bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Profiling Mass Cytometry Assay Harmonization: Multicenter Experience from CIMAC-CIDC
Authors: Sahaf Bita , Pichavant Mina , Lee Brian H. , Duault Caroline , Thrash Emily M. , Davila Melanie , Fernandez Nicolas , Millerchip Karen , Bentebibel Salah-Eddine , Haymaker Cara , Sigal Natalia , Del Valle Diane M. , Ranasinghe Srinika , Fayle Sarah , Sanchez-Espiridion Beatriz , Zhang Jiexin , Bernatchez Chantale , Wu Catherine J. , Wistuba Ignacio I. , Kim-Schulze Seunghee , Gnjatic Sacha , Bendall Sean C. , Song Minkyung , Thurin Magdalena , Lee J. Jack , Maecker Holden T. , Rahman Adeeb 
Published: July 2021

Abstract

Purpose:
The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) Network is supported by the NCI to identify biomarkers of response to cancer immunotherapies across clinical trials using state-of-the-art assays. A primary platform for CIMAC-CIDC studies is cytometry by time of flight (CyTOF), performed at all CIMAC laboratories. To ensure the ability to generate comparable CyTOF data across labs, a multistep cross-site harmonization effort was undertaken.

Experimental Design:
We first harmonized standard operating procedures (SOPs) across the CIMAC sites. Because of a new acquisition protocol comparing original narrow- or new wide-bore injector introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed cross-site assay harmonization experiments using five shared cryopreserved and one lyophilized internal control peripheral blood mononuclear cell (PBMC) with a shared lyophilized antibody cocktail consisting of 14 isotype-tagged antibodies previously validated, plus additional liquid antibodies. These reagents and samples were distributed to the CIMAC sites and the data were centrally analyzed by manual gating and automated methods (Astrolabe).

Results:
Average coefficients of variation (CV) across sites for each cell population were reported and compared with a previous multisite CyTOF study. We reached an intersite CV of under 20% for most cell subsets, very similar to a previously published study.

Conclusions:
These results establish the ability to reproduce CyTOF data across sites in multicenter clinical trials, and also highlight the importance of quality control procedures, such as the use of spike-in control samples, for tracking variability in this assay.
Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis
Authors: Bowen Charles M. , Walter Lewins , Borras Ester , Wu Wenhui , Ozcan Zuhal , Chang Kyle , Bommi Prashant V. , Taggart Melissa W. , Thirumurthi Selvi , Lynch Patrick M. , Reyes-Uribe Laura , Scheet Paul A. , Sinha Krishna M. , Vilar Eduardo 
Published: July 2021

Abstract

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP.

Prevention Relevance:
This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma
Authors: Simon Tracey G. , Kim Mi Na , Luo Xiao , Liu Xing , Yang Wanshui , Ma Yanan , Chong Dawn Q. , Fuchs Charles S. , Stampfer Meir , Giovannucci Edward L. , Chan Andrew T. , Zhang Xuehong 
Published: July 2021

Abstract

Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980–2012) and 48,026 men (1986–2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02–1.09 (Ptrend = 0.019), and 1.08; 95% CI = 1.06–1.10 (Ptrend = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01–1.08; Ptrend = 0.010), including after further adjusting for young-adult BMI (Ptrend = 0.010) and later-adult BMI (Ptrend = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5–&lt;10 kg, 10–&lt;20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67–2.16), 2.09 (95% CI = 1.11–3.95), and 2.61 (95% CI = 1.42–5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk.

Prevention Relevance:
Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab
Authors: Adusumilli Prasad S. , Zauderer Marjorie G. , Rivière Isabelle , Solomon Stephen B. , Rusch Valerie W. , O'Cearbhaill Roisin E. , Zhu Amy , Cheema Waseem , Chintala Navin K. , Halton Elizabeth , Pineda John , Perez-Johnston Rocio , Tan Kay See , Daly Bobby , Araujo Filho Jose A. , Ngai Daniel , McGee Erin , Vincent Alain , Diamonte Claudia , Sauter Jennifer L. , Modi Shanu , Sikder Devanjan , Senechal Brigitte , Wang Xiuyan , Travis William D. , Gönen Mithat , Rudin Charles M. , Brentjens Renier J. , Jones David R. , Sadelain Michel 
Published: July 2021

Abstract

Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for &gt;100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.

Significance:
Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.
See related commentary by Aldea et al., p. 2674.
This article is highlighted in the In This Issue feature, p. 2659
In Vivo Characterization of Endogenous Cardiovascular Extracellular Vesicles in Larval and Adult Zebrafish
Authors: Scott Aaron , Sueiro Ballesteros Lorena , Bradshaw Marston , (辻千里)  , Power Ann , Lorriman James , Love John , Paul Danielle , Herman Andrew , Emanueli Costanza , Richardson Rebecca J. 
Published: July 2021

Objective:
Extracellular vesicles (EVs) facilitate molecular transport across extracellular space, allowing local and systemic signaling during homeostasis and in disease. Extensive studies have described functional roles for EV populations, including during cardiovascular disease, but the in vivo characterization of endogenously produced EVs is still in its infancy. Because of their genetic tractability and live imaging amenability, zebrafish represent an ideal but under-used model to investigate endogenous EVs. We aimed to establish a transgenic zebrafish model to allow the in vivo identification, tracking, and extraction of endogenous EVs produced by different cell types.

Approach and Results:
Using a membrane-tethered fluorophore reporter system, we show that EVs can be fluorescently labeled in larval and adult zebrafish and demonstrate that multiple cell types including endothelial cells and cardiomyocytes actively produce EVs in vivo. Cell-type specific EVs can be tracked by high spatiotemporal resolution light-sheet live imaging and modified flow cytometry methods allow these EVs to be further evaluated. Additionally, cryo electron microscopy reveals the full morphological diversity of larval and adult EVs. Importantly, we demonstrate the utility of this model by showing that different cell types exchange EVs in the adult heart and that ischemic injury models dynamically alter EV production.

Conclusions:
We describe a powerful in vivo zebrafish model for the investigation of endogenous EVs in all aspects of cardiovascular biology and pathology. A cell membrane fluorophore labeling approach allows cell-type specific tracing of EV origin without bias toward the expression of individual protein markers and will allow detailed future examination of their function.
There Once Was a Really Bad Poet, It Was Automated but You Didn’t Know It
Authors: Wang Jianyou , Zhang Xiaoxuan , Zhou Yuren , Suh Christopher , Rudin Cynthia 
Published: July 2021

Abstract
Limerick generation exemplifies some of the most difficult challenges faced in poetry generation, as the poems must tell a story in only five lines, with constraints on rhyme, stress, and meter. To address these challenges, we introduce LimGen, a novel and fully automated system for limerick generation that outperforms state-of-the-art neural network-based poetry models, as well as prior rule-based poetry models. LimGen consists of three important pieces: the Adaptive Multi-Templated Constraint algorithm that constrains our search to the space of realistic poems, the Multi-Templated Beam Search algorithm which searches efficiently through the space, and the probabilistic Storyline algorithm that provides coherent storylines related to a user-provided prompt word. The resulting limericks satisfy poetic constraints and have thematically coherent storylines, which are sometimes even funny (when we are lucky).
Chrysostom’s Homily on the Word Koimeterion and on the Cross: A Translation and Commentary
Authors: Friel David M. 
Published: July 2021

Abstract
Chrysostom’s homily De coemeterio et de cruce (CPG 4337) was delivered during a full eucharistic synaxis on Good Friday in a cemetery outside the gates of late-fourth-century Antioch. It demonstrates both rhetorical and theological prowess. Chrysostom consoles his hearers by likening death to sleep and reflecting on the cemetery as a “sleeping place” (koimeterion). The text is notable for its theology of physical space, its conception of liturgical anamnesis, and its presentation of the Christus Victor atonement motif. The homily also highlights the liturgical role of the Holy Spirit, especially by alluding to the eucharistic epiclesis, and it chastises the congregation for their poor behavior during the communion rite. This article presents the homily’s full text in Greek with English translation, followed by a commentary that probes its major themes and liturgical aspects.
Cloud-dependent piecewise assimilation based on a hydrometeor-included background error covariance and its impact on regional Numerical Weather Prediction
Authors: Meng Deming , Chen Yaodeng , Li Jun , Wang Hongli , Wang Yuanbing , Sun Tao 
Published: July 2021

AbstractThe background error covariance (B) behaves differently and needs to be carefully defined in cloudy areas due to larger uncertainties caused by models’ inability to correctly represent complex physical processes. This study proposes a new cloud-dependent B strategy by adaptively adjusting the hydrometeor-included B in the cloudy areas according to the cloud index (CI) derived from the satellite-based cloud products. The adjustment coefficient is determined by comparing the error statistics of B for the clear and cloudy areas based on the two-dimensional geographical masks. The comparison highlights the larger forecast errors and manifests the necessity of using appropriate B in cloudy areas. The cloud-dependent B is then evaluated by a series of single observation tests and three-week cycling assimilation and forecasting experiments. The single observation experiments confirm that the cloud-dependent B allows cloud dependency for the multivariate analysis increments and alleviates the discontinuities at the cloud mask borders by treating the CI as an exponent. The impact study on regional numerical weather prediction (NWP) demonstrates that the application of the cloud-dependent B reduces analyses and forecasts bias and increases precipitation forecast skills. Diagnostics of a heavy rainfall case indicate that the application of the cloud-dependent B enhances the moisture, wind, and hydrometeors analyses and forecasts, resulting in more accurate forecasts of accumulated precipitation. The cloud-dependent piecewise analysis scheme proposed herein is extensible, and a more precise definition of CI can improve the analysis, which deserves future investigation.
The mediating effect of brain-derived neurotrophic factor levels on childhood trauma and psychiatric symptoms in patients with first-episode schizophrenia
Authors: Wang Leilei , Yin Yi , Zhou Yanfang , Huang Junchao , Zhang Ping , Chen Song , Fan Hongzhen , Cui Yimin , Luo Xingguang , Tan Shuping , Wang Zhiren , Li Chiang-Shan R , Tian Baopeng , Tian Li , Elliot Hong L , Tan Yunlong 
Published: July 2021

Background: Previous studies have implicated childhood trauma and abnormal brain-derived neurotrophic factor in the pathogenesis of schizophrenia. Here, we explored whether brain-derived neurotrophic factor levels mediated the relationship between childhood trauma and psychopathological symptoms in patients with first-episode schizophrenia. Methods: Patients with first-episode schizophrenia ( n = 192) and healthy controls ( n = 136) were enrolled. Childhood traumatic experiences and psychopathology were assessed by Childhood Trauma Questionnaire and Positive and Negative Syndrome Scale, respectively. Enzyme-linked immunosorbent assay was used to quantify brain-derived neurotrophic factor levels. Results: The patients with first-episode schizophrenia experienced more severe childhood trauma and had lower serum brain-derived neurotrophic factor levels than healthy controls. Emotional abuse and Childhood Trauma Questionnaire total score showed positive correlation with Positive and Negative Syndrome Scale positive, general psychopathological subscore and total score. Emotional neglect showed positive correlation with Positive and Negative Syndrome Scale positive subscore. Physical neglect was positively associated with Positive and Negative Syndrome Scale negative subscore. Emotional neglect and Childhood Trauma Questionnaire total score were negatively correlated with serum brain-derived neurotrophic factor levels. The serum brain-derived neurotrophic factor levels mediated the relationship between both Childhood Trauma Questionnaire total score and Positive and Negative Syndrome Scale total score and negative symptoms in the patients. The brain-derived neurotrophic factor levels also mediated the relationship between emotional neglect and Positive and Negative Syndrome Scale total score in the patients. Conclusion: Childhood trauma might contribute to the clinical symptoms of schizophrenia by affecting brain-derived neurotrophic factor levels. Perhaps we can prevent schizophrenia by reducing childhood traumatic experiences.
Culturally competent, safe and equitable clinical care for Ma¯ori with bipolar disorder in New Zealand: The expert critique of Ma¯ori patients and Wha¯nau
Authors: Haitana Tracy , Pitama Suzanne , Cormack Donna , Clark Mau Te Rangimarie , Lacey Cameron 
Published: July 2021

Objective: Research designed to increase knowledge about Māori with bipolar disorder is required to understand how health services support wellbeing and respond to identified levels of community need. This paper synthesises the expert critique of Māori patients with bipolar disorder and their whānau regarding the nuances of cultural competence and safety in clinical encounters with the health system. Methods: A qualitative Kaupapa Māori Research methodology was used. A total of 24 semi-structured interviews were completed with Māori patients with bipolar disorder and members of their whānau. Structural, descriptive and pattern coding was completed using an adapted cultural competence framework to organise and analyse the data. Results: Three themes were evident from participants’ critique of clinical components of the health system. Theme 1 established that the efficacy of clinical care for bipolar disorder was dependent on Māori patients and whānau having clear pathways through care, and being able to access timely, consistent care from clinically and culturally competent staff. Theme 2 identified the influence of clinical culture in bipolar disorder services, embedded into care settings, expressed by staff, affecting the safety of clinical care for Māori. Theme 3 focused on the need for bipolar disorder services to prioritise clinical work with whānau, equip staff with skills to facilitate engagement and tailor care with resources to enhance whānau as well as patient wellbeing. Conclusion: The standard of clinical care for Māori with bipolar disorder in New Zealand does not align with practice guidelines, Māori models of health or clinical frameworks designed to inform treatment and address systemic barriers to equity. Research also needs to explore the role of structural and organisational features of the health system on Māori patient and whānau experiences of care.
Del Nido cardioplegia for myocardial protection in adult cardiac surgery: a systematic review and update meta-analysis
Authors: Zhai Kerong , Cheng Xingdong , Zhang Pengbin , Wei Shilin , Huang Jian , Wu Xiangyang , Gao Bingren , Li Yongnan 
Published: July 2021

Objective: Although the application of del Nido cardioplegia solution (DNC) in adult cardiac surgery is accumulating, the feasibility and safety of this myocardial protection strategy in adults remains controversial. We aimed to update our previous meta-analysis to determine the myocardial protective effect of DNC versus conventional cardioplegia (CC) in adult cardiac surgery. Methods: A comprehensive literature search was performed using PubMed, EMBASE, the Cochrane Library, and International Clinical Trials Registry Platform databases through November 2020. Results: Thirty-seven observational studies and four randomized controlled trials (RCTs) including 21,779 patients were identified. The DNC group was associated with decreased postoperative cardiac enzymes [troponin T (cTnT) and creatine kinase-MB (CK-MB)] [standardized mean differences (SMD): −0.59, 95% confidence interval (CI): −0.99 to −0.19, p = 0.004], cardiopulmonary bypass (CPB) time (MD: −9.31, 95% CI: −13.10 to −5.51, p < 0.00001), aortic cross-clamp (ACC) time (MD: −7.20, 95% CI: −10.31 to −4.09, p < 0.00001), and cardioplegia volume (SMD: −1.95, 95% CI: −2.46 to −1.44, p < 0.00001). Intraoperative defibrillation requirement was less in the DNC group [relative risk (RR): 0.50, 95% CI: 0.33 to 0.75, p = 0.0007]. The pooled analysis revealed no significant difference in operative mortality among the patients assigned to DNC and those undergoing CC. Conclusion: In adult cardiac surgery, compared to CC, myocardial protection used with DNC yield similar or better short-term clinical outcomes. More high-quality trials and RCTs reflecting long-term follow-up morbidity and mortality are required in the future to confirm these findings.