bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colorectal and bladder prokinetic activity of [Lys5, MeLeu9, Nle10]-NKA(4–10) after intranasal or sublingual delivery in dogs
Authors: Rupniak Nadia M.J. , Katofiasc Mary A. , Bae Jungeun , Thor Karl B. , Marson Lesley 
Published: January 2023

The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, [Lys5, MeLeu9, Nle10]-NKA(4–10), was examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 µg/kg IN or 2.0–6.7 mg/kg SL increased colorectal peak pressure and area under the curve. Peak bladder pressure was also increased at the same doses, and this was accompanied by highly efficient voiding at normal physiological bladder pressure. The onset of these effects was rapid (≤2.5 min), and the primary contractions lasted ∼25 min, returning to baseline in <60 min. Slight hypotension lasting a few minutes and causing <10% change from baseline was detected after higher doses and was statistically significant after only 100 µg/kg IN. In conscious dogs, there was a dose-related increase in voiding responses and reduction in the latency to urinate and defecate after 300 and 1000 µg/kg IN; emesis was also observed at these doses. SL administration of 6.7 mg/kg induced urination within 10 min, but not defecation or emesis. These findings support the feasibility of developing a convenient dosage form of small peptide NK2 receptor agonists as on-demand defecation or urination therapies.
Holographic anisotropic background in 5D Einstien–Gauss–Bonnet gravity
Authors: Sajadi S. N. 
Published: January 2023

AbstractIn this paper, we extend the work on the AdS/QCD model to quadratic gravity to gain insight into the influence of gravity. We obtain an anisotropic black brane solution to a 5D Einstein–Gauss–Bonnet-two Maxwell-dilaton system. The background is specified by an arbitrary exponent, a dilaton field, a time component of the first Maxwell field, and a magnetic component of the second Maxwell field. The system in three cases has been investigated and in each case the effect of the parameter of theory, the anisotropic parameter has been considered. The blackening function supports the thermodynamical phase transition between small/large and AdS/large black brane for a suitable chemical potential and other parameters.
The shadow of supertranslated black hole
Authors: Zhu Qing-Hua , Han Yu-Xuan , Huang Qing-Guo 
Published: January 2023

AbstractThe supertranslated black hole proposed by Hawking, Perry, and Strominger might provide a resolution to the information paradox, which is usually defined by a complicated space-time metric. In this paper, we figure out the shadow for the supertranslated black hole by making use of supertranslated 4-velocities and the trajectories of the light rays. Based on this approach, although the photon sphere gets distorted and the position of the shadow on the projection plane is shifted by the supertranslation vector due to the supertranslation hairs, the size and shape of the shadow remain the same as those of bald black hole. However, the shift of the position of shadow should be understood by the choice of coordinate and then we conclude that there are no distinguishable effects for the supertranslated black hole.
Pertuzumab, Trastuzumab, and an Aromatase Inhibitor for HER2-Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer: PERTAIN Final Analysis
Authors: Arpino Grazia , de la Haba Rodríguez Juan , Ferrero Jean-Marc , De Placido Sabino , Osborne C. Kent , Klingbiel Dirk , Revelant Valentine , Wohlfarth Christine , Poppe Raf , Rimawi Mothaffar F. ,   for the PERTAIN Study Group
Published: January 2023

AbstractPurpose:In PERTAIN's primary analysis (31 months’ median follow-up), adding pertuzumab to trastuzumab and an aromatase inhibitor (AI) with/without chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated HER2-positive and hormone receptor–positive metastatic or locally advanced breast cancer (M/LABC). A potentially enhanced treatment effect was observed in patients with no induction chemotherapy. We present the final analysis (&gt;6 years’ median follow-up).Patients and Methods:Patients (N = 258) were randomized 1:1 to pertuzumab (loading/maintenance: 840/420 mg) plus trastuzumab (loading/maintenance: 8/6 mg/kg) every 3 weeks and an AI (1 mg anastrozole or 2.5 mg letrozole daily; Arm A), or trastuzumab and an AI (Arm B). Induction chemotherapy was at investigator discretion. Primary endpoint: PFS. Key secondary endpoints: overall survival (OS) and safety.Results:Median PFS was 20.6 versus 15.8 months in Arms A and B, respectively (stratified HR, 0.67; P = 0.006). Median OS was 60.2 versus 57.2 months (stratified HR, 1.05; P = 0.78). Pertuzumab treatment effect was potentially enhanced in patients with no induction chemotherapy (26.6 vs. 12.5 months). Any-grade adverse events (AE) occurred in 122 patients per arm (96.1% vs. 98.4%); grade ≥ 3 AEs in 72 (56.7%) and 51 (41.1%); serious AEs in 46 (36.2%) and 28 (22.6%).Conclusions:The PFS benefit of pertuzumab was maintained and OS was similar between arms at final analysis. Adding pertuzumab may enhance activity in patients who do not require first-line chemotherapy for M/LABC. No new safety concerns were reported. These data provide additional evidence of the role of first-line pertuzumab and trastuzumab in HER2-positive M/LABC.
Viewing RCC with a DNA Methylation Lens ENHANCES Understanding of ICI Resistance
Authors: Zhou Mi , Kim William Y. 
Published: January 2023

SummaryClear-cell renal cell carcinoma tumors with an enhancer demethylator phenotype (TED) harbor a worse prognosis and derive less clinical benefit from immunotherapy. The TED phenotype may help predict immunotherapy resistance.See related article by Lu et al., p. 1279
Mouse Stromal Cells Confound Proteomic Characterization and Quantification of Xenograft Models
Authors: Shi Zhaomei , Mao Binchen , Chen Xiaobo , Hao Piliang , Guo Sheng 
Published: January 2023

Xenografts are essential models for studying cancer biology and developing oncology drugs, and are more informative with omics data. Most reported xenograft proteomics projects directly profiled tumors comprising human cancer cells and mouse stromal cells, followed by computational algorithms for assigning peptides to human and mouse proteins. We evaluated the performance of three main algorithms by carrying out benchmark studies on a series of human and mouse cell line mixtures and a set of liver patient-derived xenograft (PDX) models. Our study showed that approximately half of the characterized peptides are common between human and mouse proteins, and their allocations to human or mouse proteins cannot be satisfactorily achieved by any algorithm. As a result, many human proteins are erroneously labeled as differentially expressed proteins (DEP) between samples from the same human cell line mixed with different percentages of mouse cells, and the number of such false DEPs increases superquadratically with the mouse cell percentage. When mouse stromal cells are not removed from PDX tumors, about 30%–40% of DEPs from pairwise comparisons of PDX models are false positives, and about 20% of real DEPs cannot be identified irrespective of the threshold for calling differential expression. In conclusion, our study demonstrated that it is advisable to separate human and mouse cells in xenograft tumors before proteomic profiling to obtain more accurate measurement of species-specific protein expression.Significance:This study advocates the separate-then-run over the run-then-separate approach as a better strategy for more reliable proteomic profiling of xenografts.
Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice
Authors: Reolizo Lien M. , Williams Helen , Wadey Kerry , Frankow Aleksandra , Li Ze , Gaston Kevin , Jayaraman Padma-Sheela , Johnson Jason L. , George Sarah J. 
Published: January 2023

Background:
Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs.

Methods:
PRH S163C:S177C was expressed in vitro (human saphenous vein–VSMCs and human saphenous vein–ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo.

Results:
PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein–VSMCs. PRH S163C:S177C expression in human saphenous vein–ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α–induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses.

Conclusions:
We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.
Endothelial Damage Arising From High Salt Hypertension Is Elucidated by Vascular Bed Systematic Profiling
Authors: Vinaiphat Arada , Pazhanchamy Kalailingam , JebaMercy Gnanasekaran , Ngan SoFong Cam , Leow Melvin Khee-Shing , Ho Hee Hwa , Gao Yong-Gui , Lim Kah Leong , Richards A. Mark , de Kleijn Dominique P.V. , Chen Christopher P. , Kalaria Raj N. , Liu Jian , O’Leary Deborah D. , McCarthy Neil E. , Sze Siu Kwan 
Published: January 2023

Background:
Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach.

Methods:
We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet–induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation.

Results:
Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet–induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart.

Conclusions:
These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.
Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials
Authors: Friedman Daniel J. , Al-Khatib Sana M. , Dalgaard Frederik , Fudim Marat , Abraham William T. , Cleland John G.F. , Curtis Anne B. , Gold Michael R. , Kutyifa Valentina , Linde Cecilia , Tang Anthony S. , Ali-Ahmed Fatima , Olivas-Martinez Antonio , Inoue Lurdes Y.T. , Sanders Gillian D. 
Published: January 2023

Background:
Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups.

Methods:
The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death.

Results:

Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34];
P
interaction
<0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death.

Conclusions:
CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.
School-Based Health Care and Absenteeism: Evidence from Telemedicine
Authors: Komisarow Sarah , Hemelt Steven W. 
Published: January 2023

Abstract
The prevalence of school-based health care has increased markedly over the past decade. We study a modern mode of school-based health care, telemedicine, that offers the potential to reach places and populations with historically low access to such care. School-based telemedicine clinics (SBTCs) provide students with access to health care during the regular school day through private videoconferencing with a health care provider. We exploit variation over time in SBTC openings across schools in three rural districts in North Carolina. We find that school-level SBTC access reduces the likelihood that a student is chronically absent by 2.5 percentage points (29 percent) and reduces the number of days absent by about 0.8 days (10 percent). Relatedly, access to an SBTC increases the likelihood of math and reading test-taking by between 1.8 and 2.0 percentage points (about 2 percent). Heterogeneity analyses suggest that these effects are driven by male students. Finally, we see suggestive evidence that SBTC access reduces violent or weapons-related disciplinary infractions among students but has little influence on other forms of misbehavior.
Understanding Meteorological Changes Following Severe Defoliation during a Strong Hurricane Landfall: Insights from Hurricane Michael (2018)
Authors: Nelson Shannon A. , Miller Paul W. 
Published: January 2023

Abstract
Despite prompting persistent meteorological changes, severe defoliation following a tropical cyclone (TC) landfall has received relatively little attention and is largely overlooked within hurricane preparedness and recovery planning. Changes to near-track vegetation can modify evapotranspiration for months after tropical cyclone passage, thereby altering boundary layer moisture and energy fluxes that drive the local water cycle. This study seeks to understand potential spatial and temporal changes in defoliation-driven meteorological conditions using Hurricane Michael (2018) as a testbed. In this sensitivity study, two Weather Research and Forecasting (WRF) Model simulations, a normal-landscape and a post-TC scenario, are compared to determine how a defoliation scar placed along Michael’s path alters surface heat fluxes, temperature, relative humidity, and precipitation near the storm’s track. In the month following the foliage reduction, WRF resolves a 0.7°C 2-m temperature increase, with the greatest changes occurring at night. Meanwhile, the simulations produce changes to the sensible and latent heat fluxes of +8.3 and −13.9 W m−2, respectively, while average relative humidity decreases from 73% to 70.1%. Although the accumulated precipitation in the defoliated simulation was larger along a narrow corridor paralleling and downwind of the hurricane track, neither simulation satisfactorily replicated post-Michael precipitation patterns as recorded by NCEP Stage IV QPE, casting doubt as to whether the downwind enhancement was exclusively due to the defoliation scar. This sensitivity analysis provides insight into the types of changes that may be possible following rapid and widespread defoliation during a TC landfall.
Lateral Circulation in an Elongated Curved Tidal Channel
Authors: Cheng Peng 
Published: January 2023

Abstract
The dynamic theory of curvature-induced lateral circulation has been developed for open channel flows but not for oscillatory tides. A linear three-dimensional analytical model was developed to investigate the lateral circulation in an elongated tidal channel with mildly curved bends of which the radius of curvature is larger than the width. The curvature-induced lateral circulation has two components with the same amplitude, namely, a periodic component having an overtide frequency and a steady component. The combination of the two components allows the strength of the lateral circulation to vary periodically and the rotation direction to be unchanged during a tidal period. Friction modifies the strength and structure of the lateral circulation. The phase between the lateral flow and streamwise tidal flow decreases with increasing friction, indicating that the two flows are not necessarily in phase unless friction is strong. The lateral circulations driven by the Coriolis and curvature centrifugal forces augment each other during one phase and compete in the opposite phase, and the relative importance of the two circulations is determined by the Rossby number and friction. The adaptation time is the same for spinup and spindown of the curvature-induced lateral circulation and is determined by water depth and vertical eddy viscosity. The estimation of the adaptation time depends on the leading modes because the transition solution of the curvature-induced lateral circulation comprises a series of cosine modes. These results provide a theoretical basis for interpreting curvature-induced lateral circulation in tidal channels and coastal headlands.

Significance Statement
The dynamic theory of curvature-induced lateral circulation in a tidal flow remains unexplored. The purpose of this study is to understand the essentials of curvature-induced lateral circulation in an elongated tidal channel using a three-dimensional analytical model. The results showed that the curvature-induced lateral circulation has two components with the same amplitude: a periodic component having an overtide frequency and a steady component. This is significantly different from the curvature-induced lateral circulation associated with open channel flows, which is steady and in phase with the streamwise flow. Future work may show the role of curvature-induced lateral circulation in streamwise dynamics and mass transport.
Therapeutic Effects of Pinus koraiensis on 1-Fluoro-2,4-Dinitrofluorobenzene-induced Contact Dermatitis in Mice
Authors: Kang Yuntae , Oh Seungyeop , Son Yoorae , Yang Wonjin , Kim Soyeon , Lyu Ji-Hyo , Kim Hyungwoo 
Published: January 2023

Background Korean pine nuts (Semen Pinus koraiensis ( P. koraiensis)) have been a valuable ingredient in Korean cuisine since ancient times, and the classical literature on traditional medicine states that pine nuts can moisturize skin. Aims To confirm the therapeutic efficacy of the ethanol extract of these pine nuts in an animal contact dermatitis (CD) model. Materials and Methods Korean pine nuts were extracted using 70% ethanol, and the crude extract obtained was condensed and lyophilized to produce EEPK (the 70% ethanol extract of P. koraiensis). A DNFB (1-fluoro-2,4-dinitrofluorobenzene)-induced BALB/c mouse model of CD was used to investigate the effects of EEPK on skin symptoms, histopathological abnormalities, and cytokine secretion in inflamed tissues. Results EEPK reduced skin color changes, lesion severities, and dorsal skin thickening and inhibited epidermis hyperplasia and immune cell infiltration into inflamed tissues. In addition, EEPK suppressed the productions of tumor necrosis factor-α, interferon-γ, interleukin-6, and monocyte chemoattractant protein-1 but did not affect body weights or spleen/body weight ratios. Conclusion P. koraiensis has potential as a therapeutic agent for CD and as a treatment for inflammatory skin disease management products. Furthermore, the mechanism underlying its therapeutic effects differs from that of corticosteroids.