bluuebunny/crossref_metadata_2025_split huggingface dataset:
BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome
Authors: Miller Kerry A , Cruz Walma David A , Pinkas Daniel M , Tooze Rebecca S , Bufton Joshua C , Richardson William , Manning Charlotte E , Hunt Alice E , Cros Julien , Hartill Verity , Parker Michael J , McGowan Simon J , Twigg Stephen R F , Chalk Rod , Staunton David , Johnson David , Wilkie Andrew O M , Bullock Alex N 
Published: January 2024

IntroductionKCTD15encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.MethodsExome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution withinKCTD15led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein.ResultsA heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain ofKCTD15was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures.ConclusionBTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.
Risk stratification of delayed causative aneurysm detection and long-term outcome in angiographically negative spontaneous subarachnoid haemorrhage
Authors: Wang Jie , Meng Jian-Feng , Wang Shuo , Zhao Ji-Zong , Cao Yong 
Published: January 2024

BackgroundThe risk factors of aetiology and poor outcome in angiographically negative subarachnoid haemorrhage (anSAH) were unclearly.MethodsThe authors performed a retrospective review of a prospectively maintained database for anSAH patients between 2014 and 2018. AnSAH was defined as SAH presents in CT with no underlying vascular abnormality on initial digital subtraction angiography (DSA) within 72 hours of admission. Baseline and follow-up information, including medical history, bleeding pattern (perimesencephalic angiogram-negative SAH (PAN-SAH) and non-PAN-negative SAH (NPAN-SAH)), modified Fisher Scale (mFS), Glasgow Coma Score (GCS), Hunt-Hess grade, repeated imaging and causative vascular lesions and follow-up modified Rankin Scale (mRS) were reviewed. Poor outcome was defined as mRS scored 3–6 at last clinical follow-up.ResultsAmong 303 enrolled patients, 272 patients underwent at least once repeated imaging examination (median follow-up time, 3.0 months). Twenty-one (7.7%) aneurysms were detected. Multivariate logistic analysis showed that NPAN-SAH and mFS 3–4 were associated with a high rate of aneurysm detection in anSAH patients. Based on risk stratification, the aneurysm detection rate in the high-risk group (both NPAN-SAH and mFS 3–4) was as high as 20.370 per 100 person-years. Furthermore, of 251 non-aneurysm anSAH patients, after a total follow-up time of 1265.83 patient-years, poor outcome occurred in 18 (7.2%) patients. Multivariate Cox analysis found that NPAN-SAH and GCS 3–12 were associated with a high rate of poor outcome of anSAH. The cumulative 5-year incidence rate for poor outcome in the non-aneurysm anSAH patients in the high-risk group (both NPAN-SAH and GCS 3–12) was as high as 75.302 per 100 person-years.ConclusionsEven in anSAH confirmed by initial DSA, patients with NPAN-SAH and mFS 3–4 should be monitored for delayed causative aneurysm detection, meanwhile in non-aneurysm anSAH patients, NPAN-SAH and initial functional impairment are associated with poor prognosis.
Anisotropic power-law inflation for models of non-canonical scalar fields non-minimally coupled to a two-form field
Authors: Pham Tuyen M. , Nguyen Duy H. , Do Tuan Q. , Kao W. F. 
Published: January 2024

AbstractIn this paper, we investigate the validity of the so-called cosmic no-hair conjecture in the framework of anisotropic inflation models of non-canonical scalar fields non-minimally coupled to a two-form field. In particular, we focus on two typical k-inflation and Dirac–Born–Infeld inflation models, in which we find a set of exact anisotropic power-law inflationary solutions. Interestingly, these solutions are shown to be stable and attractive during an inflationary phase using the dynamical system analysis. The obtained results indicate that the non-minimal coupling between the scalar and two-form fields acts as a non-trivial source of generating stable spatial anisotropies during the inflationary phase and therefore violates the prediction of the cosmic no-hair conjecture, even when the scalar field is of non-canonical forms. In connection with the Planck 2018 data, tensor-to-scalar ratios of these anisotropic solutions are investigated. As a result, it appears that the tensor-to-scalar ratio of the anisotropic power-law inflationary solution of k-inflation model turns out to be more highly consistent with the Planck 2018 data than that of Dirac-Born-Infeld model.
The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer
Authors: Kumarasamy Vishnu , Wang Jianxin , Frangou Costakis , Wan Yin , Dynka Andrew , Rosenheck Hanna , Dey Prasenjit , Abel Ethan V. , Knudsen Erik S. , Witkiewicz Agnieszka K. 
Published: January 2024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacologic inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures. On the basis of CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as a target to enhance the therapeutic response to MRTX1133 by regulating mechanotransduction signaling and YAP/TAZ expression, which was confirmed by gene-specific knockdown and combinatorial drug synergy. Interestingly, MRTX1133 was considerably more efficacious in 3D cell cultures. Moreover, MRTX1133 elicited a pronounced cytostatic effect in vivo and controlled tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition led to tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicated that MRTX1133-mediated KRAS inhibition enhanced IFNγ signaling and induced antigen presentation that modulated the tumor microenvironment. Further investigation of the immunologic response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and -extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of patients with PDAC.

Significance:
Pharmacologic inhibition of KRAS elicits varied responses in pancreatic cancer 2D cell lines, 3D organoid cultures, and xenografts, underscoring the importance of mechanotransduction and the tumor microenvironment in regulating therapeutic responses.
Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M. 
Published: January 2024

Abstract

Purpose:
We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models.

Experimental Design:
We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis.

Results:
Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest.

Conclusions:
Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.
Model-Informed Clinical Pharmacology Profile of a Novel Fixed-Dose Combination of Nivolumab and Relatlimab in Adult and Adolescent Patients with Solid Tumors
Authors: Zhao Yue , Hu Zheyi , Bathena Sai Praneeth , Keidel Sarah , Miller-Moslin Karen , Statkevich Paul , Bello Akintunde , Roy Amit , Suryawanshi Satyendra 
Published: January 2024

Abstract

Purpose:
Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 mg fixed-dose combination (FDC) every 4 weeks (Q4W) versus nivolumab alone in patients with previously untreated advanced melanoma in RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response with nivolumab plus relatlimab in previously treated patients. Here, we evaluate the clinical pharmacology profile (CPP) of nivolumab plus relatlimab to support the approved regimen for adult and adolescent patients with advanced melanoma and its continued clinical development in solid tumors.

Experimental Design:
The pharmacokinetics (PK) and immunogenicity of relatlimab and nivolumab were assessed using data from RELATIVITY-047 and RELATIVITY-020. Patients with advanced solid tumors received relatlimab alone or nivolumab plus relatlimab as single-agent vials (SAV) or FDC. PK was characterized using a population PK (popPK) model.

Results:
Relatlimab demonstrated nonlinear and time-varying PK. Nonlinearity in relatlimab PK represented approximately 31% of total CL of relatlimab 160 mg Q4W. Relatlimab PK was dose proportional at doses ≥160 mg Q4W. Geometric mean exposures were similar for SAV and FDC cohorts receiving equivalent dosing regimens. No dose adjustment was required for covariates. Incidence of relatlimab antidrug antibodies was &lt;6% for nivolumab plus relatlimab and had no clinically meaningful impact. There was no PK-related drug interaction of nivolumab plus relatlimab.

Conclusions:
The CPP of relatlimab alone or in combination with nivolumab supports the approved dosing in advanced melanoma and the continued evaluation of nivolumab and relatlimab across other solid tumors.
See related commentary by Gopalakrishnan and Amaria, p. 2862
Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A
Authors: Huang Dan , Wu Zhipeng , Wu Zhengyi , Li Nuoya , Hao Liang , Li Kuangfan , Zeng Junquan , Qiu Bingbing , Zhang Shouhua , Yan Jinlong 
Published: January 2024

Abstract
In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.
Reperfusion in Patients With ST-Segment–Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times
Authors: van Diepen Sean , Zheng Yinggan , Senaratne Janek M. , Tyrrell Benjamin D. , Das Debraj , Thiele Holger , Henry Timothy D. , Bainey Kevin R. , Welsh Robert C. 
Published: January 2024

BACKGROUND:
In patients with ST-segment–elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times.

METHODS:
In a retrospective analysis of geographically extensive ST-segment–elevation myocardial infarction network (2006–2021), 426 patients with cardiogenic shock and ST-segment–elevation myocardial infarction presented to a non–PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment–elevation.

RESULTS:

Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment–elevation <1 mm (57.3% versus 46.3%;
P
=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment–elevation resolution ≥50% (77.4% versus 81.8%;
P
=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26–0.72];
P
<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14–1.09];
P
=0.08).

CONCLUSIONS:
In patients with ST-segment–elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.
Cardiac Arrest Following Drug Overdose in the United States: An Analysis of the Cardiac Arrest Registry to Enhance Survival
Authors: Shekhar Aditya C. , Nathanson Brian H. , Mader Timothy J. , Coute Ryan A. 
Published: January 2024

Background
Given increases in drug overdose‐associated mortality, there is interest in better understanding of drug overdose out‐of‐hospital cardiac arrest (OHCA). A comparison between overdose‐attributable OHCA and nonoverdose‐attributable OHCA will inform public health measures.

Methods and Results

We analyzed data from 2017 to 2021 in the Cardiac Arrest Registry to Enhance Survival (CARES), comparing overdose‐attributable OHCA (OD‐OHCA) with OHCA from other nontraumatic causes (non‐OD‐OHCA). Arrests involving patients <18 years, health care facility residents, patients with cancer diagnoses, and patients with select missing data were excluded. Our main outcome of interest was survival with good neurological outcome, defined as Cerebral Performance Category score 1 or 2. From a data set with 537 100 entries, 29 500 OD‐OHCA cases and 338 073 non‐OD‐OHCA cases met inclusion criteria. OD‐OHCA cases involved younger patients with fewer comorbidities, were less likely to be witnessed, and less likely to present with a shockable rhythm. Unadjusted survival to hospital discharge with Cerebral Performance Category score =1 or 2 was significantly higher in the OD‐OHCA cohort (OD: 15.2% versus non‐OD: 6.9%). Adjusted results showed comparable survival with Cerebral Performance Category score =1 or 2 when the first monitored arrest rhythm was shockable (OD: 28.9% versus non‐OD: 23.5%,
P
=0.087) but significantly higher survival rates with Cerebral Performance Category score =1 or 2 for OD‐OHCA when the first monitored arrest rhythm was nonshockable (OD: 9.6% versus non‐OD: 3.1%,
P
<0.001).

Conclusions
Among patients presenting with nonshockable rhythms, OD‐OHCA is associated with significantly better outcomes. Further research should explore cardiac arrest causes, and public health efforts should attempt to reduce the burden from drug overdoses.
Use of Direct‐Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Significant Tricuspid Regurgitation
Authors: Yang Yujin , Kim Mijin , Kim Jun , Cho Min Soo , Lee Sahmin , Song Jong‐Min , Kim Dae‐Hee 
Published: January 2024

Background
There are limited data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation with significant tricuspid regurgitation (TR), which can lead to hepatic dysfunction and intestinal malabsorption. We aimed to compare the efficacy and safety of DOACs and warfarin for patients with atrial fibrillation with significant (moderate to severe) TR.

Methods and Results

A total of 1215 patients with significant TR and atrial fibrillation who were treated with warfarin (N=491) or DOACs (N=724) were retrospectively analyzed. The primary outcomes were ischemic stroke, systemic embolic events, and hospitalization for major bleeding. The secondary outcomes were intracranial hemorrhage, hospitalization for gastrointestinal bleeding, all‐cause mortality, and a composite outcome. The median follow‐up duration was 2.4 years. In the inverse probability treatment weighting–adjusted cohort, DOACs and warfarin had a similar risk for ischemic stroke and systemic embolic events (adjusted hazard ratio [aHR], 0.95 [95% CI, 0.67–1.36];
P
=0.79) and major bleeding (aHR, 0.78 [95% CI, 0.57–1.06];
P
=0.11). For the secondary outcomes, relative to warfarin, DOACs had a lower risk of intracranial hemorrhage and the composite outcome, and a comparable risk for gastrointestinal bleeding and all‐cause mortality. In the subgroup analysis, the effects of DOACs on ischemic stroke and systemic embolic events were comparable to the effects of warfarin, even in patients with inferior vena cava plethora (increased right atrial pressure) or severe TR.

Conclusions
In this study, relative to warfarin, DOACs demonstrated comparable efficacy for ischemic stroke and systemic embolic events and major bleeding, with a lower intracranial hemorrhage risk in patients with significant TR and atrial fibrillation, indicating their effectiveness and safety.
Prospective Observational Study for the Comparison of Screening Methods Including Tongue Pressure and Repetitive Saliva Swallowing With Detailed Videofluoroscopic Swallowing Study Findings in Patients With Acute Stroke
Authors: Nakamori Masahiro , Imamura Eiji , Maetani Yuta , Yoshida Mitsuyoshi , Yoshikawa Mineka , Nagasaki Toshikazu , Masuda Shin , Kayashita Jun , Mizoue Tatsuya , Wakabayashi Shinichi , Maruyama Hirofumi , Hosomi Naohisa 
Published: January 2024

Background
Simple, noninvasive, and repeatable screening methods are essential for assessing swallowing disorders. We focused on patients with acute stroke and aimed to assess the characteristics of swallowing screening tests, including the modified Mann Assessment of Swallowing Ability score, tongue pressure, and repetitive saliva swallowing test (RSST), compared with detailed videofluoroscopic swallowing study (VFSS) findings to contribute as a helpful resource for their comprehensive and complementary use.

Methods and Results
We enrolled first‐ever patients with acute stroke conducting simultaneous assessments, including VFSS, modified Mann Assessment of Swallowing Ability score, tongue pressure measurement, and RSST. VFSS assessed aspiration, laryngeal penetration, oral cavity residue, vallecular residue, pharyngeal residue, and swallowing reflex delay. Screening tests were compared with VFSS findings, and multiple logistic analysis determined variable importance. Cutoff values for each abnormal VFSS finding were assessed using receiver operating characteristic analyses. We evaluated 346 patients (70.5±12.6 years of age, 143 women). The modified Mann Assessment of Swallowing Ability score was significantly associated with all findings except aspiration. Tongue pressure was significantly associated with oral cavity and pharyngeal residue. The RSST was significantly associated with all findings except oral cavity residue. Receiver operating characteristic analyses revealed that the minimum cutoff value for all VFSS abnormal findings was RSST ≤2.

Conclusions
The modified Mann Assessment of Swallowing Ability is useful for broadly detecting swallowing disorders but may miss mild issues and aspiration. The RSST, with a score of ≤2, is valuable for indicating abnormal VFSS findings. Tongue pressure, especially in oral and pharyngeal residues, is useful. Combining these tests might enhance accuracy of the swallowing evaluation.