevate NO, which could suggest temporal angiogenesis and vasodilation to facilitate growth.
Single-particle spectrum of doped $$\textrm{C}_{20}\textrm{H}_{12}$$-perylene
Authors: Rodekamp Marcel , Berkowitz Evan , Gäntgen Christoph , Krieg Stefan , Luu Thomas , Ostmeyer Johann , Pederiva Giovanni
Published: February 2025

We present a Hamiltonian Monte Carlo study of doped perylene

$$\textrm{C}_{20}\textrm{H}_{12}$$

C
20

H
12

described with the Hubbard model. Doped perylene can be used for organic light-emitting diodes (OLEDs) or as acceptor material in organic solar cells. Therefore, central to this study is a scan over charge chemical potential. A variational basis of operators allows for the extraction of the single-particle spectrum through a mostly automatic fitting procedure. Finite chemical potential simulations suffer from a sign problem which we ameliorate through contour deformation. The on-site interaction is kept at

$$\nicefrac {U}{\kappa }=2$$

U
κ

=
2

. Discretization effects are handled through a continuum limit extrapolation. Our first-principles calculation shows significant deviation from non-interacting results especially at large chemical potentials.

Graphic abstract
On scale-separated supersymmetric $$\hbox {AdS}_2$$ flux vacua
Authors: Cribiori Niccolò , Farakos Fotis , Liatsos Nikolaos
Published: February 2025

We argue that scale-separated

$$\hbox {AdS}_2$$

AdS
2

vacua with at least two preserved supercharges cannot arise from flux compactifications in a regime of computational control. We deduce this by showing that the

$$\hbox {AdS}_2$$

AdS
2

scale is parametrically of the same order as the tension of a fundamental BPS domain wall, which provides an upper bound on the UV cutoff. Since the latter does not need to be associated to any geometric scale, the argument excludes scale separation in a broader sense than what commonly considered. Our claim is exemplified by a bottom-up 2D supergravity analysis as well as top-down models from Type II flux compactifications.
From Academia to UX: Embodied Cognition, Creativity, and Generative AI
Authors: Rashedi Roxanne N.
Published: February 2025

The
Interactions
website (interactions.acm.org) hosts a stable of bloggers who share insights and observations on HCI, often challenging current practices. Each issue we'll publish selected posts from some of the leading and emerging voices in the field.
Supplementary figure 6 from Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis
Authors: Kaur Japneet , Adhikari Manish , Sabol Hayley M. , Anloague Aric , Khan Sharmin , Kurihara Noriyoshi , Diaz-delCastillo Marta , Andreasen Christina Møller , Barnes Charles Lowry , Stambough Jeffrey B. , Palmieri Michela , Reyes-Castro Olivia , Zarrer Jennifer , Taipaleenmäki Hanna , Ambrogini Elena , Almeida Maria , O’Brien Charles A. , Nookaew Intawat , Delgado-Calle Jesus
Published: February 2025

Supplementary figure 6
Supplementary figure 14 from Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis
Authors: Kaur Japneet , Adhikari Manish , Sabol Hayley M. , Anloague Aric , Khan Sharmin , Kurihara Noriyoshi , Diaz-delCastillo Marta , Andreasen Christina Møller , Barnes Charles Lowry , Stambough Jeffrey B. , Palmieri Michela , Reyes-Castro Olivia , Zarrer Jennifer , Taipaleenmäki Hanna , Ambrogini Elena , Almeida Maria , O’Brien Charles A. , Nookaew Intawat , Delgado-Calle Jesus
Published: February 2025

Supplementary figure 14
Supplementary figure 11 from Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis
Authors: Kaur Japneet , Adhikari Manish , Sabol Hayley M. , Anloague Aric , Khan Sharmin , Kurihara Noriyoshi , Diaz-delCastillo Marta , Andreasen Christina Møller , Barnes Charles Lowry , Stambough Jeffrey B. , Palmieri Michela , Reyes-Castro Olivia , Zarrer Jennifer , Taipaleenmäki Hanna , Ambrogini Elena , Almeida Maria , O’Brien Charles A. , Nookaew Intawat , Delgado-Calle Jesus
Published: February 2025

Supplementary figure 11
GPR65 inactivation in tumor cells drives antigen-independent CAR-T cell resistance via macrophage remodeling
Authors: Mavuluri Jayadev , Dhungana Yogesh , Jones Lindsay L. , Bhatara Sheetal , Shi Hao , Yang Xu , Lim Song-Eun , Reyes Noemi , Chi Hongbo , Yu Jiyang , Geiger Terrence L.
Published: February 2025

Chimeric antigen receptor (CAR)-T cell therapies, while promising for CD19+ hematological malignancies, often face setbacks due to relapses. Our research identifies GPR65 as a tumor-specific determinant affecting the efficacy of CAR-T cell therapy. In human patients and an immune-competent mouse model of B-cell acute lymphoblastic leukemia (B-ALL), low GPR65 expression correlates with resistance to CD19+ CAR-T treatment. GPR65 knockout (GPR65 KO) tumors in mice similarly exhibit resistance. Through single-cell network analyses, we discovered that GPR65 deficiency reshapes tumor interactions with host macrophages by increasing tumor VEGFA levels, leading to macrophage expansion and preferential M2 polarization. Depleting host macrophages or by deletion of VEGFA in GPR65 KO tumors, restores CAR-T cell therapy responsiveness. Moreover, combining anti-VEGFA therapy with CAR-T cell treatment significantly prolongs the survival of mice bearing GPR65 KO tumors. These findings emphasize the profound impact of tumor gene expression on the tumor microenvironment and subsequent CAR-T cell therapy outcomes.
Impact of epidural anesthesia on the outcome of elderly patients with endometrial cancer – results of a propensity score matched analysis
Authors: Linz Valerie Catherine , Battista Marco Johannes , Hummel Regina , Schepers Markus , Griemert Eva-Verena , Schmidt Mona Wanda , Schmidt Marcus , Hasenburg Annette , Gillen Katharina
Published: February 2025

Introduction: Epidural anesthesia is a standard procedure to mitigate pain during surgery for endometrial cancer (EC). Little data exist about the influence of epidural anesthesia on the oncological outcome in elderly patients with EC. This retrospective study aims to investigate potential correlations between epidural anesthesia and cancer recurrence in patients with EC.
Methods: We screened the medical records of patients ≥ 60 years treated surgically for EC at the University Medical Center Mainz between January 2008 and December 2019. All women underwent general anesthesia (GA) alone or combined with epidural anesthesia (EGA). Cox regression, the Kaplan-Meier method and propensity score matching were used to analyze the prognostic influence of the anesthesiologic regime on survival.
Results: A total of 152 women with EC were included. 29 patients (19.1%) formed the EGA cohort. The median time of follow-up (FU) was 31 months [interquartile range (IQR): 8-67.5]. The EGA cohort showed more in-hospital complications (27.6 vs. 8.9%; p=0.006), especially thromboembolic events (3 vs. 0 events; p=0.006), as well as a longer hospital stay (11 (IQR: 8-13) vs. 7 (IQR: 4-9) days; p <0.001). 26 patients (17.1%) developed a recurrence in the follow-up at a median of 13 months [IQR: 7.75-29.5]. 32 patients died during FU (21.1%). The EGA cohort showed higher FIGO stages and a higher histological grading than the GA cohort. In Kaplan-Meier analysis, EGA showed a significantly reduced 5-year recurrence-free survival (RFS) (36.5% vs. 72.6%, p<0.001) and overall survival (OS) (58.6% vs. 79.9%, p=0.008). However, in multivariate Cox regression analysis including FIGO stages and histological grading, EGA did not influence RFS (HR: 2.02; 95%-CI [0.99-4.12], p=0.054), and OS (HR: 1.03; 95%-CI [0.40-2.66], p=0.951). This was backed up by the propensity score matched analysis for survival (RFS: p=0.604, OS: p=0.86).
Conclusion: Considering risk factors, epidural anesthesia in combination with GA did not differ in recurrence-free and overall survival compared to GA. Prospective randomized trials are warranted in order to further evaluate this topic.
Age-related outcomes of transcatheter aortic valve replacement in patients with pure severe aortic regurgitation
Authors: Fan Jianing , Lin Dawei , Miao Jiaxin , Weng Zilong , Qi Yi-ming , Zhan Zhi , Li Mingfei , Chen Sha-sha , Long Yuliang , Hong Nanchao , Li Yuhao , Zhang Xiaochun , Pan Wenzhi , Zhou Daxin , Ge Junbo
Published: February 2025

Background: Transcatheter aortic valve replacement (TAVR) has emerged as the recommended treatment for older patients with pure severe aortic regurgitation (PSAR). However, the efficacy of TAVR in younger patients with aortic regurgitation (AR) remains unclear. This study explored the therapeutic efficacy and safety of TAVR in these two groups and compared their outcomes.
Methods: Patients with AR who underwent TAVR at Zhongshan Hospital between June 2021 and September 2023 were included and categorized into younger- and older age groups based on whether they were ≥75 years old. The baseline characteristics, clinical test information, and follow-up data of the patients were collected.
Results: A total of 82 patients were included in this study (72.7±7.60 years old, 52[63.4%] male). The younger and older age groups each comprised 41 patients. Young patients had better clinical conditions (diabetes mellitus [0% vs. 17.1%, p=0.006], symptoms [29.3% vs. 70.7%, p=0.025], and permanent pacemaker implantation [PPMI] [0% vs. 9.8%, p=0.040]). Significant improvements in AR as well as left and right heart functions were observed in both groups. A reduced occurrence rate of mild perivalvular leaks (PVL) was observed in the younger age group at the 1-month follow-up visit (2.4% vs. 14.6%; p=0.048).
Conclusion: TAVR is safe and effective for both younger and older patients undergoing PSAR. Younger patients who underwent AR-TAVR experienced fewer perivalvular leaks compared to those experienced by older patients. Therefore, TAVR may be an alternative for younger patients with PSAR. Further Large-scale multicenter prospective studies are needed to validate our findings.
Prognostic impact of coronary calcifications in patients with recently diagnosed prostate cancer
Authors: Stødkilde-Jørgensen Nina , Tinggaard Andreas Bugge , Winther Simon , Sjoeholm-Christensen Andreas , Ejlersen June Anita , Jensen Jørgen Bjerggaard , Böttcher Morten
Published: February 2025

Background. Patients with prostate cancer are at increased risk of cardiovascular events. A non-electrocardiogram gated CT scan of the thorax is part of the diagnostic workup, allowing for assessment of coronary calcifications. However, the prognostic impact of a coronary artery calcium score (CACS) obtained from such CT scans is uncertain.
Objectives. To investigate the association between CACS and a combined endpoint of all-cause death, myocardial infarction, or stroke in patients with recently diagnosed prostate cancer.
Methods. The primary analysis included patients (N=571) with recently diagnosed prostate cancer and without known coronary artery disease undergoing prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT). Patients were stratified into four CACS groups. Cox proportional hazard models adjusted for risk factors were used to examine the association between CACS and the combined endpoint.
Results. Patients were distributed in the four CACS groups as follows: CACS 0-10 (26%), 11-99 (21%), 100-399 (24%) and ≥400 (29%). An increased risk of the combined endpoint was found with increasing CACS. Compared with CACS 0-10, the hazard ratios for CACS 11-99, 100-399 and ≥400 were 0.95 (95% CI: 0.37-2.42), 2.39 (95% CI: 1.13-5.09) and 3.14 (95% CI: 1.52-6.48), respectively. Only 53% of patients in the CACS ≥400 group received statins.
Conclusion. In patients with prostate cancer, assessment of a CACS from the initial PET/CT scan allows for the identification of patients with a threefold higher risk of death, myocardial infarction, or stroke. Initiation of preventive statin treatment in these patients could reduce cardiovascular events.
Fetal Megacystis – A practical guide
Authors: El-Achi Vanessa , Deshpande Aniruddh , Scott Fergus , Smet Maria-Elisabeth
Published: February 2025

Fetal megacystis is the enlargement of the fetal bladder seen on prenatal ultrasound. Diagnosing the underlying cause of fetal megacystis in the antenatal period is often challenging due to the many possible underlying aetiologies, including various obstructive and non-obstructive causes. This review article is a practical guide to help practitioners distinguish between the various causes, counsel and manage fetal megacystis. It summarizes the evidence on each differential diagnosis and highlights the more recent changes to the definitions of megacystsis in the different trimesters.

What’s already known about the topic?
- Detection of fetal megacystis leads to an extensive diagnostic conundrum.
- Counselling, prognostication, and prenatal management may prove challenging.
- Prenatal intervention has been trialled with limited success.
What does this review add?
- A summary of differential diagnoses of fetal megacystis and how to distinguish between them.
- A practical guide to assist with the diagnosis, management and counselling for fetal megacystis in each trimester.
Cytological Diagnosis by Fine-needle Aspiration or Core Biopsy with Touch Preparation for Renal Cystic or Solid Lesions: A single center clinicopathological analysis
Authors: Liu Jiayan , Yang Changwei , Wu Xiaohui , Yang Li , Xu Hong
Published: February 2025

Introduction: A retrospective study analyzed real-life data from a single center cohort of renal fine-needle aspiration (FNA) and core biopsy (CB) with touch preparation (TP) procedures over an 18-year period, aimed to provide a comprehensive overview of the evaluation of cytological diagnostic performance, challenges, and accuracy concerning renal cystic, solid, and mixed cystic-solid lesions. Methods: All percutaneous ultrasound-guided FNA and CT-guided CB with TP performed at our institution from 2006 to 2024 were identified. Results: A total of 89 renal cytology procedures were performed during the study period. Sixty-two (69.7%) lesions displayed cystic radiological features, 20 (22.5%) lesions presented solid mass, and only 7 (7.8%) lesions exhibited mixed cystic-solid radiological features. Of the procedures performed, seventy-five (84.3%) were ultrasound-guided FNA biopsies, while 14 (15.7%) were CT-guided CB with TP. Of the 62 renal cystic lesions, 54 (87.1%) were simple renal cysts. Twelve (60%) in 20 solid lesions were malignant, mainly involving clear cell renal cell carcinoma (RCC), urothelial carcinoma, and collecting duct carcinoma. Cytological diagnoses of renal mixed cystic-solid lesions mainly involved tuberculosis and clear cell RCC. However, only 22 cases had corresponding histopathological specimens available for comparison. The concordance rate between cytologic diagnoses and surgical pathology specimens for cystic, solid, and mixed cystic-solid renal lesions was 100%, 92.3% and 80%, respectively. Conclusion: In our series, FNA or CB with TP demonstrates significant diagnostic utility in the evaluation of renal lesions. The diagnostic accuracy of FNA cytology for renal lesions has been enhanced through the application of immunocytochemical (ICC) staining on cell blocks.
Gut microbiome dysbiosis and inflammatory bowel disease complement each other
Authors: Zhang Huan , Xiang Jingrong , Feng Jie , Zhang Mengting , Xi Qinhua
Published: February 2025

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. The worldwide increase in the incidence of IBD imposes a significant economic burden on patients and communities. Recently, numerous studies have shown that disruption of the balance between the host and microbes, known as dysbiosis, is strongly associated with the development of IBD.
Summary: Dysbiosis can be influenced by diet, lifestyle rhythms, hygiene conditions, drugs, and the inflammatory state of IBD patients. In the microbiome microenvironment, dysbiosis can be influenced by the microbiome and metabolites. Gut microbiome dysbiosis in IBD patients can play a proinflammatory role by disrupting the intestinal barrier and modulating the immune system, leading to the worsening or recurrence of IBD. In future studies, the mechanisms of dysbiosis in IBD and its influencing factors should be investigated from a more macroscopic perspective to propose new valuable diagnostic and therapeutic approaches.
Key Messages: Gut microbiome dysbiosis can lead to the development of inflammatory bowel disease, and inflammatory bowel disease can in turn exacerbate gut microbiome dysbiosis, creating a vicious cycle.
Validity and Reliability of Intraoral OCT and Bitewing Radiography for Detecting Approximal Carious Lesions
Authors: Strumpski Michaela , Schneider Hartmut , Rüger Claudia , Schmidt Jana , Schulz-Kornas Ellen , Haak Rainer
Published: February 2025

Objectives: This in vitro study evaluated the validity and reliability of spectral domain optical coherence tomography (SD-OCT) to detect approximal carious lesions compared to bitewing radiography.
Methods: Forty extracted human premolars and molars with fifty-four unrestored approximal surfaces (ICDAS ll score 0 – 3) were mounted in a patient-equivalent simulator and imaged by digital radiography (DR) and the prototype of an intraoral OCT probe. The lesion status of the tooth surfaces was validated histologically and by microtomography (µCT). Five calibrated raters with low to high level of clinical expertise analyzed the DR and OCT images at intervals of 2 to 4 weeks each. Intra- and interrater agreement (weighted Cohen's kappa κ, Fleiss' kappa), sensitivity, and specificity were calculated.
Results: The sensitivity of OCT (0.66 - 0.91) was higher than that of DR (0.46 - 0.82), as was the specificity (OCT: 0.67 - 0.92; DR: 0.33 - 0.58). Intra-rater agreement with OCT was moderate to substantial (κ: 0.53 - 0.77; p < 0.001) and fair to substantial for DR (κ: 0.36 - 0.78; p < 0.05). The DR interpersonal agreement ranged from slight to substantial (κ: 0.1 - 0.74, Fleiss’-κ: 0.23/0.24; p < 0.001), towards fair to substantial with OCT (κ: 0.27 - 0.62; Fleiss’­κ: 0.23/0.18; p < 0.001). Agreement between histology and µCT was almost perfect (κ: 0.82; p < 0.001).
Conclusions: In a clinically oriented simulation, OCT was more sensitive in detecting early approximal carious lesions than DR without impairing specificity or reproducibility. Clinical studies will have to show whether OCT can confirm these promising results.
Clinical significance: Non-invasive real-time OCT imaging of the approximal spaces may validly and reproducibly supplement established diagnostic procedures for detecting and monitoring early approximal lesions. Training of examiners might further improve the interpretation of OCT images.
ChatGPT-4o in risk of bias assessments in neonatology – a validity analysis
Authors: Kuitunen Ilari , Nyrhi Lauri , De Luca Daniele
Published: February 2025

Background: Only a few studies have addressed the potential of large language models (LLM) in risk of bias assessments and the results have been varying. The aim of this study was to analyze how well ChatGPT performs in risk of bias assessments of neonatal studies.
Methods: We searched all Cochrane neonatal intervention reviews published in 2024 and extracted all risk of bias assessments. Then the full reports were retrieved and uploaded alongside the guidance to perform a Cochrane original risk of bias analysis in ChatGPT-4o. The concordance between the original assessment and that provided by ChatGPT-4o was evaluated by inter-class correlation coefficients and Cohen’s Kappa statistics (with 95% confidence intervals for each risk of bias domain and for the overall assessment.
Results: From nine reviews a total of 61 randomized studies were analyzed. A total of 427 judgements were compared. The overall kappa was 0.43 (95%CI 0.35-0.51) and the overall intraclass correlation coefficient was 0.65 (95%CI: 0.59-0.70). The Cohen’s kappa was assessed for each domain and the best agreement was observed in the allocation concealment (kappa=0.73, 95%CI: 0.55-0.90), whereas the poorest agreement was found in incomplete outcome data (kappa=-0.03, 95%CI: -0.07-0.02).
Conclusion: ChatGPT-4o failed to achieve sufficient agreement in the risk of bias assessments. Future studies should examine whether the performance of other LLM would be better or whether the agreement in ChatGPT-4o could be further enhanced by better prompting. Currently the use of ChatGPT-4o in risk of bias assessments should not be promoted.
Development of a Core Confounder Set for Real-world Essential Hypertension Studies
Authors: Chen Jianrong , Zhou Xu , Chen Rong , Xu Sheng , Li Shuqing , Wang Jiancheng
Published: February 2025

Introduction: This study aimed to establish a core set of confounders for real-world essential hypertension studies to improve the reasonable control of confounding bias.
Methods: Controlled clinical studies of essential hypertension published between January 2001 and June 2020 were retrieved from PubMed. Matched or adjusted confounders from these studies were compiled to form a pool of potential candidates. The importance of each confounder was assessed through Delphi expert consultation, considering its statistical significance for impacting the prognosis of essential hypertension in published studies and its applicability in real-world essential hypertension studies. The most essential confounders were ultimately selected to constitute the core confounder set.
Results: Following a comprehensive literature review and group discussion, a total of 50 confounders were included in the Delphi questionnaire. Twenty-nine cardiologists from across China were invited to participate in the Delphi consultation, and consensus was reached after two rounds of consultation. As a result, a core set of 13 confounders was established comprising three confounders in the demographic characteristic and lifestyle domain, four in the baseline hypertension status domain, three in the comorbidity domain, one in the cointervention domain, and two in the common factor domain (study center and time). Additionally, a recommendation regarding the prioritization of controlling these confounders was formulated.
Conclusion: This study established a core set of confounders for real-world essential hypertension studies that can effectively control confounding bias and are readily accessible. These findings can serve as valuable references for protocol design and data analysis in real-world essential hypertension studies.