bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models
Authors: Yang Gang , Guan Wenfang , Cao Zhe , Guo Wenbo , Xiong Guangbing , Zhao Fangyu , Feng Mengyu , Qiu Jiangdong , Liu Yueze , Zhang Michael Q. , You Lei , Zhang Taiping , Zhao Yupei , Gu Jin 
Published: March 2021

Abstract

Purpose:
Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment.

Experimental Design:
In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA–based high-content screening was implemented to validate the function of the deregulated genes.

Results:
The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance.

Conclusions:
This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.
Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias
Authors: Mäkelä Eleonora , Pavic Karolina , Varila Taru , Salmenniemi Urpu , Löyttyniemi Eliisa , Nagelli Srikar G. , Ammunét Tea , Kähäri Veli-Matti , Clark Richard E. , Elo Laura L. , Bachanaboyina Venkata Kumari , Lucas Claire M. , Itälä-Remes Maija , Westermarck Jukka 
Published: March 2021

Abstract

Purpose:
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However, CIP2A mRNA variants remain uncharacterized. Here, we report the discovery of a CIP2A splicing variant, novel CIP2A variant (NOCIVA).

Experimental Design:
Characterization of CIP2A variants was performed by both 3′ and 5′ rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.

Results:
NOCIVA contains CIP2A exons 1 to 13 fused to 349 nucleotides from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA-specific sequence are in the coding frame with exon 13 of CIP2A and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, AML and CML patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, a high NOCIVA/CIP2A mRNA expression ratio is a marker for adverse overall survival. In CML, high NOCIVA expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.

Conclusions:
We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.
In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure
Authors: Gargalovic Peter , Wong Pancras , Onorato Joelle , Finlay Heather , Wang Tao , Yan Mujing , Crain Earl , St-Onge Stéphane , Héroux Madeleine , Bouvier Michel , Xu Carrie , Chen Xue-Qing , Generaux Claudia , Lawrence Michael , Wexler Ruth , Gordon David 
Published: March 2021

Background:
New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin’s short half-life limits its therapeutic utility. Here, we describe the preclinical characterization of a novel, orally bioavailable APJ agonist, BMS-986224.

Methods:

BMS-986224 pharmacology was compared with (Pyr
1
) apelin-13 using radio ligand binding and signaling pathway assays downstream of APJ (cAMP, phosphorylated ERK [extracellular signal-regulated kinase], bioluminescence resonance energy transfer–based G-protein assays, β-arrestin recruitment, and receptor internalization). Acute effects on cardiac function were studied in anesthetized instrumented rats. Chronic effects of BMS-986224 were assessed echocardiographically in the RHR (renal hypertensive rat) model of cardiac hypertrophy and decreased cardiac output.

Results:

BMS-986224 was a potent (Kd=0.3 nmol/L) and selective APJ agonist, exhibiting similar receptor binding and signaling profile to (Pyr
1
) apelin-13. G-protein signaling assays in human embryonic kidney 293 cells and human cardiomyocytes confirmed this and demonstrated a lack of signaling bias relative to (Pyr
1
) apelin-13. In anesthetized instrumented rats, short-term BMS-986224 infusion increased cardiac output (10%–15%) without affecting heart rate, which was similar to (Pyr
1
) apelin-13 but differentiated from dobutamine. Subcutaneous and oral BMS-986224 administration in the RHR model increased stroke volume and cardiac output to levels seen in healthy animals but without preventing cardiac hypertrophy and fibrosis, effects differentiated from enalapril.

Conclusions:

We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr
1
) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure.
LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis
Authors: Yu Huijing , Zhang Fang , Yan Pengyi , Zhang Shasha , Lou Yingmei , Geng Zilong , Li Zixuan , Zhang Yan , Xu Yuejuan , Lu Yanan , Chen Chen , Wang Daowen , Zhu Wei , Hu Xinyang , Wang Jian’an , Zhuang Tao , Zhang Yuzhen , Wu Gengze , Liu Junling , Zeng Chunyu , Pu William T. , Sun Kun , Zhang Bing 
Published: March 2021

Background:
Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

Methods:

We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific
LARP7
knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated
LARP7
somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

Results:

LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive
LARP7
knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus–mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

Conclusions:
LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
Water source and transmission in Haloxylon ammodendron in the desert margin of the Manas River Basin, China
Authors: Li Wanjing , Zhao Li , Yang Guang , Yan Ke , He Xinlin , Gao Yongli , Xue Lianqing , Li Fadong , Wu Yage 
Published: March 2021

Abstract
Analysis of water source and moisture transfer characteristics of desert plants is of great significance for ecological restoration in arid areas. In this study, the water source utilized by the desert plant, Haloxylon ammodendron, was analysed using the stable isotope technique, and the water transportation characteristics were obtained based on the proportional heat balance method under different weather conditions. The results showed that (1) before raining, the moisture of H. ammodendron mainly relied on groundwater (the average contribution rate was 34.14%) and on soil water located at a depth of 120–180 cm (the average contribution rate was 29.87%). After the rain, H. ammodendron mainly absorbed soil water from a depth of 60–120 cm (the average contribution rate was 33.19%) and groundwater (the average contribution rate was 30.67%); (2) the stem flow of H. ammodendron showed an obvious diurnal variation, showing a “midday rest” phenomenon. The stem flow showed a peak value, and in sunny days, it was ~2 fold higher than that in cloudy days. (3) The stem flow rate of H. ammodendron varied regularly overtime as follows: August > July > September > June > May, and the meteorological factors affecting its stem flow were solar radiation (0.826) > atmospheric temperature (0.598) > humidity (-0.573). The results provide basic support for the ecological conservation of the desert plant H. ammodendron, while also having important implications for ecological restoration in arid regions.
An appropriate and reactive response to the repeated waves of the COVID-19 pandemic by the national medico-psychological network (CUMP) in France
Authors: Prieto Nathalie , Vignaud Philippe , Darbon Remy , Cheucle Eric , Philippe Jean-Marc 
Published: March 2021

Introduction: France has been impacted by the COVID-19 pandemic. Anxiety, depression, burn out and the high proportion of post-traumatic stress disorder proved to be the most expected troubles caused by this pandemic and the confinement. Medico-psychological emergency units (CUMP) have been solicited at the very early stage of the pandemic because CUMP units are very well known by the French government and systematically associated to emergency plans. Methods: In this article we describe the process which has been developed to cope with the psychological needs in the general population. At a first level, platforms of volunteers specialised into listening were available. Then those platforms could directly mobilise the CUMP in case of psychiatric disorders. It ran over the whole first wave and it has been reactivated because of the second confinement in France. Results: During the first wave, approximately 1% of all the calls made on the national Covid number required to be redirected to the listening platforms. Of this group, 4% were related to reactive pathology or a psychiatric decompensating that required adapted and specialised care. Conclusion: The high rates of psychological distress detected in the general population in recent scientific literature seem discrepant with our findings of relatively low reorientation towards the CUMP. Nevertheless, our study highlights that the response of the CUMP network in France during the first wave was supportive. The second wave displays its adaptability to the public health policies.
Preparing public health at the front lines: effectiveness of training received by environmental health inspectors in the Caribbean
Authors: Shah Kalim U. 
Published: March 2021

Environmental health departments in the Caribbean continue to contend with environmental determinants of health related to an increasingly complex array of challenges, including climatic change, disasters, pollution, bioterrorism, and global pandemics. Building the human resource capacity to meet these challenges requires access to modernized, context-relevant training, especially for environmental health inspectors who interface with the public. This study focuses on the standardized Three-Step training program delivered by education institutions across the Caribbean, which is the primary training required by ministries of health for entry into the environmental health inspectorate. A total of 22 focus groups were completed in five countries—Barbados, Guyana, Jamaica, Saint Lucia, and Trinidad and Tobago—with 94 participants drawn from the education institutions delivering training and the inspectors who have received the training. Findings suggest: program strengths in core academic content; weaknesses in faculty experts to deliver advanced subjects; opportunities for enhancing field-training experiences in collaboration with ministries; and threats to program survival due to bottlenecks in public sector hiring that reduce the attractiveness of entering the profession. Interestingly, academic trainers and practitioners differ on the importance of certain knowledge sets, such as legal and court procedural skills and epidemiological data analysis. As ministries of health in these countries contemplate ways to modernize the inspectorates, these findings can guide how ministries and education institutions work together to modernize the Three-Step training program. Points for practitioners Environmental health inspectors interfacing with the public are well placed to contribute perspectives to the public health modernization discourse. Formal training programs must be periodically and frequently recalibrated to societal needs and the state of the art in subject area knowledge. Strengthening the local teaching institutions’ capacity to deliver relevant educational programs will translate into better-prepared frontline professionals. Formal training lags in integrating some emergent subject areas, such as climate change and environmental health determinants.
Connected to the spirit of the frog: An Internet-based survey on Kambô, the secretion of the Amazonian Giant Maki Frog (Phyllomedusa bicolor): Motivations for use, settings and subjective experiences
Authors: Majić Tomislav , Sauter Meike , Bermpohl Felix , Schmidt Timo T 
Published: March 2021

Background/aim: Kambô is a name for the secretion of the Giant Maki Frog ( Phyllomedusa bicolor), which has been used by indigenous cultures from the Amazonas basin and has recently become popular in alternative healing circles in Western countries, with a certain overlap with psychedelic self-exploration. Methods: We carried out an online-based survey in English (54.92%) and German investigating motivations for using Kambô, settings in which rituals take place, and subjective experiences during and after the application. Results: Participants ( n = 386, mean age: 38.08 years, (standard deviation = 9.95)) were well-educated individuals with an increased lifetime prevalence of the use of ayahuasca (67.88%). A plethora of motivations for using Kambô was reported, including general healing, detoxification and spiritual growth. Acute effects included severe physical reactions and mild psychoactive effects, most surprisingly, the feeling of being connected to the frog’s spirit (41.97%), whereas predominantly positive persisting psychological effects were reported. Few participants reported long-lasting physical (2.85%) or mental (1.81%) health problems which they attributed to Kambô. Of the participants, 87.31% reported an increase in personal well-being or life satisfaction, and 64.26% considered Kambô to have been at least of ‘very much’ spiritual significance for their lives. Conclusions: The majority of users claimed beneficial effects including more health-orientated behaviors, whereas only very few participants complained about new health problems which they ascribed to Kambô. In retrospect, Kambô was given a high personal and spiritual significance by many participants. Additional research is needed to determine in how far reported effects are modulated by setting and subjective expectations.
Hierarchically Demineralized Cortical Bone Combined With Stem Cell–Derived Extracellular Matrix for Regeneration of the Tendon-Bone Interface
Authors: He Shu-Kun , Ning Liang-Ju , Yao Xuan , Hu Ruo-Nan , Cui Jing , Zhang Yi , Ding Wei , Luo Jing-Cong , Qin Ting-Wu 
Published: March 2021

Background: Poor healing of the tendon-bone interface after rotator cuff repair is one of the main causes of surgical failure. Previous studies demonstrated that demineralized cortical bone (DCB) could improve healing of the enthesis. Purpose: To evaluate the outcomes of hierarchically demineralized cortical bone (hDCB) coated with stem cell–derived extracellular matrix (hDCB-ECM) in the repair of the rotator cuff in a rabbit model. Study Design: Controlled laboratory study. Methods: Tendon-derived stem cells (TDSCs) were isolated, cultured, and identified. Then, hDCB was prepared by the graded demineralization procedure. Finally, hDCB-ECM was fabricated via 2-week cell culture and decellularization, and the morphologic features and biochemical compositions of the hDCB-ECM were evaluated. A total of 24 rabbits (48 samples) were randomly divided into 4 groups: control, DCB, hDCB, and hDCB-ECM. All rabbits underwent bilateral detachment of the infraspinatus tendon, and the tendon-bone interface was repaired with or without scaffolds. After surgery, 8 rabbits were assessed by immunofluorescence staining at 2 weeks, and the others were assessed by micro–computed tomography (CT) examination, immunohistochemical staining, histological staining, and biomechanical testing at 12 weeks. Results: TDSCs were identified to have universal stem cell characteristics including cell markers, clonogenicity, and multilineage differentiation. The hDCB-ECM contained 3 components (bone, partial DCB, and DCB coated with ECM) with a gradient of calcium and phosphorus elements, and the ECM had stromal cell-derived factor 1, biglycan, and fibromodulin. Macroscopic observations demonstrated the absence of infection and rupture around the enthesis. The results of immunofluorescence staining showed that hDCB-ECM promoted stromal cell recruitment. Results of micro-CT analysis, immunohistochemical staining, and histological staining showed that hDCB-ECM enhanced bone and fibrocartilage formation at the tendon-bone interface. Biomechanical analysis showed that the hDCB-ECM group had higher ultimate tensile stress and Young modulus than the DCB group. Conclusion: The administration of hDCB-ECM promoted healing of the tendon-bone interface. Clinical Relevance: hDCB-ECM could provide useful information for the design of scaffolds to repair the tendon-bone interface, and further studies are needed to determine its effectiveness.
“Mtoto Wa Nyoka Ni Nyoka,” The Child of a Snake is a Snake: A Narrative Analysis of Adverse Childhood Experiences and Perpetration of Interpersonal Violence Among Men in Dar es Salaam, Tanzania
Authors: Zietz Susannah , Kajula Lusajo , Martin Sandra , Moracco Beth , Shanahan Meghan , Maman Suzanne 
Published: March 2021

Childhood exposure to adversity, including abuse and neglect, is consistently found to be a predictor of intimate partner violence (IPV) and peer violence (PV) perpetration in adulthood. The purpose of this study is to qualitatively examine factors that may facilitate or impede the use of violence among those who have been exposed to adversity early in life. We are particularly interested in protective experiences or environments for these participants. The qualitative data were analyzed through thematic coding and narrative analysis of participant life histories. We found three salient themes: (a) parental acceptance and early attachment is protective for coping with stress with intimate partners in adulthood; (b) certain key life turning points can provide a protective context against violent behavior in adulthood; and (c) poverty in adulthood compromises one’s ability to cope with stress and anger in adulthood. Our findings contextualize the different factors that may affect the behavior of perpetration of interpersonal violence among high-risk men in Dar es Salaam who have been exposed to adversity in childhood. These findings provide important information on the risk and protective factors for interpersonal violence spanning from childhood to adulthood. This study highlights the importance of child development interventions in this situation, both for the primary prevention of child adversity and for promoting resilience and mitigating the effects of childhood adversity that put men at risk for perpetration of interpersonal violence in adulthood.