bluuebunny/crossref_metadata_2025 huggingface dataset:
ABCA12 Promotes Proliferation and Migration and Inhibits Apoptosis of Pancreatic Cancer Cells Through the AKT Signaling Pathway
Authors: Zheng Songyuan , Liu Dongyan , Wang Feifei , Jin Youyan , Zhao Siqiao , Sun Siyu , Wang Sheng
Published: June 2022

Background: As a malignant tumor, pancreatic cancer is difficult to detect in its early stage. Pancreatic cancer progresses rapidly and has a short survival time. Most cases have metastasized to distant organs before diagnosis. The mechanism of induction of pancreatic cancer is not fully understood.

Methods: In this study, bioinformatics predicted ATP binding cassette subfamily A member 12 (ABCA12) expression in pancreatic tissues and performed survival analysis, risk assessment, and enrichment analysis. The expression of ABCA12 in 30 pairs of clinical samples was detected by immunohistochemistry and we analyzed its correlation with clinical information. Both reverse transcription polymerase chain reaction (RT–PCR) and western blot analysis were used to detect mRNA and protein expression in cell lines. Two different siRNAs and SW1990 cell line were used to construct pancreatic cancer cell models with ABCA12 knockdown. Cell viability was evaluated by cell counting kit-8 (CCK-8) and EdU proliferation assays. Wound healing assays and Transwell assays were used to measure the ability of cell migration and invasion. Flow cytometry was used to investigate the effect of ABCA12 on the proliferation cycle and apoptosis of pancreatic cancer. Western blot analysis detected changes in apoptosis, migration, and other pathway proteins in SW1990 cells after transfection.

Results:ABCA12 is highly expressed in pancreatic cancer tissues and cells. After ABCA12 was knocked down, the proliferation, invasion, and migration of SW1990 cells were significantly reduced, and apoptosis was increased. The changes in pathway proteins suggested that ABCA12 may regulate the progression of pancreatic cancer through the AKT pathway.

Conclusion: We found that ABCA12 is differentially expressed in pancreatic tissues and cells. ABCA12 can also affect the biological behavior of pancreatic cancer cells effectively, which may serve as a new target for pancreatic cancer diagnosis and treatment.
Necroptosis-Related Genes Associated With Immune Activity and Prognosis of Colorectal Cancer
Authors: Peng Xinyi , Xu Zhili , Guo Yong , Zhu Ying
Published: June 2022

This study aims at screening out the key necroptosis-related genes in colorectal cancer and elucidating the role of necroptosis-related genes in the immune activity and prognosis of colorectal cancer (CRC). The CRC patients’ data were downloaded from The Cancer Genome Atlas (TCGA). The non-negative matrix factorization method was applied to identify new molecular subgroups. Survival analysis and single sample Gene Set Enrichment Analysis were performed to determinate the differences in the overall survival time and immune status of the subgroups. Prognostic model was constructed on the basis of univariate Cox regression and LASSO analysis. Functional analyses were used to explore the potential mechanisms. Based on prognostic related necroptosis genes, we identify two molecular subgroups with significantly different survival. The better prognosis was associated with more active immune infiltration and upregulated expression of immune checkpoints. We screened nine necroptosis related genes as key prognostic genes and established a risk model, which showed a good potential for survival prediction in colorectal cancer. Nomogram assessment showed that the model had high reliability for predicting the prognosis of colorectal cancer patients. The high-risk and low-risk group also has different sensitivity to immunotherapy and commonly used drugs for colorectal cancer. Overall, necroptosis related genes were involved in the immune microenvironment of colorectal cancer patient, could be utilized to predict the prognosis of colorectal cancer and develop more individualized treatment.
Identification and Validation of Prognostic Model for Pancreatic Ductal Adenocarcinoma Based on Necroptosis-Related Genes
Authors: Xie Haoran , Xu Jingxian , Xie Zhiwen , Xie Ni , Lu Jiawei , Yu Lanting , Li Baiwen , Cheng Li
Published: June 2022

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a poor prognosis. Recently, necroptosis has been reported to participate in the progression of multiple tumors. However, few studies have revealed the relationship between necroptosis and PDAC, and the role of necroptosis in PDAC has not yet been clarified.

Methods: The mRNA expression data and corresponding clinical information of PDAC patients were downloaded from the TCGA and GEO databases. The necroptosis-related genes (NRGs) were obtained from the CUSABIO website. Consensus clustering was performed to divide PDAC patients into two clusters. Univariate and LASSO Cox regression analyses were applied to screen the NRGs related to prognosis to construct the prognostic model. The predictive value of the prognostic model was evaluated by Kaplan-Meier survival analysis and ROC curve. Univariate and multivariate Cox regression analyses were used to evaluate whether the risk score could be used as an independent predictor of PDAC prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and single-sample gene set enrichment analysis (ssGSEA) were used for functional enrichment analysis. Finally, using qRT-PCR examined NRGs mRNA expression in vitro.

Results: Based on the TCGA database, a total of 22 differential expressed NRGs were identified, among which eight NRGs (CAPN2, CHMP4C, PLA2G4F, PYGB, BCL2, JAK3, PLA2G4C and STAT4) that may be related to prognosis were screened by univariate Cox regression analysis. And CAPN2, CHMP4C, PLA2G4C and STAT4 were further selected to construct the prognostic model. Kaplan-Meier survival analysis and ROC curve showed that there was a significant correlation between the risk model and prognosis. Univariate and multivariate Cox regression analyses showed that the risk score of the prognostic model could be used as an independent predictor. The model efficacy was further demonstrated in the GEO cohort. Functional analysis revealed that there were significant differences in immune status between high and low-risk groups. Finally, the qRT-PCR results revealed a similar dysregulation of NRGs in PDAC cell lines.

Conclusion: This study successfully constructed and verified a prognostic model based on NRGs, which has a good predictive value for the prognosis of PDAC patients.
Virus-Like Particles Are Efficient Tools for Boosting mRNA-Induced Antibodies
Authors: Vogt Anne-Cathrine S. , Jörg Lukas , Martina Byron , Krenger Pascal S. , Chang Xinyue , Zeltins Andris , Vogel Monique , Mohsen Mona O. , Bachmann Martin F.
Published: June 2022

mRNA based vaccines against COVID-19 have proven most successful at keeping SARS-CoV-2 pandemic at bay in many countries. Recently, there is an increased interest in heterologous prime-boost vaccination strategies for COVID-19 to maintain antibody responses for the control of continuously emerging SARS-CoV-2 variants of concern (VoCs) and to overcome other obstacles such as supply shortage, costs and reduced safety issues or inadequatly induced immune-responses. In this study, we investigated the antibody responses induced by heterologous prime-boost with vaccines based on mRNA and virus-like particles (VLPs). The VLP-based mCuMVTT-RBM vaccine candidate and the approved mRNA-1273 vaccine were used for this purpose. We find that homologous prime boost regimens with either mRNA or VLP induced high levels of high avidity antibodies. Optimal antibody responses were, however, induced by heterologous regimens both for priming with mRNA and boosting with VLP and vice versa, priming with VLP and boosting with mRNA. Thus, heterologous prime boost strategies may be able to optimize efficacy and economics of novel vaccine strategies.
Dynamic Changes in Uterine NK Cell Subset Frequency and Function Over the Menstrual Cycle and Pregnancy
Authors: Whettlock Emily M. , Woon Ee Von , Cuff Antonia O. , Browne Brendan , Johnson Mark R. , Male Victoria
Published: June 2022

Uterine natural killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single-cell RNA sequencing (scRNAseq) on first-trimester decidua showed that uNK can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype, and function of uNK1–3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, and third trimester; and postpartum). We found that uNK1 and uNK2 peak in the first trimester, but by the third trimester, the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation and that uNK1 and uNK2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function change dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia, and pre-term labour.
The Antibody Dependant Neurite Outgrowth Modulation Response Involvement in Spinal Cord Injury
Authors: Capuz Alice , Karnoub Mélodie-Anne , Osien Sylvain , Rose Mélanie , Mériaux Céline , Fournier Isabelle , Devos David , Vanden Abeele Fabien , Rodet Franck , Cizkova Dasa , Salzet Michel
Published: June 2022

Spinal cord injury (SCI) represents a major medical challenge. At present, there is still no cure to treat it efficiently and enable functional recovery below the injury site. Previously, we demonstrated that inflammation determines the fate of the physiopathology. To decipher the molecular mechanisms involved in this process, we performed a meta-analysis of our spatio-temporal proteomic studies in the time course of SCI. This highlighted the presence of IgG isotypes in both spinal cord explants and their secretomes. These IgGs were detected in the spinal cord even if no SCI occurred. However, during the time course following SCI, abundance of IgG1 and IgG2 subclasses (a, b, c) varied according to the spatial repartition. IgG1 was clearly mostly abundant at 12 h, and a switch to IgG2a was observed after 24 h. This IgG stayed predominant 3, 7, and 10 days after SCI. A protein related to IgM as well as a variable heavy chain were only detected 12 h after lesion. Interestingly, treatment with RhoA inhibitor influenced the abundance of the various IgG isotypes and a preferential switch to IgG2c was observed. By data reuse of rat dorsal root ganglion (DRG) neurons RNAseq datasets and RT-PCR experiments performed on cDNA from DRG sensory neurons ND7/23 and N27 dopaminergic neural cell lines, we confirmed expression of immunoglobulin heavy and light chains (constant and variable) encoding genes in neurons. We then identified CD16 and CD32b as their specific receptors in sensory neuron cell line ND7/23 and their activation regulated neurites outgrowth. These results suggest that during SCI, neuronal IgG isotypes are released to modulate neurites outgrowth. Therefore, we propose a new view of the SCI response involving an antibody dependent neurite outgrowth modulation (ADNM) which could be a precursor to the neuroinflammatory response in pathological conditions.
Case Report: Primary Cardiac T-Cell Lymphoma With Complete Atrio-Ventricular Block Diagnosed by Endomyocardial Biopsy
Authors: Chen Panpan , Hao Yuanyuan , Qiu Xi , Xiao Xibin , Zhu Wei , Xu Yang , Qian Wenbin
Published: June 2022

Primary cardiac lymphoma (PCL) is a rare disease, the definite diagnosis of which is sometimes difficult and mainly relies on endomyocardial biopsy. Primary cardiac T-cell lymphoma (PCTL) is an extremely rare sub-type of PCL. Here, we report on a 47-year-old female with PCTL who presented with fever, syncope, palpitations, and a third-degree atrioventricular block (AVB) on electrocardiogram. Chemotherapy was administered with two courses of methotrexate, cyclophosphamide, liposomal doxorubicin, vincristine, and dexamethasone (MTX-CHOP). As the tumor vanished, AVB changed from third degree to second degree and finally to sinus rhythm. In conclusion, endomyocardial biopsy is valuable in the diagnosis of primary cardiac lymphoma. It is worth noting that alterations in the electrocardiogram may indicate an attack on the heart by PCTL.
Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model
Authors: Ahmed Umair , Graf John F. , Daytz Anna , Yaipen Omar , Mughrabi Ibrahim , Jayaprakash Naveen , Cotero Victoria , Morton Christine , Deutschman Clifford Scott , Zanos Stavros , Puleo Chris
Published: June 2022

Interfaces between the nervous and immune systems have been shown essential for the coordination and regulation of immune responses. Non-invasive ultrasound stimulation targeted to the spleen has recently been shown capable of activating one such interface, the splenic cholinergic anti-inflammatory pathway (CAP). Over the past decade, CAP and other neuroimmune pathways have been activated using implanted nerve stimulators and tested to prevent cytokine release and inflammation. However, CAP studies have typically been performed in models of severe, systemic (e.g., endotoxemia) or chronic inflammation (e.g., collagen-induced arthritis or DSS-induced colitis). Herein, we examined the effects of activation of the splenic CAP with ultrasound in a model of local bacterial infection by lung instillation of 105 CFU of Streptococcus pneumoniae. We demonstrate a time-dependent effect of CAP activation on the cytokine response assay during infection progression. CAP activation-induced cytokine suppression is absent at intermediate times post-infection (16 hours following inoculation), but present during the early (4 hours) and later phases (48 hours). These results indicate that cytokine inhibition associated with splenic CAP activation is not observed at all timepoints following bacterial infection and highlights the importance of further studying neuroimmune interfaces within the context of different immune system and inflammatory states.
Secondary Lymphoid Organs in Mesenchymal Stromal Cell Therapy: More Than Just a Filter
Authors: Zheng Di , Bhuvan Tejasvini , Payne Natalie L. , Heng Tracy S. P.
Published: June 2022

Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in inflammatory models of human disease. However, clinical translation has fallen short of expectations, with many trials failing to meet primary endpoints. Failure to fully understand their mechanisms of action is a key factor contributing to the lack of successful commercialisation. Indeed, it remains unclear how the long-ranging immunomodulatory effects of MSCs can be attributed to their secretome, when MSCs undergo apoptosis in the lung shortly after intravenous infusion. Their apoptotic fate suggests that efficacy is not based solely on their viable properties, but also on the immune response to dying MSCs. The secondary lymphoid organs (SLOs) orchestrate immune responses and play a key role in immune regulation. In this review, we will discuss how apoptotic cells can modify immune responses and highlight the importance of MSC-immune cell interactions in SLOs for therapeutic outcomes.
The H2S Donor Sodium Thiosulfate (Na2S2O3) Does Not Improve Inflammation and Organ Damage After Hemorrhagic Shock in Cardiovascular Healthy Swine
Authors: Messerer David Alexander Christian , Gaessler Holger , Hoffmann Andrea , Gröger Michael , Benz Kathrin , Huhn Aileen , Hezel Felix , Calzia Enrico , Radermacher Peter , Datzmann Thomas
Published: June 2022

We previously demonstrated marked lung-protective properties of the H2S donor sodium thiosulfate (Na2S2O3, STS) in a blinded, randomized, controlled, long-term, resuscitated porcine model of swine with coronary artery disease, i.e., with decreased expression of the H2S-producing enzyme cystathionine-γ-lyase (CSE). We confirmed these beneficial effects of STS by attenuation of lung, liver and kidney injury in mice with genetic CSE deletion (CSE-ko) undergoing trauma-and-hemorrhage and subsequent intensive care-based resuscitation. However, we had previously also shown that any possible efficacy of a therapeutic intervention in shock states depends both on the severity of shock as well as on the presence or absence of chronic underlying co-morbidity. Therefore, this prospective, randomized, controlled, blinded experimental study investigated the effects of the STS in cardiovascular healthy swine. After anesthesia and surgical instrumentation, 17 adult Bretoncelles-Meishan-Willebrand pigs were subjected to 3 hours of hemorrhage by removal of 30% of the blood volume and titration of the mean arterial pressure (MAP) ≈ 40 ± 5 mmHg. Afterwards, the animals received standardized resuscitation including re-transfusion of shed blood, fluids, and, if needed, continuous i.v. noradrenaline to maintain MAP at pre-shock values. Animals were randomly allocated to either receive Na2S2O3 or vehicle control starting 2 hours after initiation of shock until 24 hours of resuscitation. The administration of Na2S2O3 did not alter survival during the observation period of 68 hours after the initiation of shock. No differences in cardio-circulatory functions were noted despite a significantly higher cardiac output, which coincided with significantly more pronounced lactic acidosis at 24 hours of resuscitation in the Na2S2O3 group. Parameters of liver, lung, and kidney function and injury were similar in both groups. However, urine output was significantly higher in the Na2S2O3 group at 24 hours of treatment. Taken together, this study reports no beneficial effect of Na2S2O3 in a clinically relevant model of hemorrhagic shock-and-resuscitation in animals without underlying chronic cardiovascular co-morbidity.
Highly Efficient Water-Based Extraction of Biliprotein R-Phycoerythrin From Marine the Red-Macroalga Sarcopeltis skottsbergii by Ultrasound and High-Pressure Homogenization Methods
Authors: Castro-Varela Pablo , Celis-Pla Paula S.M. , Figueroa Felix L. , Rubilar Monica
Published: June 2022

Sarcopeltis skottsbergii is an endemic species of the southern region of South America, with R-phycoerythrin (R-PE) as an accessory photosynthetic pigment. The production of S. skottsbergii is around twenty thousand tons of dry alga per year. The evaluation of (R-PE) in a biorefinery model is still incipient in the algal biotechnology area and will be used in the food, pharmaceutical, cosmeceutical, and nutraceutical industries. This work evaluated the cell disruption and separation processes by using two green technologies, ultrasound-assisted extraction (UAE) and high-pressure homogenization (HPH), to obtain an R-phycoerythrin enriched extract from S. skottsbergii. Two-levels three-factor central composite design (CCD) and response surface methodology (RSM) were carried out to optimize the extraction conditions, including the factors for UAE (time, amplitude, and solvent) and HPH (Pressure, number of passes, and solvent). Additionally, a second-order polynomial fit was performed to fit the experimental data by the green method. HPH method was the most efficient extraction method under the conditions obtained of 100-400 MPa pressure power, 2-3 number of passes, and distilled water as solvent. Furthermore, the experimental extraction yields ranged from 4.4-5.7 mg of PE g-1 of dry biomass under the optimal extraction conditions (400 MPa; 2 passes), which agreed with the predictive yield of 4.6-5.5 mg g-1 DW. The ultrafiltration membrane used for the separation process for both methods exhibited a rejection of R-phycoerythrin concentrated at 30 KDa. Furthermore, R-phycoerythrin showed a positive correlation between the antioxidant capacity (ORAC) in the best-selected extractions. After the extraction, the same pattern was observed in Chlorophyll a and total carotenoids with DPPH. Thus, it was an attractive non-aggressive extraction alternative with biological activity of interest for formulating biotechnological products for the food industry is suggested.
Meta-Estimation of Araucanian Herring, Strangomera bentincki (Norman, 1936), Biological Indicators in the Central-South Zone of Chile (32°–47° LS)
Authors: Aranis Antonio , de la Cruz Rolando , Montenegro Carlos , Ramírez Marlene , Caballero Leonardo , Gómez Alejandra , Walker Karen
Published: June 2022

Araucanian herring, Strangomera bentincki, is ecologically and economically important. Its complexity, like that of other pelagic fish, arises from seasonal population changes related to distribution with different spatial dynamics and demographic fractions, subject to strong environmental and fishing exploitation variations. This implies the necessity for a thorough understanding of biological processes, which are interpreted with the help of various activities, and directly or indirectly allow to infer and deliver adequate indicators. These activities facilitate a correct technical analysis and consistent conclusions for resource management and administration. In this context, the present study identified and addressed the need to integrate information on Araucanian herring lengths made available in historical series from commercial fleet fishing and sources such as special monitoring, hydroacoustic cruises, and monitoring during closed seasons. The study focused on methodologies widely used in biostatistics that allow analyzing the feasibility of integrating data from different origins, focused on evaluating the correct management of size structures that vary by origin, sample size, and volumes extracted. We call this tool meta-estimation. It estimates the integration of biological-fishery size indicators that originated mainly from commercial fishing and research fisheries for central-south pelagic fishery with data of catch between January and July 2018.
Biomass Turnover Rates in Metabolically Active and Inactive Marine Calanoid Copepods
Authors: Mayor Daniel J. , Cook Kathryn B. , Thornton Barry , Atherden Florence , Tarling Geraint A. , Anderson Thomas R.
Published: June 2022

Lipid-storing copepods are fundamental to the functioning of marine ecosystems, transferring energy from primary producers to higher trophic levels and sequestering atmospheric carbon (C) in the deep ocean. Quantifying trophic transfer and biogeochemical cycling by copepods requires improved understanding of copepod metabolic rates in both surface waters and during lipid-fueled metabolism over winter. Here we present new biomass turnover rates of C and nitrogen (N) inCalanoides acutus,Calanoides natalis,Calanus glacialisandCalanus hyperboreusalongside published data forCalanus finmarchicusandCalanus pacificus. Turnover rates in metabolically active animals, normalised to 10°C, ranged between 0.007 – 0.105 d-1and 0.004 – 0.065 d-1for C and N, respectively. Turnover rates of C were typically faster than those for N, supporting the understanding that non-protein C, e.g. lipid, is catabolised faster than protein. Re-analysis of published data indicates that inactive, overwinteringC. finmarchicusturn over wax ester lipids at a rate of 0.0016 d-1. These and other basal rate data will facilitate the mechanistic representation of copepod physiology in global biogeochemical models, thereby reducing uncertainties in our predictions of future ocean ecosystem functioning and C sequestration.
Differences in External Morphology, Body Composition and Swimming Performance Between Hatchery- and Wild-Origin Marbled Rockfish (Sebastiscus marmoratus)
Authors: Guo Haoyu , Zhang Xiaofeng , Näslund Joacim , Peng Liye , Liu Chenhui , Tian Mengjia , Chai Xuejun , Zhang Dingyuan , Zhang Xiumei
Published: June 2022

Stock enhancement based on hatchery-reared fish has become one of the most common forms of management practices in marine fisheries resource restoration. However, unnatural rearing environments may cause hatchery-reared fish to diverge phenotypically from wild conspecifics, with negative consequences for post-release performance in the natural environments. To better evaluate the suitability of releasing hatchery-reared fish, it is necessary to understand the phenotypic effects of captive rearing, through comparisons with wild conspecifics. In this study, we compared body morphology, swimming performance, and biochemical body composition between hatchery-reared and wild marbled rockfish (Sebastiscus marmoratus) from the same general gene pool. The results show that the overall body profile differed significantly between the groups, with hatchery-reared individuals having a deeper body (in particular in the head and trunk regions), narrower caudal peduncles, and higher condition factor, as compared to wild conspecifics. Hatchery-reared marbled rockfish also had relatively shorter fins, for a given size. In terms of swimming performance, the hatchery-reared marbled rockfish performed worse than the wild, with slower burst swimming speeds and poorer endurance. Wild rockfish had higher body protein content but lower lipid levels compared to the hatchery-reared individuals. These results suggest that hatchery rearing conditions have a great impact on the phenotypic development, with possibly high effects on their post-release performance of the hatchery-reared marbled rockfish. Modifications for the hatchery environment and operation should be investigated with an aim to minimize the divergence in phenotypic development for production of more wild-like fish for stocking.
Three-Dimensional Impact Localization on Concrete Structures Using Novel Enhanced Cross-Correlation Algorithm and Designed Concrete Implantable Module
Authors: Chen Qingjun , Yang Ziqian , Li Xiuquan , Sun Xiangtao , Kong Qingzhao
Published: June 2022

Concrete structures are often subjected to undesirable impact loads. Impact localization in near real time is greatly essential for providing early warnings and evaluating impact load effects. In this article, a novel enhanced cross-correlation (ECC) algorithm enabled by a designed concrete implantable module (CIM) is proposed for precise prediction of the impact location on concrete structures. The stability of the ECC algorithm under the noise condition was numerically studied. The numerical results demonstrate that the proposed ECC algorithm has high adaptability in the low signal-to-noise ratio (SNR) condition compared with the traditional algorithm, which provides the possibility for employing this approach in real projects. In the experimental study, a series of impact tests on a concrete beam specimen were conducted to verify the accuracy of the proposed method for impact localization. The results indicate that the maximum and minimum distance errors between the real and predicted impact positions are 54.1 and 12.5 mm, respectively. Both the numerical and experimental studies demonstrate the feasibility of the proposed method for the prediction of impact locations.
Wrinkling of Elastic Cylinders With Material Properties Varying in Radial Direction
Authors: Zhan Chunxiao , Wang Meiqin , Li Hao , Wu Zhigen
Published: June 2022

Although the instability of graded elastic cylinders has been analyzed by many researchers, most of them focused on the core-shell cylinders and film-substrate structures with inhomogeneous Young’s modulus. For a radially graded elastic cylinder subjected to the axial compression, the variation of Poisson’s ratio may result in the radial and circumferential stresses and thereby affects the critical condition of instability. By assuming linear elasticity with nonlinear kinematics, the governing equation for the incremental stress field is developed for instability analysis of the cylinder with radially graded material properties (Young’s modulus and Poisson’s ratio). Considering the arbitrariness of material properties, the state space technique is implemented and a semi-analytical solution is acquired. The obtained solution is validated by the finite element results. Numerical examples show that the critical condition of instability for graded elastic cylinders is related to whether Poisson’s ratio is assumed to be constant.
The Efficiency of Convalescent Plasma Therapy in the Management of Critically Ill Patients Infected With COVID-19: A Matched Cohort Study
Authors: Pan Chun , Chen Hui , Xie Jianfeng , Huang Yingzi , Yang Yi , Du Bin , Qiu Haibo
Published: June 2022

Background

The convalescent plasma of patients who recover from coronavirus disease 2019 (COVID-19) contains high titers of neutralizing antibodies, which has potential effects on the viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and improving the prognosis of patients with COVID-19. The goal of this study was to clarify the effects of convalescent plasma therapy on the 60-day mortality and negative conversion rate of SARS-CoV-2 during the hospitalization of patients with severe and life-threatening COVID-19 infection.

Methods

This was a retrospective, case-matched cohort study that involved patients with severe COVID-19 infections. The patients who received convalescent plasma therapy were matched by age, sex, diabetes, hypertension, heart failure, the onset of symptoms to hospital admission, respiratory support pattern, lymphocyte count, troponin, Sequential organ failure assessment (SOFA), glucocorticoid, and antiviral agents to no more than three patients with COVID-19 who did not receive convalescent plasma therapy. A Cox regression model and competing risk analysis were used to evaluate the effects of convalescent plasma therapy on these patients.

Results

Twenty-six patients were in the convalescent plasma therapy group, and 78 patients were in the control group. Demographic characteristics were similar in both groups, except for the SOFA score. Convalescent plasma therapy did not improve 60-day mortality [hazard ratio (HR) 1.44, 95% CI 0.82–2.51, p = 0.20], but the SARS-CoV-2 negative conversion rate for 60 days after admission was higher in the convalescent plasma group (26.9 vs. 65.4%, p = 0.002) than in the control. Then, a competing risk analysis was performed, which considered events of interest (the negative conversion rate of SARS-CoV-2) and competing events (death) in the same model. Convalescent plasma therapy improved events of interest (p = 0.0002).

Conclusion

Convalescent plasma therapy could improve the SARS-CoV-2 negative conversion rate but could not improve 60-day mortality in patients with severe and life-threatening COVID-19 infection.

Clinical Trial Number

The study was registered at ClinicalTrials.gov (NCT04616976).
Hepatic Arterial Infusion Chemotherapy With Folfirinox or Oxaliplatin Alone in Metastatic Colorectal Cancer
Authors: Randrian Violaine , Pernot Simon , Sionneau Baptiste , Smith Denis , Lim Annie , Touchefeu Yann , Gallois Claire , Turpin Anthony , Javed Sahir , Guimbaud Rosine , Rivera Pascale , Karoui Mehdi , Auclin Edouard , Taieb Julien
Published: June 2022

Background

Hepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox.

Methods

Patients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers.

Results

Data were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox (n = 52) or HAI-Ox (n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15–32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4–34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9–10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0–7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox (p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20–0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6–9.0; p = 0.002).

Conclusion

Hepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC.
CK5/6 and GATA3 Defined Phenotypes of Muscle-Invasive Bladder Cancer: Impact in Adjuvant Chemotherapy and Molecular Subtyping of Negative Cases
Authors: Koll Florestan J. , Schwarz Alina , Köllermann Jens , Banek Severine , Kluth Luis , Wittler Clarissa , Bankov Katrin , Döring Claudia , Becker Nina , Chun Felix K.H. , Wild Peter J. , Reis Henning
Published: June 2022

Introduction and Objective

Identifying patients that benefit from cisplatin-based adjuvant chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC). The purpose of this study is to correlate “luminal” and “basal” type protein expression with histological subtypes, to investigate the prognostic impact on survival after adjuvant chemotherapy and to define molecular consensus subtypes of “double negative” patients (i.e., without expression of CK5/6 or GATA3).

Materials and Methods

We performed immunohistochemical (IHC) analysis of CK5/6 and GATA3 for surrogate molecular subtyping in 181 MIBC samples. The mRNA expression profiles for molecular consensus classification were determined in CK5/6 and GATA3 (double) negative cases using a transcriptome panel with 19.398 mRNA targets (HTG Molecular Diagnostics). Data of 110 patients undergoing radical cystectomy were available for survival analysis.

Results

The expression of CK5/6 correlated with squamous histological subtype (96%) and expression of GATA3 was associated with micropapillary histology (100%). In the multivariate Cox-regression model, patients receiving adjuvant chemotherapy had a significant survival benefit (hazard ratio [HR]: 0.19 95% confidence interval [CI]: 0.1–0.4, p < 0.001) and double-negative cases had decreased OS (HR: 4.07; 95% CI: 1.5–10.9, p = 0.005). Double negative cases were classified as NE-like (30%), stroma-rich (30%), and Ba/Sq (40%) consensus molecular subtypes and displaying different histological subtypes.

Conclusion

Immunohistochemical-based classification was associated with histological subtypes of urothelial MIBC. IHC markers like CK5/6 and GATA3 that are used in pathological routine could help to identify patients with basal and luminal tumor characteristics. However, a two-sided classification system might not sufficiently reflect the heterogeneity of bladder cancer to make treatment decisions. Especially the group of IHC-double negative cases, as further analyzed by mRNA expression profiling, are a heterogeneous group with different implications for therapy.
Detection of Post-COVID-19 Patients Using Medical Scent Detection Dogs—A Pilot Study
Authors: Twele Friederike , ten Hagen Nele Alexandra , Meller Sebastian , Schulz Claudia , Osterhaus Albert , Jendrny Paula , Ebbers Hans , Pink Isabell , Drick Nora , Welte Tobias , Schalke Esther , Volk Holger Andreas
Published: June 2022

There is a growing number of COVID-19 patients experiencing long-term symptoms months after their acute SARS-CoV-2 infection. Previous research proved dogs' ability to detect acute SARS-CoV-2 infections, but has not yet shown if dogs also indicate samples of patients with post-COVID-19 condition (Long COVID). Nine dogs, previously trained to detect samples of acute COVID-19 patients, were confronted with samples of Long COVID patients in two testing scenarios. In test scenario I (samples of acute COVID-19 vs. Long COVID) dogs achieved a mean sensitivity (for acute COVID-19) of 86.7% (95%CI: 75.4–98.0%) and a specificity of 95.8% (95%CI: 92.5–99.0%). When dogs were confronted with Long COVID and negative control samples in scenario IIa, dogs achieved a mean sensitivity (for Long COVID) of 94.4 (95%CI: 70.5–100.0%) and a specificity of 96.1% (95%CI: 87.6–100.0%). In comparison, when acute SARS-CoV-2 positive samples and negative control samples were comparatively presented (scenario IIb), a mean sensitivity of 86.9 (95%CI: 55.7–100.0%) and a specificity of 88.1% (95%CI: 82.7–93.6%) was attained. This pilot study supports the hypothesis of volatile organic compounds (VOCs) being long-term present after the initial infection in post-COVID-19 patients. Detection dogs, trained with samples of acute COVID-19 patients, also identified samples of Long COVID patients with a high sensitivity when presented next to samples of healthy individuals. This data may be used for further studies evaluating the pathophysiology underlying Long COVID and the composition of specific VOC-patterns released by SARS-CoV-2 infected patients throughout the course of this complex disease.
Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection
Authors: Hirschberger Simon , Gellert Luca , Effinger David , Muenchhoff Maximilian , Herrmann Markus , Briegel Josef-Maria , Zwißler Bernhard , Kreth Simone
Published: June 2022

Severe COVID-19 is characterized by profound CD8+ T-cell dysfunction, which cannot be specifically treated to date. We here investigate whether metabolic CD8+ T-cell reprogramming by ketone bodies could be a promising strategy to overcome the immunoparalysis in COVID-19 patients. This approach was triggered by our recent pioneering study, which has provided evidence that CD8+ T-cell capacity in healthy subjects could be significantly empowered by a Ketogenic Diet. These improvements were achieved by immunometabolic rewiring toward oxidative phosphorylation. We here report similar strengthening of CD8+ T cells obtained from severely diseased COVID-19 patients: Flow cytometry and ELISA revealed elevated cytokine expression and secretion (up to + 24%) upon ketone treatment and enhanced cell lysis capacity (+ 21%). Metabolic analyses using Seahorse technology revealed upregulated mitochondrial respiratory chain activity (+ 25%), enabling both superior energy supply (+ 44%) and higher mitochondrial reactive oxygen species signaling. These beneficial effects of ketones might represent evolutionary conserved mechanisms to strengthen human immunity. Our findings pave the road for metabolic treatment studies in COVID-19.
A Proposal for Value-Based Managed Entry Agreements in an Environment of Technological Change and Economic Challenge for Publicly Funded Healthcare Systems
Authors: Xoxi Entela , Rumi Filippo , Kanavos Panos , Dauben Hans-Peter , Gutierrez-Ibarluzea Iñaki , Wong Olivier , Rasi Guido , Cicchetti Americo
Published: June 2022

Managed entry agreements (MEA) represent one of the main topics of discussion between the European National Payers Authorities. Several initiatives on the subject have been organized over the past few years and the scientific literature is full of publications on the subject. There is currently little international sharing of information between payers, mainly as a result of the confidentiality issues. There are potential benefits from the mutual sharing of information, both about the existence of MEAs and on the outcomes and results. The importance of involving all the players in the decision-making process on market access for a medicinal product (MP) is that it may help to make new therapies available to patients in a shorter time. The aim of this project is to propose a new pathway of value-based MEA (VBMEA), based on the analysis of the current Italian pricing and reimbursement framework. This requires elaboration of a transparent appraisal and MEA details with at least a 24-month contract. The price of the MP is therefore valued based on the analysis of the VBMEA registries of the Italian Medicines Agency. Although the proposal focuses on the Italian context, a similar approach could also be adapted in other nations, considering the particularities of the single health technology assessment (HTA)/payer system.
Machine Learning Approaches for Hospital Acquired Pressure Injuries: A Retrospective Study of Electronic Medical Records
Authors: Levy Joshua J. , Lima Jorge F. , Miller Megan W. , Freed Gary L. , O'Malley A. James , Emeny Rebecca T.
Published: June 2022

Background

Many machine learning heuristics integrate well with Electronic Medical Record (EMR) systems yet often fail to surpass traditional statistical models for biomedical applications.

Objective

We sought to compare predictive performances of 12 machine learning and traditional statistical techniques to predict the occurrence of Hospital Acquired Pressure Injuries (HAPI).

Methods

EMR information was collected from 57,227 hospitalizations acquired from Dartmouth Hitchcock Medical Center (April 2011 to December 2016). Twelve classification algorithms, chosen based upon classic regression and recent machine learning techniques, were trained to predict HAPI incidence and performance was assessed using the Area Under the Receiver Operating Characteristic Curve (AUC).

Results

Logistic regression achieved a performance (AUC = 0.91 ± 0.034) comparable to the other machine learning approaches. We report discordance between machine learning derived predictors compared to the traditional statistical model. We visually assessed important patient-specific factors through Shapley Additive Explanations.

Conclusions

Machine learning models will continue to inform clinical decision-making processes but should be compared to traditional modeling approaches to ensure proper utilization. Disagreements between important predictors found by traditional and machine learning modeling approaches can potentially confuse clinicians and need to be reconciled. These developments represent important steps forward in developing real-time predictive models that can be integrated into EMR systems to reduce unnecessary harm.
Cat8 Response to Nutritional Changes and Interaction With Ehrlich Pathway Related Factors
Authors: Du Zhengda , Deng Hong , Cheng Yanfei , Zhai Zhiguang , Guo Xuena , Wang Zhaoyue , He Xiuping
Published: June 2022

Cat8 is an important transcription factor regulating the utilization of non-fermentative carbon sources inSaccharomyces cerevisiae. However, our previous studies found that Cat8 may play a critical role in nitrogen metabolism, but the regulatory mechanism has not been elucidated. In this study, the nuclear localization and analysis of regulatory activity showed that the Cat8 function relies on Snf1 kinase. In the fermentation with glucose or glycerol as carbon sources under phenylalanine (Phe) induction, by comparing the changes of cellular gene expression and Cat8 target gene binding profiles after Cat8 overexpression, enhanced transcription was shown among key genes involved in the Ehrlich pathway (e.g.,ARO9,ARO10, andADH2) and its upstream and downstream related factors (e.g.,GAP1,AGP1,GAT1,PDR12, andESPB6), indicating that Cat8 participated in the regulation of nitrogen metabolism. Moreover, highly active Cat8 interacts with transcriptional activator Aro80 and GATA activator Gat1 coordinately to regulate the transcription ofARO10. Altogether, our results showed that Cat8 may act as a global transcription factor in response to nutritional changes, regulating both carbon and nitrogen utilization. This provides a new insight for us to explore the regulation of cell nutrient metabolism networks in yeast.
New Insights Into the Persistent Effects of Acute Exposure to AFB1 on Rat Liver
Authors: Yan Jiahui , Chen Lin , Zhang Li , Zhang Zhaohuan , Zhao Yong , Wang Yuan , Ou Jie
Published: June 2022

Aflatoxin B1 (AFB1) has mutagenesis, carcinogenesis and teratogenesis effects and mainly found in food crops and their processed foods. AFB1 exposure can cause acute or chronic liver poisoning, but there were few studies on the persistent effects of acute AFB1 exposure on the liver. In this study, rat liver injury models were established 2 and 7 days after single exposure to high and low doses of AFB1. The persistent effects of AFB1 single acute exposure (ASAE) on rat liver were analyzed from the phenotypic and genetic levels. The results showed that compared with the control group, liver function indexes, MDA content in liver and the number of apoptotic hepatocytes in model groups increased to the highest on the 2nd day after ASAE (p < 0.001). However, the changes of liver coefficient were most significant on the 7th day after ASAE (p < 0.01). The results of liver pathology showed that the liver injury was not alleviated and the activities of antioxidant enzymes GSH-Px and SOD were the lowest on the 7th day (p < 0.001). RNA-Seq results indicated that there were 236, 33, 679, and 78 significantly differentially expressed genes (DEGs) in the model groups (LA-2d, LA-7d, HA-2d, HA-7d) compared with the control group. Among them, the Gtse1 gene related to the proliferation, differentiation and metastasis of liver cancer cells, the Lama5 and Fabp4 gene related to the inflammatory response were significantly DEGs in the four model groups, and the differential expression of the immune system-related Bcl6 gene increased with the prolonged observation time after ASAE. In conclusion, ASAE can cause persistent liver damage in rats. The persistently affected genes Lama5, Gtse1, Fabp4, and Bcl6 possess the potential to be therapeutic targets for liver disease induced by AFB1.