bluuebunny/crossref_metadata_2025_split huggingface dataset:
HDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAFV600E-mutant microsatellite stable colorectal cancer
Authors: Sun Zhuang , Shi Mengyuan , Xia Jinhong , Li Xin , Chen Nan , Wang Hanyang , Gao Zhaoya , Jia Jinying , Yang Peng , Ji Dengbo , Gu Jin 
Published: January 2025

BackgroundB-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.MethodsWe first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAFV600EMSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAFV637Emouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice.ResultsDrug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAFV600EMSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAFV600EMSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate–adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells’ DNA mismatch repair capacity. Notably, BRAFV600EMSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1+cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8+T-cell infiltration.ConclusionsOur findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAFV600E-mutant MSS CRC, warranting further investigation in clinical settings.
Utilization of primary tumor samples for cancer neoantigen discovery
Authors: Leko Vid , Groh Eric , Levi Shoshana T , Copeland Amy R , White Bradley Sinclair , Gasmi Billel , Li Yong , Hill Victoria , Gurusamy Devikala , Levin Noam , Kim Sanghyun Peter , Sindiri Sivasish , Gartner Jared J , Prickett Todd D , Parkhust Maria , Lowery Frank J , Goff Stephanie L , Rosenberg Steven A , Robbins Paul 
Published: January 2025

BackgroundThe use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.MethodWhole-exome sequencing was conducted on matched primary and metastatic colorectal cancer samples from 22 patients. The distribution of metastatic tumor mutations that were confirmed as neoantigens through cognate TIL screening was evaluated in the corresponding primary tumors. Mutations unique to primary tumors were screened for recognition by metastasis-derived TIL and circulating T lymphocytes.ResultsWe found that 25 (65.8%) of the 38 validated neoantigens identified in metastatic tumors from 18 patients with colorectal cancer were also present in matched primary tumor samples. This included all 12 neoantigens encoded by putative cancer driver genes, which are generally regarded as superior targets for adoptive cell therapy. The detection rate for other neoantigens, representing mutations without an established role in cancer biology, was 50% (13/26). Gene products encoding neoantigens detected in the primary tumors were not more likely to be clonal or broadly distributed among the analyzed metastatic lesions compared with those undetected in the primary tumors. Additionally, we found that mutations detected only in primary tumor samples did not elicit recognition by metastatic tumor-derived TIL but could elicit specific recognition by the autologous circulating memory T cells.ConclusionsOur findings indicate that primary FFPE tumor-derived screening libraries could be used to discover most neoantigens present in metastatic tumors requiring treatment. Furthermore, this approach can reveal additional neoantigens not present in resected metastatic tumors, prompting further research to understand their clinical relevance as potential therapeutic targets.
Association between left ventricular reverse remodelling and the B-type natriuretic peptide–cGMP cascade after anterior acute myocardial infarction
Authors: Arai Marina , Asaumi Yasuhide , Honda Satoshi , Ogata Soshiro , Kiyoshige Eri , Nakao Kazuhiro , Miura Hiroyuki , Morita Yoshiaki , Nakashima Takahiro , Murai Kota , Iwai Takamasa , Sawada Kenichiro , Matama Hideo , Fujino Masashi , Takahama Hiroyuki , Yoneda Shuichi , Takagi Kensuke , Otsuka Fumiyuki , Kataoka Yu , Nishimura Kunihiro , Noguchi Teruo , Minamino Naoto , Yasuda Satoshi 
Published: January 2025

BackgroundThe role of cyclic guanosine 3′,5′-monophosphate (cGMP) after acute myocardial infarction (AMI) is not well understood despite its significance as a second messenger of natriuretic peptides (NPs) in cardiovascular disease. We investigated the association between the NP-cGMP cascade and left ventricular reverse remodelling (LVRR) in anterior AMI.Methods67 patients with their first anterior AMI (median age, 64 years; male, 76%) underwent prospective evaluation of plasma concentrations of the molecular forms of A-type and B-type natriuretic peptide (BNP) and cGMP from immediately after primary percutaneous coronary intervention (PPCI) to 10 months post-AMI. The estimated mature BNP (emBNP) concentration was calculated as the difference between total BNP and prohormone of BNP (proBNP) concentrations. Patients were divided into LVRR and non-LVRR groups on the basis of residuals between observed change in left ventricular end-systolic volume index on MR during the first 11 months after AMI and change adjusted for proBNP concentration immediately post-PPCI, which was calculated with regression. The LVRR group (n=33) had residuals below the median; the non-LVRR group (n=34) had residuals at or above the median.ResultsThe LVRR group had higher freedom from major adverse cardiac and cerebrovascular events (MACCEs) than the non-LVRR group during a median follow-up of 9.9 years (p=0.008). The presence of LVRR (HR 0.256; 95% CI 0.081 to 0.809; p=0.028) and peak creatine phosphokinase–myocardial band level (per 100 IU/L) (HR 1.22; 95% CI 1.02 to 1.46; p=0.027) were independent predictors of MACCE after adjusting for age, male sex, infarct size and hypertension. Multivariable analyses identified logarithmic proBNP and emBNP concentrations from 12 hours to 5 days post-AMI and logarithmic cGMP concentration from immediately post-PPCI to 3 days post-AMI as independent predictors of LVRR (p<0.05).ConclusionsEarly-phase BNP-cGMP cascade activation might play a crucial role in LVRR in anterior AMI.
Can aortic valve calcium score predict a need for permanent pacemaker implantation after transcatheter aortic valve implantation?
Authors: Barbe Thomas , Fauvel Charles , Hemery Thibaut , Le Pessec Guillaume , Tron Christophe , Bouhzam Najime , Bettinger Nicolas , Burdeau Julie , Makke Jade , Laissac Quentin , Dacher Jean-Nicolas , Eltchaninoff Helene , Durand Eric 
Published: January 2025

IntroductionConductive disturbances requiring permanent pacemaker (PPM) implantation remain a major concern after transcatheter aortic valve implantation (TAVI).AimsTo assess the impact of aortic valve calcium score (AVCS) on conductive disturbances requiring PPM after TAVI.MethodsAll patients who underwent TAVI with accessible AVCS from the preprocedural CT scan report were included in this retrospective single-centre study. The primary endpoint was the occurrence of a conductive disturbance requiring PPM at 30 days. The association between PPM and AVCS, with its incremental prognostic value, was analysed using multivariable logistic regression, receiver operating characteristic curve analysis and likelihood ratio (LR) test.ResultsWe included 761 patients of which 125 (16%) required PPM at 30 days. AVCS score was significantly higher in patients requiring PPM (3788 (2487–5218) vs 3050 (2043–4367) AU, p<0.001). Using multivariable analysis, preprocedural right bundle branch block (RBBB) (OR 6.61, 95% CI 3.82 to 11.5, p<0.001), first atrioventricular block (OR 1.71, 95% CI 1.03 to 2.83, p=0.037), self-expanding valve (OR 3.25, 95% CI 1.17 to 9.09, p=0.025) and AVCS>4510 AU (OR 1.83, 95% CI 1.04 to 3.20, p=0.035) were independently associated with PPM. AVCS had an incremental discriminative value (C-index 0.79 vs 0.77, LR test p=0.036) over and above traditional PPM risk factors. An algorithm was proposed based on the initial presence of RBBB, AVCS and the type of implanted valve.ConclusionEven if RBBB remained the strongest predictor of PPM post-TAVI, this study suggests that a high AVCS may help identifying patients at increased risk of PPM after TAVI, especially among those without pre-existing RBBB.
End-to-end deep-learning model for the detection of coronary artery stenosis on coronary CT images
Authors: Gupta Vibha , Petursson Petur , Rawshani Aidin , Boren Jan , Ramunddal Truls , Bhatt Deepak L , Omerovic Elmir , Angerås Oskar , Smith Gustav , Sattar Naveed , Andersson Erik , Redfors Björn , Hilgendorf Lukas , Bergström Göran , Pirazzi Carlo , Skoglund Kristofer , Rawshani Araz 
Published: January 2025

PurposeWe examined whether end-to-end deep-learning models could detect moderate (≥50%) or severe (≥70%) stenosis in the left anterior descending artery (LAD), right coronary artery (RCA) or left circumflex artery (LCX) in iodine contrast-enhanced ECG-gated coronary CT angiography (CCTA) scans.MethodsFrom a database of 6293 CCTA scans, we used pre-existing curved multiplanar reformations (CMR) images of the LAD, RCA and LCX arteries to create end-to-end deep-learning models for the detection of moderate or severe stenoses. We preprocessed the images by exploiting domain knowledge and employed a transfer learning approach using EfficientNet, ResNet, DenseNet and Inception-ResNet, with a class-weighted strategy optimised through cross-validation. Heatmaps were generated to indicate critical areas identified by the models, aiding clinicians in understanding the model’s decision-making process.ResultsAmong the 900 CMR cases, 279 involved the LAD artery, 259 the RCA artery and 253 the LCX artery. EfficientNet models outperformed others, with EfficientNetB3 and EfficientNetB0 demonstrating the highest accuracy for LAD, EfficientNetB2 for RCA and EfficientNetB0 for LCX. The area under the curve for receiver operating characteristic (AUROC) reached 0.95 for moderate and 0.94 for severe stenosis in the LAD. For the RCA, the AUROC was 0.92 for both moderate and severe stenosis detection. The LCX achieved an AUROC of 0.88 for the detection of moderate stenoses, though the calibration curve exhibited significant overestimation. Calibration curves matched probabilities for the LAD but showed discrepancies for the RCA. Heatmap visualisations confirmed the models’ precision in delineating stenotic lesions. Decision curve analysis and net reclassification index assessments reinforced the efficacy of EfficientNet models, confirming their superior diagnostic capabilities.ConclusionOur end-to-end deep-learning model demonstrates, for the LAD artery, excellent discriminatory ability and calibration during internal validation, despite a small dataset used to train the network. The model reliably produces precise, highly interpretable images.
Diabetes is associated with a higher incidence of short-term mortality risk and readmission in patients who undergo surgical but not transcatheter aortic valve replacement
Authors: D Souza Ahston , Bsheish Khalifa , Dargham Soha , Jayyousi Amin , Al Suwaidi Jassim , Abi Khalil Charbel 
Published: January 2025

BackgroundTranscatheter aortic valve replacement (TAVR) is increasingly used for aortic valve replacement instead of surgical aortic valve replacement (sAVR). We aimed to examine the impact of diabetes on 30-day mortality, 30-day readmission and compare outcomes between TAVR and sAVR.MethodsData were extracted from the Nationwide Readmissions Database from 2012 to 2017. The primary outcome was 30-day mortality, and the secondary outcome was 30-day readmission.ResultsThe study included 110 135 patients who underwent aortic valve replacement. Of these, 59 466 (54.0%) were hospitalised for TAVR, and 50 669 (46.0%) underwent sAVR. Diabetes was present in 36.4% of TAVR patients and 29.1% of sAVR patients. In TAVR patients, the adjusted risk of 30-day readmission and mortality was similar regardless of diabetes status (aHR=0.94 (0.86–1.03); 0.97 (0.84–1.12); respectively). However, sAVR patients with diabetes had a higher adjusted risk of 30-day mortality (aHR=1.13 (1.01–1.25)) but not readmission (aHR=0.92 (0.84–1.01)). When comparing outcomes between TAVR and sAVR in patients with diabetes, TAVR patients were older and had a higher prevalence of chronic kidney disease (CKD). Nevertheless, 30-day readmission and mortality were lower in patients who underwent TAVR (aHR=0.59 (0.53–0.67), aHR=0.29 (0.25–0.34), respectively) compared with sAVR. Coronary artery disease was the most significant predictor of readmission in patients with diabetes. CKD increased the risk of mortality by almost twofold in both techniques.ConclusionDiabetes increases the risk of short-term mortality in sAVR but not TAVR. Moreover, the incidence of 30-day mortality and readmission is lower in TAVR compared with TAVR among patients with diabetes.
Evaluation of three diagnostic algorithms to reduce normal scan rates, radiation exposure and costs in patients with suspected chronic coronary syndrome referred for 82Rb-Positron Emission Tomography (82Rb-PET)
Authors: Frey Simon M , Huré Gabrielle , Leibfarth Jan-Philipp , Thommen Kathrin , Amrein Melissa L , Schaefer Ibrahim , Rumora Klara , Schneider Igor G , Caobelli Federico , Wild Damian , Haaf Philip , Mahfoud Felix , Müller Christian , Zellweger Michael J 
Published: January 2025

BackgroundThe majority of functional ischemia tests in patients with suspected chronic coronary syndromes (CCS) yield normal results. Implementing gatekeepers for patient preselection, such as pretest probability (PTP) and/or coronary artery calcium score (CACS), could reduce the number of normal scan results, radiation exposure and costs. However, the efficacy and safety of these approaches remain unclear.MethodsThree diagnostic algorithms based on PTP, as summarised in the 2019 European Society of Cardiology (ESC) CCS guidelines, were retrospectively applied to 1792 patients with suspected CCS referred for 82Rb-Positron Emission Tomography (82Rb-PET): (1) defer testing if PTP ≤5%; (2) defer if PTP <15%; and (3) defer if PTP ≤5% or PTP 5–15% and CACS 0. The proportion of missed ischemia, number of scans and reduction of normal scan results, radiation exposure and costs were compared with the current gold standard (CACS+PET in every patient). Endpoints were defined as small ischemia (SDS ≥2) and relevant ischemia (≥10% of myocardium).ResultsThe mean age of the patients was 65±11 years, and 43% were female. PTP ≤5% and <15% were present in 7.5% and 41.0%, respectively. Algorithm 1 reduced scans, radiation and costs by 7.5% without significantly missing ischemia (sensitivity/negative predictive value (NPV) 98.6%/99.7%). Algorithm 2 showed the largest reduction (41.0%), but sensitivity was significantly reduced (80.2%). Algorithm 3 demonstrated optimal performance, reducing radiation by 17.0% and costs by 17.3% without significantly missing ischemia suggesting excellent safety (sensitivity/NPV 98.0%/99.5%).ConclusionUsing a diagnostic algorithm combining PTP and CACS (algorithm 3), the number of normal scan results, radiation exposure and costs could be significantly reduced without a significant increase in missed diagnoses suggesting similar outcome and excellent patients safety. Consequently, this approach could help to optimally allocate limited healthcare resources while maintaining patient’s safety.
Diagnostic accuracy in coronary CT angiography analysis: artificial intelligence versus human assessment
Authors: Bernardo Rachel , Nurmohamed Nick S , Bom Michiel J , Jukema Ruurt , de Winter Ruben W , Sprengers Ralf , Stroes Erik S G , Min James K , Earls James , Danad Ibrahim , Choi Andrew D , Knaapen Paul 
Published: January 2025

BackgroundVisual assessment of coronary CT angiography (CCTA) is time-consuming, influenced by reader experience and prone to interobserver variability. This study evaluated a novel algorithm for coronary stenosis quantification (atherosclerosis imaging quantitative CT, AI-QCT).MethodsThe study included 208 patients with suspected coronary artery disease (CAD) undergoing CCTA in Perfusion Imaging and CT Coronary Angiography With Invasive Coronary Angiography-1. AI-QCT and blinded readers assessed coronary artery stenosis following the Coronary Artery Disease Reporting and Data System consensus. Accuracy of AI-QCT was compared with a level 3 and two level 2 clinical readers against an invasive quantitative coronary angiography (QCA) reference standard (≥50% stenosis) in an area under the curve (AUC) analysis, evaluated per-patient and per-vessel and stratified by plaque volume.ResultsAmong 208 patients with a mean age of 58±9 years and 37% women, AI-QCT demonstrated superior concordance with QCA compared with clinical CCTA assessments. For the detection of obstructive stenosis (≥50%), AI-QCT achieved an AUC of 0.91 on a per-patient level, outperforming level 3 (AUC 0.77; p<0.002) and level 2 readers (AUC 0.79; p<0.001 and AUC 0.76; p<0.001). The advantage of AI-QCT was most prominent in those with above median plaque volume. At the per-vessel level, AI-QCT achieved an AUC of 0.86, similar to level 3 (AUC 0.82; p=0.098) stenosis, but superior to level 2 readers (both AUC 0.69; p<0.001).ConclusionsAI-QCT demonstrated superior agreement with invasive QCA compared to clinical CCTA assessments, particularly compared to level 2 readers in those with extensive CAD. Integrating AI-QCT into routine clinical practice holds promise for improving the accuracy of stenosis quantification through CCTA.
Automated electronic health record-based screening for Fabry disease in unexplained left ventricular hypertrophy (FAPREV-HCM)
Authors: Lau Kolja , Sokalski Victoria , Lorenz Lora , Fette Georg , Sommer Claudia , Üçeyler Nurcan , Wanner Christoph , Nordbeck Peter 
Published: January 2025

Background and aimsHypertrophic cardiomyopathy (HCM) has various aetiologies, including genetic conditions like Fabry disease (FD), a lysosomal storage disorder. FD prevalence in high-risk HCM populations ranges from 0.3% to 11.8%. Early diagnosis of FD is crucial due to available treatments, but its rarity and diverse symptoms complicate identification. Heart-specific FD variants often lead to late diagnoses due to the absence of typical FD symptoms. This prospective study (NCT04943991) was conducted to identify patients with undiagnosed FD using electronic health records (EHR) at a German tertiary-care hospital.MethodsOver 20 years (2000–2020), 2824 patients with ‘left ventricular hypertrophy (LVH)’ or ‘hypertrophic cardiomyopathy (HCM)’ were identified by full-text search. Exclusion criteria were age over 85, other diagnosed cardiomyopathies, significant valvular heart disease, death, active malignancy and prior FD testing. The remaining patients received an invitation for FD genetic testing.ResultsOf the 2824 identified patients, 2626 (93%) fulfilled the exclusion criteria. Among the 198 included patients, 96 responded, and 55 underwent genetic testing, yielding a response rate of 48% and a testing rate of 28%. In one patient (1.8% of tested), FD was diagnosed with thep.N215Svariant. Subsequent family screening revealed six additional FD cases, with four initiating FD-specific therapies. Comprehensive clinical evaluations were conducted in five of the seven identified patients.ConclusionsGenetic testing of patients with unexplained LVH/HCM using EHR is effective for identifying FD. Subsequent family screening further identified at-risk individuals, promoting regular follow-ups and if needed FD-specific therapies. This approach highlights the potential for broader application in high-risk populations to uncover treatable genetic conditions. The next phase should focus on automating the executed search process.Trial registration numberNCT04943991.
SAFE-GOALS: a protocol for goals of care discussions in the intensive care unit
Authors: Velez David Ray , Irons Thomas Dresser , Opimo Anthony Brando , Brown Emily , Foley Doug , Velez Jamie Lynn , McNickle Allison G 
Published: January 2025

IntroductionIn critical care, there is often a lack of understanding regarding patient preferences toward end-of-life care. Goals of care discussions are poorly defined and inhibited by clinician apprehension, prognostic uncertainty, and discomfort from both sides. In the delivery of bad news, protocol-based discussions have proven beneficial, yet no such protocol exists for goals of care discussions in the intensive care unit (ICU). We therefore assembled a multidisciplinary team to define a specific protocol dedicated to leading goals of care discussions in the ICU setting.SAFE-GOALS protocolS: set upA: acknowledgmentF: family understandingE: events of hospital courseG: get to know the patientO: optionsAL: active listening and discussionS: steps going forwardConclusionThis protocol provides a framework for leading goals of care conversations in the ICU. Specific training should be incorporated and better emphasized in the modern medical education.
Πίστις—‮פסטס‬‎
Authors: Monnickendam Yifat 
Published: January 2025

Abstract
The term pistis, in its legal context, refers to various forms of trusts, loans, securities, credits, guarantees, and means of inheritance. One of its uses in Greek Egyptian papyri was interpreted as referring to title-transfer security or to fictitious ownership. This paper adds rabbinic sources from Greco-Roman Palestine to the discussion on pistis. The comparison sheds light on the rabbinic sources, as well as expands our understanding of the use and spread of a Greek legal term and concept in the eastern Roman Empire. It therefore serves as a test case for the importance of rabbinic literature as a source in the study of Greek and Roman legal traditions, supplying new evidence for using this term as referring to fictitious ownership and for its use as referring to title-transfer security. This use of the term pistis changes in the Babylonian Talmud, preserving only echoes of its original meaning.