bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies
Authors: Li Yu-Wei , Dai Lei-Jie , Wu Xiang-Rong , Zhao Shen , Xu Yu-Zheng , Jin Xi , Xiao Yi , Wang Ying , Lin Cai-Jin , Zhou Yi-Fan , Fu Tong , Yang Wen-Tao , Li Ming , Lv Hong , Chen Siyuan , Grigoriadis Anita , Jiang Yi-Zhou , Ma Ding , Shao Zhi-Ming 
Published: August 2024

Abstract
HER2-positive breast cancer is an aggressive subtype that accounts for 15% to 20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. In this study, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor–positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%) had a poor response to current dual HER2-targeted therapy and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment.
Significance: Illumination of the inherent heterogeneity within HER2-positive breast cancers through the delineation of distinct molecular subtypes lays the groundwork for developing more personalized treatment strategies based on specific patient characteristics.
Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis
Authors: Saba Nabil F. , Chaudhary Ritu , Kirtane Kedar , Marra Angelo , Ekpenyong Asari , McCook-Veal Ashley , Schmitt Nicole C. , Gross Jennifer H. , Patel Mihir R. , Remick Jill , Bates James E. , McDonald Mark W. , Rudra Soumon F. , Stokes William A. , Biernacki Maria , Song Xiaofei , Slebos Robbert J.C. , Liu Yuan , Steuer Conor E. , Shin Dong M. , Teng Yong , Chung Christine H. 
Published: August 2024

Abstract

Purpose:
Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis.

Patients and Methods:
This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry.

Results:
With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%–56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%–76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%–81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively].

Conclusions:
Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings.
Microtubules Sequester Acetylated YAP in the Cytoplasm and Inhibit Heart Regeneration
Authors: Liu Shijie , Deshmukh Vaibhav , Meng Fansen , Wang Yidan , Morikawa Yuka , Steimle Jeffrey D. , Li Rich Gang , Wang Jun , Martin James F. 
Published: August 2024

BACKGROUND:
The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined.

METHODS:

We identified YAP acetylation at site K265 by in vitro acetylation followed by mass spectrometry analysis. We used adeno-associated virus to express YAP-containing mutations that either abolished acetylation (YAP-K265R) or mimicked acetylation (YAP-K265Q) and studied how acetylation regulates YAP subcellular localization in mouse hearts. We generated a cell line with YAP-K265R mutation and investigated the protein-protein interactors by YAP immunoprecipitation followed by mass spectrometry, then validated the YAP interaction in neonatal rat ventricular myocytes. We examined colocalization of YAP and TUBA4A (tubulin α 4A) by superresolution imaging. Furthermore, we developed YAP-K265R and
αMHC-MerCreMer (MCM); Yap-loxP/K265R
mutant mice to examine the pathophysiological role of YAP acetylation in cardiomyocytes during cardiac regeneration.

RESULTS:
We found that YAP is acetylated at K265 by CBP (CREB-binding protein)/P300 (E1A-binding protein P300) and is deacetylated by nicotinamide phosphoribosyltransferase/nicotinamide adenine dinucleotide/sirtuins axis in cardiomyocytes. After myocardial infarction, YAP acetylation is increased, which promotes YAP cytoplasmic localization. Compared with controls, mice that were genetically engineered to express a K265R mutation that prevents YAP K265 acetylation showed improved cardiac regenerative ability and increased YAP nuclear localization. Mechanistically, YAP acetylation facilitates its interaction with TUBA4A, a component of the microtubule network that sequesters acetylated YAP in the cytoplasm. After myocardial infarction, the microtubule network increased in cardiomyocytes, resulting in the accumulation of YAP in the cytoplasm.

CONCLUSIONS:
After myocardial infarction, decreased sirtuin activity enriches YAP acetylation at K265. The growing TUBA4A network sequesters acetylated YAP within the cytoplasm, which is detrimental to cardiac regeneration.
Heart Failure Risk Prediction in a Population With a High Burden of Diabetes: Evidence From the Strong Heart Study
Authors: Martinez‐Morata Irene , Domingo‐Relloso Arce , Zhang Ying , Fretts Amanda M. , Pichler Gernot , Garcia Pinilla Jose Manuel , Umans Jason G. , Cole Shelley A. , Sun Yifei , Shimbo Daichi , Navas‐Acien Ana , Devereux Richard B. 
Published: August 2024

Background
Despite the high burden of diabetes and cardiovascular risk factors in American Indian communities in the United States, prospective studies of heart failure (HF) in this population group are scarce, and the generalizability of previous HF risk scales may be limited. We developed a parsimonious HF risk prediction equation that accounts for relevant risk factors affecting American Indian communities, focusing on diabetes and kidney damage.

Methods and Results
A total of 3059 participants from the SHS (Strong Heart Study) (56±8 years of age, 58% women) were included. Five hundred seven developed HF. Progressively adjusted Cox proportional hazards models were used to identify risk factors for HF and HF subtypes. Predictors of risk at 5 and 10 years included older age (hazard ratio [HR], 1.79 [95% CI, 1.43–2.25]; HR, 1.68 [95% CI, 1.44–1.95]), smoking (HR, 2.26 [95% CI, 1.23–4.13]; HR, 2.08 [95% CI, 1.41–3.06]), macroalbuminuria (HR, 8.38 [95% CI, 4.44–15.83]; HR, 5.20 [95% CI, 3.42–7.9]), microalbuminuria (HR, 2.72 [95% CI, 1.51–4.90]; HR, 1.92 [95% CI, 1.33, 2.78]), and previous myocardial infarction (HR, 6.58 [95% CI, 2.54–17.03]; HR, 3.87 [95% CI, 2.29–6.54]), respectively. These predictors, together with diabetes diagnosis and glycated hemoglobin were significant at 10 and 28 years. High discrimination performance was achieved (C index, 0.81 [95% CI, 0.76–0.84]; C index, 0.78 [95% CI, 0.75–0.81]; and C index, 0.77 [95% CI, 0.74–0.78] at 5, 10, and up to 28 years of follow up, respectively). Some associations varied across HF subtypes, although diabetes, albuminuria, and previous myocardial infarction were associated with all subtypes.

Conclusions
This prospective study of HF risk factors in American Indian communities identifies that smoking, body mass index, and indicators of diabetes control and kidney damage (glycated hemoglobin and albuminuria) are major determinants of HF. Our findings can improve HF risk assessment in populations with a high burden of diabetes.
Robust Contracts: A Revealed Preference Approach
Authors: Antic Nemanja , Georgiadis George 
Published: August 2024

Abstract
We study an agency model in which the principal knows the agent-optimal actions in response to K “known” contracts but is unaware of other actions available or their costs, and seeks a contract to maximize worst-case profits. The optimal contract is a mixture of the known contracts and output. Moreover, when K = 1, the single known contract maximizes the principal's profit guarantee, whereas with two known contracts, the optimal mixture puts positive weight on one of the known contracts. Our methodology is straightforward to implement, a point that we demonstrate using data from an experimental study of different incentive schemes.
Quality Control of Geostationary Lightning Mapper Observations for Tropical Cyclone Applications
Authors: Trabing Benjamin C. , Hilburn K. , Stevenson S. , Musgrave K. D. , DeMaria M. 
Published: August 2024

Abstract
The Geostationary Lightning Mapper (GLM) has been providing unprecedented observations of total lightning since becoming operational in 2017. The potential for GLM observations to be used for forecasting and analyzing tropical cyclone (TC) structure and intensity has been complicated by inconsistencies in the GLM data from a number of artifacts. The algorithm that processes raw GLM data has improved with time; however, the need for a consistent long-term dataset has motivated the development of quality control (QC) techniques to help remove clear artifacts such as blooming events, spurious false lightning, “bar” effects, and sun glint. Simple QC methods are applied that include scaled maximum energy thresholds and minima in the variance of lightning group area and group energy. QC and anomaly detection methods based on machine learning (ML) are also explored. Each QC method is successfully able to remove artifacts in the GLM observations while maintaining the fidelity of the GLM observations within TCs. As the GLM processing algorithm has improved with time, the amount of QC flagged lightning within 100 km of Atlantic TCs is reduced, from 70% during 2017, to 10% in 2018, to 2% during 2021. These QC methods are relevant to the design of ML-based forecasting techniques which could pick up on artifacts rather than the signal of interest in TCs if QC was not applied beforehand.

Significance Statement
The Geostationary Lightning Mapper (GLM) provides total lightning observations in tropical cyclones that can benefit forecasts of intensity change. However, nonlightning artifacts in GLM observations make interpreting lightning observations challenging for automated techniques to predict intensity change. Quality control procedures have been developed to aid the TC community in using GLM observations for statistical and pattern-matching techniques.
Minding the gap between public administration curriculum and practice: The studio of public reasoning
Authors: Şahin Savaş Zafer 
Published: August 2024

It has always been a crucial question as to what kind of education should be provided to practitioners working at different levels of public administration, starting from the street level onwards, and what kind of interactions should be used to develop their competencies once in office. However, especially in the last 30 years, as we have entered a period of accelerating technological and institutional transformations, this issue has gained a dimension beyond the discussions on higher education and training for service. In addition to how public administration education will relate to practice as seen in traditional debates, new questions have emerged, such as how this engagement with practice can provide a perspective on institutional transformation, how those working in institutions can perceive their transformation processes more accurately, and ultimately, what kind of interaction can be achieved between those receiving public administration education and those working in public institutions. To answer these questions, an innovative model called “studio of public reasoning” was developed in 2009 for a university in public administration education in Turkey to create a platform for interaction with the external stakeholders of the university through an applied course. This Program has been implemented continuously for 15 years at the same university and more than 1000 students, about 100 public institutions of different scales and about 300 public administrators have benefited from the Program. In this paper, based on this experience, the gains of innovative teaching practices in public administration discipline in interacting with external stakeholders are critically evaluated through interviews with students, academics and administrators to assess whether alternatives are possible in establishing non-hierarchical external stakeholder interaction together with formal higher education for public administration.
Osteochondral Allograft Reaming Significantly Affects Chondrocyte Viability
Authors: Elias Tristan J. , Allahabadi Sachin , Haneberg Erik , Morgan Vince , Walker Alexandra , Beals Corey , Cole Brian J. , Yanke Adam B. 
Published: August 2024

Background: Chondrocyte viability is associated with the clinical success of osteochondral allograft (OCA) transplantation. Purpose: To investigate the effect of distal femoral OCA plug harvest and recipient site preparation on regional cell viability using traditional handheld saline irrigation versus saline submersion. Study Design: Controlled laboratory study. Methods: For each of 13 femoral hemicondyles, 4 cartilage samples were harvested: (1) 5-mm control cartilage, (2) 15-mm OCA donor plug harvested with a powered coring reamer and concurrent handheld saline irrigation (“traditional”), (3) 15-mm OCA donor plug harvested while submerged under normal saline (“submerged”), and (4) 5-mm cartilage from the peripheral rim of a recipient socket created with a 15-mm cannulated counterbore reamer to a total depth of 7 mm with concurrent handheld saline irrigation (“recipient”). The 15 mm–diameter plugs were divided into the central 5 mm and the peripheral 5 mm (2 edges) for comparisons. Samples were stained using calcein and ethidium, and live/dead cell percentages were calculated and compared across groups. Results: Compared with the submerged group, the traditional group had significantly lower percentages of live cells across the whole plug (71.54% ± 4.82% vs 61.42% ± 4.98%, respectively; P = .003), at the center of the plug (72.76% ± 5.87% vs 62.30% ± 6.11%, respectively; P = .005), and at the periphery of the plug (70.93% ± 4.51% vs 60.91% ± 4.75%, respectively; P = .003). The traditional group had significantly fewer live cells in all plug regions compared with the control group (77.51% ± 9.23%; P < .0001). There were no significant differences in cell viability between the control and submerged groups (whole: P = .590; center: P = .713; periphery: P = .799). There were no differences between the central and peripheral 5-mm plug regions for the traditional (62.30% ± 6.11% vs 60.91% ± 4.75%, respectively; P = .108) and submerged (72.76% ± 5.87% vs 70.93% ± 4.51%, respectively; P = .061) groups. The recipient group (61.10% ± 5.02%) had significantly lower cell viability compared with the control group ( P < .0001) and the periphery of the submerged group ( P = .009) but was equivalent to the periphery of the traditional group ( P = .990). Conclusion: There was a significant amount of chondrocyte death induced by OCA donor plug harvesting using a powered coring reamer with traditional handheld saline irrigation, which was mitigated by harvesting the plug while the allograft was submerged under saline. Clinical Relevance: Mitigating this thermally induced damage by harvesting the OCA plug while the allograft was submerged in saline maintained chondrocyte viability throughout the plug and may help to improve the integration and survival of OCAs.
Cryo–Pneumatic Compression Results in a Significant Decrease in Opioid Consumption After Shoulder Surgery: A Multicenter Randomized Controlled Trial
Authors: Khan Moin , Phillips Steven A. , Mathew Paul , Venkateswaran Vikram , Haverstock John , Dagher Danielle , Yardley Darryl , Dick David , Bhandari Mohit 
Published: August 2024

Background: The management of pain after shoulder surgery typically includes the use of cryotherapy and the prescription of opioid analgesics. Much focus has been placed lately on the opioid epidemic, which in part is fueled by excessive prescription of opioid medication. Previous studies have found a combination of cryotherapy and compression effective at reducing analgesic consumption and increasing recovery in patients undergoing knee and spine surgery; however, efficacy in patients undergoing shoulder surgery has not been evaluated. Purpose: To evaluate the effectiveness of a cryo–pneumatic compression device on postoperative shoulder pain, narcotic use, and quality of life when compared with standard care cryotherapy. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: In total, 200 patients older than 18 years scheduled for unilateral shoulder surgery were enrolled. Patients were randomized to receive either postoperative cryo–pneumatic compression or standard care. The intervention group received a cryo–pneumatic device, while the standard care group received the treating surgeon’s preferred method of postoperative care, including standard cryotherapy. Narcotic use was evaluated by the number of oral morphine milligram equivalents consumed during the postoperative period, as well as the time to cessation of narcotic use. Patient-reported outcome measures consisted of a numeric rating scale pain score, 36-item Short Form Survey, patient experience assessed using the net promoter score, and adverse events. Outcomes were evaluated at 2, 6, and 12 weeks postoperatively. Results: Patients receiving cryo–pneumatic compression reported a significant decrease in opioid consumption when compared with standard care (oral morphine milligram equivalents median, 56.1 vs 112; P = .02468). A significant increase in self-reported function was seen in the cryo–pneumatic compression group at 2 weeks when compared with standard care (mean, 61.2 vs 54.2; P = .0412). Conclusion: In patients undergoing unilateral shoulder surgery, the use of cryotherapy with pneumatic compression, when compared with standard care, resulted in significantly decreased opioid consumption as well as increased function at 2 weeks. Registration: NCT04185064 (ClinicalTrials.gov identifier).
Influence of Increased Joint Line Obliquity on Survivorship After Lateral Closing-Wedge High Tibial Osteotomy
Authors: Xie Tianshun , de Vries Astrid J. , van der Veen Hugo C. , Brouwer Reinoud W. 
Published: August 2024

Background: Although high tibial osteotomy (HTO) has emerged as a powerful intervention for treating symptomatic medial osteoarthritis and varus malalignment, it can result in an increase in knee joint line obliquity (KJLO) in the frontal plane. Limited current evidence hinders understanding of the effect of increased KJLO on HTO survivorship. Purpose: To investigate the influence of KJLO and other potential risk factors on the survivorship of lateral closing-wedge HTO. Study Design: Cohort study; Level of evidence, 3. Methods: Patients with symptomatic medial knee osteoarthritis and varus malalignment treated with lateral closing-wedge HTO at a single hospital were screened with a minimum follow-up of 5 years. HTO survival rate was assessed using Kaplan-Meier survival analysis. The influence of postoperative increased KJLO (medial proximal tibial angle ≥95°), age (≥55 years), sex (female), preoperative malalignment (hip-knee-ankle angle ≥10° of varus), postoperative untargeted alignment (hip-knee-ankle angle <2° or >6° of valgus), and preoperative osteoarthritis severity (Kellgren-Lawrence grade ≥3) on survivorship of HTO was evaluated using Cox regression analysis. A failure of HTO was defined as a conversion to total knee arthroplasty (TKA). Results: A total of 410 patients (463 knees) were included, with a mean follow-up of 13.0 years (range, 5.0-18.1 years) and a mean survival time of 11.2 years (range, 1.2-18.1 years) for patients who reached the endpoint of TKA. HTO survival rates at 5, 10, and 15 years postoperatively were 91%, 78%, and 60%, respectively. Multivariate Cox regression analysis showed no significant difference in survivorship between patients with increased KJLO and those with acceptable KJLO (178 vs 285 knees; hazard ratio [HR], 0.8; 95% CI, 0.6-1.1; P = .148), with no significant between-group difference observed in the mean follow-up length (12.9 ± 3.0 years vs 13.1 ± 3.3 years; P = .105). Female sex (HR, 2.0; P < .001) and postoperative untargeted alignment (HR, 1.6; P = .003) were risk factors for a conversion to TKA. Conclusion: Increased postoperative KJLO (medial proximal tibial angle ≥95°) had no significant influence on the survivorship of lateral closing-wedge HTO. Men demonstrated superior survival outcomes compared with women, and it was important to achieve a targeted postoperative alignment (HKA 2°-6° of valgus) to ensure favorable HTO survivorship.