bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mini-Aortic Valve Replacement versus Transcatheter Aortic Valve Implantation: A Propensity-Matched Study
Authors: Monteagudo-Vela María , Monguió-Santín Emilio , de Antonio Antón Nieves , Aguirre Fernanda , Bernal Gallego Begoña , Reyes-Copa Guillermo , Panoulas Vasileios 
Published: August 2023

Background. Total sternotomy for aortic valve replacement has been superseded by less invasive approaches such as mini-sternotomy or transcatheter procedures. There has been an exponential uptake in transcatheter aortic valve implantation (TAVI) in younger and lower risk patients following recent randomized trials. This study aims to compare the outcomes of patients with aortic stenosis treated with minimally invasive approaches: mini-sternotomy for aortic valve replacement (mini-AVR) and TAVI implantation. Methods. Between January 2015 and December 2021, a total of 1437 TAVI and 176 mini-AVR patients from 2 tertiary centers fulfilled the criteria and were included in the propensity matching model. Results. A total of 256 TAVIs and 146 mini-AVR were included in the matched cohort. There was no significant difference in 30-day mortality in the two groups (TAVI vs. mini-AVR 2.7% vs. 2.8%,

p
=
0.935

). TAVI confers slightly lower gradients in the follow-up echo when compared with mini-AVR (peak gradient 20 ± 8.7 mmHg vs. 24.5 ± 10 mmHg,

p

<
0.001

; mean gradient 10.9 ± 5.6 mmHg vs. 13.2 ± 5.7 mmHg,

p
<
0.001

). On the other hand, mini-AVR exhibits remarkably lower rates of paravalvular leak (mild leak 8% vs. 41.5%,

p
<
0.001

; moderate leak 2.8% vs. 0%,

p
<
0.001

) and of need for permanent pacemaker implantation (2% vs. 12.2%,

p
<
0.001

). Unsurprisingly, TAVI has lower in-hospital stay 3 (2 to 6) days vs. 10 (8 to 13) days,

p
<
0.001

). Conclusions. For eligible aortic stenosis patients in the 7th decade of life, mini-AVR remains an excellent therapeutic option.
Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib
Authors: Zeng Xiangyu , Zhao Fei , Jia Jie , Ma Xianxiong , Jiang Qi , Zhang Ruizhi , Li Chengguo , Wang Tao , Liu Weizhen , Hao Yalan , Tao Kaixiong , Lou Zhenkun , Zhang Peng 
Published: August 2023

Abstract

Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST.

Significance:
BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.
Memory-like Differentiation, Tumor-Targeting mAbs, and Chimeric Antigen Receptors Enhance Natural Killer Cell Responses to Head and Neck Cancer
Authors: Jacobs Miriam T. , Wong Pamela , Zhou Alice Y. , Becker-Hapak Michelle , Marin Nancy D. , Marsala Lynne , Foster Mark , Foltz Jennifer A. , Cubitt Celia C. , Tran Jennifer , Russler-Germain David A. , Neal Carly , Kersting-Schadek Samantha , Chang Lily , Schappe Timothy , Pence Patrick , McClain Ethan , Zevallos Jose P. , Rich Jason T. , Paniello Randal C. , Jackson Ryan S. , Pipkorn Patrik , Adkins Douglas R. , DeSelm Carl J. , Berrien-Elliott Melissa M. , Puram Sidharth V. , Fehniger Todd A. 
Published: August 2023

Abstract

Purpose:
Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy–refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC.

Experimental Design:
We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells.

Results:
Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets.

Conclusions:
These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.
Data from MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids
Authors: Pickles Oliver J. , Wanigasooriya Kasun , Ptasinska Anetta , Patel Akshay J. , Robbins Helen L. , Bryer Claire , Whalley Celina M. , Tee Louise , Lal Neeraj , Pinna Claudia M.A. , Elzefzafy Nahla , Taniere Philippe , Beggs Andrew D. , Middleton Gary M. 
Published: August 2023

<div><p>Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4<sup>+</sup> T cell–mediated lysis. In colorectal cancer, tsMHC-II negativity is common, in cell lines due to <i>CIITA</i> promoter methylation. To clarify mechanisms of tsMHC-II repression in colorectal cancer, we analyzed colorectal cancer organoids which are epigenetically faithful to tissue of origin. 15 primary colorectal cancer organoids were treated with IFNγ ± epigenetic modifiers: flow cytometry was used for tsMHC-II expression. qRT-PCR, total RNA sequencing, nanopore sequencing, bisulfite conversion/pyrosequencing, and Western blotting was used to quantitate CIITA, STAT1, IRF1, and JAK1 expression, mutations and promoter methylation and chromatin immunoprecipitation to quantitate H3K9ac, H3K9Me2, and EZH2 occupancy at <i>CIITA</i>.</p><p>We define three types of response to IFNγ in colorectal cancer: strong, weak, and noninducibility. Delayed and restricted expression even with prolonged IFNγ exposure was due to IFNγ-mediated EZH2 occupancy at <i>CIITA.</i> tsMHC-II expression was enhanced by EZH2 and histone deacetylase inhibition in the weakly inducible organoids. Noninducibility is seen in three consensus molecular subtype 1 (CMS1) organoids due to JAK1 mutation. No organoid demonstrates CIITA promoter methylation.</p><p>Providing IFNγ signaling is intact, most colorectal cancer organoids are class II inducible. Upregulation of tsMHC-II through targeted epigenetic therapy is seen in one of fifteen organoids. Our approach can serve as a blueprint for investigating the heterogeneity of specific epigenetic mechanisms of immune suppression across individual patients in other cancers and how these might be targeted to inform the conduct of future trials of epigenetic therapies as immune adjuvants more strategically in cancer.</p>Significance:<p>Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.</p></div>
PARP Inhibitors Effectively Reduce MAPK Inhibitor Resistant Melanoma Cell Growth and Synergize with MAPK Inhibitors through a Synthetic Lethal Interaction In Vitro and In Vivo
Authors: Fröhlich Lisa Marie , Niessner Heike , Sauer Birgit , Kämereit Sofie , Chatziioannou Eftychia , Riel Simon , Sinnberg Tobias , Schittek Birgit 
Published: August 2023

The efficacy of targeting the MAPK signaling pathway in patients with melanoma is limited by the rapid development of resistance mechanisms that result in disease relapse. In this article, we focus on targeting the DNA repair pathway as an antimelanoma therapy, especially in MAPK inhibitor resistant melanoma cells using PARP inhibitors. We found that MAPK inhibitor resistant melanoma cells are particularly sensitive to PARP inhibitor treatment due to a lower basal expression of the DNA damage sensor ataxia-telangiectasia mutated (ATM). As a consequence, MAPK inhibitor resistant melanoma cells have decreased homologous recombination repair activity leading to a reduced repair of double-strand breaks caused by the PARP inhibitors. We validated the clinical relevance of our findings by ATM expression analysis in biopsies from patients with melanoma before and after development of resistance to MAPK inhibitors. Furthermore, we show that inhibition of the MAPK pathway induces a homologous recombination repair deficient phenotype in melanoma cells irrespective of their MAPK inhibitor sensitivity status. MAPK inhibition results in a synthetic lethal interaction of a combinatorial treatment with PARP inhibitors, which significantly reduces melanoma cell growth in vitro and in vivo. In conclusion, this study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression.

Significance:
We show that MAPK inhibitor resistant melanoma cells exhibit low ATM expression increasing their sensitivity toward PARP inhibitors and that a combination of MAPK/PARP inhibitors act synthetically lethal in melanoma cells. Our study shows that PARP inhibitor treatment is a valuable therapy option for patients with melanoma, either as a single treatment or as a combination with MAPK inhibitors depending on ATM expression, which could serve as a novel biomarker for treatment response.
Projection of Future Heatwaves in the Pearl River Delta through CMIP6-WRF Dynamical Downscaling
Authors: Zuo Ziping , Fung Jimmy C. H. , Li Zhenning , Huang Yiyi , Wong Mau Fung , Lau Alexis K. H. , Lu Xingcheng 
Published: August 2023

Abstract
Recent worldwide heatwaves have shattered temperature records in many regions. In this study, we applied a dynamical downscaling method on the high-resolution version of the Max Planck Institute Earth System Model (MPI-ESM-1-2-HR) to obtain projections of the summer thermal environments and heatwaves in the Pearl River Delta (PRD) considering three shared socioeconomic pathways (SSP1-2.6, SSP2-4.5, and SSP5-8.5) in the middle and late twenty-first century. Results indicated that relative to the temperatures in the 2010s, the mean increases in the summer (June–September) daytime and nighttime temperatures in the 2040s will be 0.7°–0.8°C and 0.9°–1.1°C, respectively. In the 2090s, the mean difference will be 0.5°–3.1°C and 0.7°–3.4°C, respectively. SSP1-2.6 is the only scenario in which the temperatures in the 2090s are expected to be lower than those in the 2040s. When compared with those in the 2010s, hot extremes are expected to be more frequent, intense, extensive, and longer-lasting in the future in the SSP2-4.5 and SSP5-8.5 scenarios. In the 2010s, a heatwave occurred in the PRD lasted for 6 days on average, with a mean daily maximum temperature of 34.4°C. In the 2040s, the heatwave duration and intensity are expected to increase by 2–3 days and 0.2°–0.4°C in all three scenarios. In the 2090s, these values will become 23 days and 36.0°C in SSP5-8.5. Moreover, a 10-yr extreme high temperature in the 2010s is expected to occur at a monthly frequency from June to September in the 2090s.

Significance Statement
Pearl River Delta (PRD) has been experiencing record-shattering heatwaves in recent years. This study aims to investigate the future trends of summer heatwaves in the PRD by modeling three future scenarios including a sustainable scenario, an intermediate scenario, and a worst-case scenario. Except for the sustainable scenario, summer temperatures in the intermediate and worst-case scenarios will keep increasing, and heatwaves will become more frequent, intense, extensive, and longer-lasting. In the worst-case scenario, extreme heat events that occurred once in 10 years in the 2010s will shorten to once a month in the 2090s. A better understanding of heatwave trends will benefit implementing climate mitigation methods, urban planning, and improving social infrastructure.
Sea Ice Loss, Water Vapor Increases, and Their Interactions with Atmospheric Energy Transport in Driving Seasonal Polar Amplification
Authors: Chung Po-Chun , Feldl Nicole 
Published: August 2023

Abstract
The ice–albedo feedback associated with sea ice loss contributes to polar amplification, while the water vapor feedback contributes to tropical amplification of surface warming. However, these feedbacks are not independent of atmospheric energy transport, raising the possibility of complex interactions that may obscure the drivers of polar amplification, in particular its manifestation across the seasonal cycle. Here, we apply a radiative transfer hierarchy to an idealized aquaplanet global climate model coupled to a thermodynamic sea ice model. The climate responses and radiative feedbacks are decomposed into the contributions from sea ice loss, including both retreat and thinning, and the radiative effect of water vapor changes. We find that summer sea ice retreat causes winter polar amplification through ocean heat uptake and release, and the resulting decrease in dry energy transport weakens the magnitude of warming. Moreover, sea ice thinning is found to suppress summer warming and enhance winter warming, additionally contributing to winter amplification. The water vapor radiative effect produces seasonally symmetric polar warming via offsetting effects: enhanced moisture in the summer hemisphere induces the summer water vapor feedback and simultaneously strengthens the winter latent energy transport in the winter hemisphere by increasing the meridional moisture gradient. These results reveal the importance of changes in atmospheric energy transport induced by sea ice retreat and increased water vapor to seasonal polar amplification, elucidating the interactions among these physical processes.
Assessment of common extensor tendon vascularization using superb microvascular imaging: a potential tool in the evaluation of extracorporeal shock wave therapy and therapeutic ultrasound effectiveness in lateral epicondylitis
Authors: Ustabaşıoğlu Fatma , Günay Burak , Samancı Cesur , Emre Ustabaşıoğlu Fethi 
Published: August 2023

Background Lateral epicondylitis, also known as tennis elbow, is the most common elbow pain in the adult age group. Purpose To evaluate common extensor tendon (CET) vascularity with superb microvascular imaging (SMI) before and after extracorporeal shock wave therapy (ESWT) and ultrasound (US) treatment in patients with lateral epycondylitis and to compare the effects of two different treatments on tendon vascularity. Material and Methods Patients with lateral epycondylitis were divided into two groups; 30 patients were treated with ESWT (group 1) and 30 patients were treated with therapeutic US (group 2). We performed a high-frequency (14-MHz) linear array transducer to evaluate tendon anatomy and vascularity before and after treatment in both groups. Results The decrease in Patient-Rated Tennis Elbow Evaluation (PRTEE) score after treatment was statistically significant compared to pre-treatment for both groups ( P < 0.001). Likewise, the decrease in visual analog scale (VAS) score after treatment was statistically significant compared to pre-treatment for both groups ( P < 0.001). A significant difference was found between the CET SMI values of group 1 and group 2 after treatment, according to the chi-square test ( P < 0.001). In the post-treatment VAS and PRTEE comparison of both groups, the score reduction in group 1 was higher than in group 2, and this decrease was statistically significant ( P < 0.001). Conclusion We can evaluate CET vascularization with the SMI method as a new potential diagnostic tool in comparing the effectiveness of different treatments in cases of lateral epicondylitis.
The Effect of Investment Inefficiency on Expected Returns
Authors: Chacko Jains P. , Padmakumari Lakshmi 
Published: August 2023

The majority of Indian firms have a promoter and family-owner-dominated ownership structure; therefore, the agency problem prevailing in such a setting would be the conflict of interest between the majority and minority shareholders. This motivated us to examine the adverse effect of not investing at the level implied by the firms’ characteristics, termed investment inefficiency, on the ex-ante measure of expected returns, the implied cost of capital. Our study finds a positive relationship between investment inefficiency and expected returns in the baseline results estimated using pooled ordinary least squares (OLS) and the robustness results estimated using a two-step generalized method of moments (GMM). The sample of the study consists of listed firms in India from 2016 to 2021. JEL Codes: G11, G31
Capturing the Work of Patients' Family Members in the Medical Intensive Care Unit Using Naturalistic Observations
Authors: Papautsky Elizabeth Lerner , Abdulbaseer Ummesalmah 
Published: August 2023

Background: The contributions of cognitive and behavioral work of patients' family members in intensive care units remain largely unrecognized. Objective: The objective of this study was to develop a framework of outwardly observable family work, with specific focus on describing the physical space. Methods: We conducted approximately 50 hrs of naturalistic observations of family activities on a medical intensive care unit (MICU) at a large, Midwestern teaching hospital. Results: We created a framework of activities that include requesting, receiving, or delivering either information or action, along with examples. Further, we identified clinician and staff roles with whom families interact and characterized the physical spaces in which interactions take place. Conclusions: Knowledge contribution is a proposed framework of family activities in the MICU. It has the potential to guide and be further described by future research and to inform development of human-centered family-facing interventions to support cognitive and behavioral cognitive and behavioral work.
Glucocorticoid-Induced Transcript 1(GLCCI1) SNP rs37937 Is Associated With the Risk of Developing Allergic Rhinitis and the Response to Intranasal Corticosteroids in a Chinese Han Population
Authors: Liang Xu , Jin Peng , Zhan Changcui , Zhao Li , Zi Xiaoxue , Zhi Lili , Yu Kena 
Published: August 2023

Background Evidence has shown that glucocorticoid-induced transcript 1 (GLCCI1) single nucleotide polymorphism (SNP) rs37937 is associated with asthma. Objectives The objective of this study was to investigate whether the GLCCI1 SNP rs37937 is a risk factor for allergic rhinitis (AR) in a Chinese Han population. Methods A total of 220 individuals including 109 AR patients and 111 healthy subjects were included. The genotyping of GLCCI1 rs37973 was performed by the SNaPshot method. The correlations of rs37973 polymorphism, AR risk, and clinical characteristics were further analyzed, as well as the treatment response to intranasal corticosteroids (INCS) in AR patients of different genotypes. Results Three GLCCI1 rs37973 SNP genotypes were identified in both AR patients and healthy subjects. Significant association between rs37973 polymorphism and AR under allele model, dominant model, heterozygote model, and homozygote model were shown. The A allele frequency of SNP rs37973 in AR was significantly higher than that in controls. The serum total immunoglobulin E (IgE) in AR patients of AA genotype was significantly higher than in patients of GA and GG genotype, and the serum total IgE in GA genotype was significantly higher than in GG genotype. Interestingly, after 4 weeks of INCS treatment for AR patients, the improvement of the nasal itching score, sneezing score, runny nose score, total nasal symptom score, and visual analog scale score of the GG genotype were worse than the AA or GA genotype. Conclusion The GLCCI1 rs37937 polymorphism is associated with the risk of developing AR and the response to INCS treatment in the Chinese Han population.
Cost-Effectiveness Analysis of Regenerative Endodontics versus MTA Apexification
Authors: Naved N. , Umer F. , Khowaja A.R. 
Published: August 2023

Introduction: With the introduction of stem cell engineering in dentistry, regenerative endodontics has emerged as a potential alternative to mineral trioxide aggregate (MTA) apexification in the management of necrotic immature permanent teeth. However, the utility of this modality in terms of cost-effectiveness has not yet been established. Therefore, we performed cost-effectiveness analysis to determine the dominant treatment modality that would influence decision making from the private payer perspective. Methods: A Markov model was constructed with a necrotic immature permanent tooth in a 7-y-old patient, followed over the lifetime using TreeAge Pro Healthcare 2022. Transition probabilities were estimated based on the existing literature. Costs were estimated based on United States health care, and cost-effectiveness was determined using Monte Carlo microsimulations. The model was validated internally by sensitivity analyses, and face validation was performed by an experienced endodontist and health economist. Results: In the base-case scenario, regenerative endodontics did not turn out to be a dominant treatment option as it was associated with an additional cost of USD$1,012 and fewer retained tooth-years (15.48 y). Likewise, in the probabilistic sensitivity analysis, regenerative endodontics was again dominated by apexification against different willingness-to-pay values. Conclusion: Based on current evidence, regenerative endodontic treatment was not cost-effective compared with apexification in the management of necrotic immature permanent teeth over an individual's lifetime. Knowledge Transfer Statement: The study provides valuable insight regarding the cost valuation and cost-efficacy of regenerative endodontic treatment versus apexification in the management of necrotic immature permanent teeth, as this would aid in effective clinical decision making, allowing for the functional allocation of resources.