bluuebunny/crossref_metadata_2025 huggingface dataset:
Phytoplankton Community Performance Depends on the Frequency of Temperature Fluctuations
Authors: Kunze Charlotte , Gerhard Miriam , Jacob Marrit , Franke Niklas Alexander , Schröder Matthias , Striebel Maren
Published: January 2022

With increasing frequency and intensity of climate change events, it is crucial to understand how different components of temperature fluctuations affect the thermal tolerance and performance of marine primary producers. We used a controlled indoor-mesocosm set-up to test the effect of a temperature fluctuation frequency gradient on a natural phytoplankton community. Within a frequency gradient, we allowed the temperature to fluctuate from 18 ± 3°C at different rates (6, 12, 24, 36, and 48 h). The temperature fluctuation frequency gradient was contrasted to a constant temperature treatment with the same mean temperature (18°C). Phytoplankton biomass tended to increase with faster fluctuations but was lowest in the diurnal frequency treatment (24 h). In comparison with constant conditions, diurnal or slower fluctuation frequencies showed lower or comparable performance, whereas faster fluctuations showed higher performance. In addition, minor differences in community structure were observed, but species diversity remained comparable over time. Similarly, resource use efficiency and stoichiometry did not change according to fluctuation frequency treatments. We conclude that the effect of temperature fluctuations on phytoplankton biomass depends on the fluctuation frequency; this suggests that the fluctuation frequency determines how organisms average their environments. However, this trend is not driven by species identity but physiological responses. Our results also indicate that phytoplankton communities may be already well adapted to fluctuating environments and can adjust physiologically to temperature variability.
The Mechanism of Carbonate Alkalinity Exposure on Juvenile Exopalaemon carinicauda With the Transcriptome and MicroRNA Analysis
Authors: Shi Kunpeng , Li Mingdong , Qin Zhen , Wang Jiajia , Liu Ping , Li Jian , Li Jitao
Published: January 2022

Saline-alkali water is distributed all over the world and affects the development of fisheries. The ridge tail white prawn Exopalaemon carinicauda is an economically important shrimp in China, which has excellent environmental tolerance. However, due to its complex genetic structure, there have been few studies on its alkalinity-adaptation mechanisms. In order to explore the molecular mechanisms of E. carinicauda in adapting to the alkaline water, mRNA and miRNA transcriptomes from the gills of E. carinicauda were determined. The results showed that after alkalinity stress, the structures of the gill and hepatopancreas were disorganized; however, E. carinicauda could still maintain vital signs. Transcriptome results showed that ATP binding protein and carbonic anhydrase played an important role in alkalinity-adaptation. At the same time, a large number of immune-related genes were up-regulated, which protect E. carinicauda from bacterial infection. MiRNAs also played an important role in alkalinity-adaptation. A total of 24 miRNAs were identified as differentially expressed after alkalinity stress, and up-regulated miRNAs might active the GnRH signaling pathway and accelerate the synthesis and secretion of aldosterone, which might maintain the balance of osmotic pressure in E. carinicauda to adapt to alkaline environment. These results provide a better understanding of the alkalinity-adaptation mechanism of economic aquatic animals and provide theoretical basis for breeding in the future.
Association of Evaluated Glomerular Filtration Rate and Incident Diabetes Mellitus: A Secondary Retrospective Analysis Based on a Chinese Cohort Study
Authors: Mo Zihe , Hu Haofei , Du Xiaoqing , Huang Qingli , Chen Ping , Lai Linjing , Yu Zhiqun
Published: January 2022

Background

Previous studies have revealed that chronic kidney disease (CKD) is a significant risk factor for insulin resistance and diabetes. However, few studies are on the association between estimated glomerular filtration rate (eGFR) and incident diabetes, especially in the Chinese population with eGFR>60 mL/min·1.73 m2. This study explored the relationship between eGFR and incident diabetes in a large cohort in the Chinese community.

Methods

This study was a retrospective cohort study. A total of 1,99,435 adults from Rich Healthcare Group in China were studied, including all medical records for participants who received a health check from 2010 to 2016. The target-independent and target-dependent variables were eGFR measured at baseline, and incident diabetes mellitus appeared during the follow-up. After testing the proportion hypothesis, Cox proportional hazards regression was used to investigate the association between eGFR and incident diabetes. A Cox proportional hazards regression with cubic spline functions and smooth curve fitting (the cubic spline smoothing) was used to identify non-linear relationships between eGFR and the risk of diabetes. Additionally, we also performed subgroup analysis and a series sensitivity analysis. It was stated that the data had been uploaded to the DATADRYAD website.

Result

After adjusting gender, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), smoking and drinking status, and family history of diabetes, the result showed that eGFR was negatively associated with incident diabetes [HR = 0.986, 95% CI (0.984, 0.988)]. A non-linear relationship was detected between eGFR and incident diabetes, with an inflection point of eGFR of 98.034 mL/min·1.73 m2. The effect sizes and the confidence intervals (Cis) on the left and right sides of the inflection point were 0.998 (0.993, 1.003) and 0.976 (0.972, 0.980), respectively. Subgroup analysis showed a stronger association in the population with FPG <6.1 mmol/L, BMI <24 kg/m2, SBP <140 mmHg, DBP <90 mmHg and family history without diabetes. The same trend was also seen in women and the population who never smoke.

Conclusion

Estimated glomerular filtration rate is independently associated with incident diabetes. The relationship between eGFR and incident diabetes is also non-linear. eGFR is strongly related to incident diabetes when eGFR was above 98.034 mL/min·1.73 m2.
Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection
Authors: Koslik Marius Andreas , Friebus-Kardash Justa , Heinemann Falko Markus , Kribben Andreas , Bräsen Jan Hinrich , Eisenberger Ute
Published: January 2022

Background

Antibody-mediated rejection (ABMR) is the main cause of renal allograft loss. The most common treatment strategy is based on plasmapheresis plus the subsequent administration of intravenous immunoglobulin (IVIG). Unfortunately, no approved long-term therapy is available for ABMR. The current study was designed to analyze the effect of various ABMR treatment approaches on allograft survival and to compare treatment effects in the presence or absence of donor-specific antibodies (DSAs).

Methods

This single-center study retrospectively analyzed 102 renal allograft recipients who had biopsy-proven ABMR after transplant. DSA was detectable in 61 of the 102 patients. Initial standard treatment of ABMR consisted of plasmapheresis (PS) or immunoadsorption (IA), followed by a single course of IVIG. In case of nonresponse or recurrence, additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab, were administered. In a second step, persistent ABMR was treated with increased maintenance immunosuppression, long-term therapy with IVIG (more than 1 year), or both.

Results

Overall graft survival among transplant patients with ABMR was <50% after 3 years of follow-up. Compared to the use of PS/IA and IVIG alone, the use of additional immunosuppressive medications had no beneficial effect on allograft survival (p = 0.83). Remarkably, allografts survival rates were comparable between patients treated with the combination of PS/IA and IVIG and those treated with a single administration of IVIG (p = 0.18). Renal transplant patients with ABMR but without DSAs benefited more from increased maintenance immunosuppression than did DSA-positive patients with ABMR (p = 0.01). Recipients with DSA-positive ABMR exhibited significantly better allograft survival after long-term application of IVIG for more than 1 year than did recipients with DSA-negative ABMR (p = 0.02).

Conclusions

The results of our single-center cohort study involving kidney transplant recipients with ABMR suggest that long-term application of IVIG is more favorable for DSA-positive recipients, whereas intensification of maintenance immunosuppression is more effective for recipients with DSA-negative ABMR.
C4d as a Screening Tool and an Independent Predictor of Clinical Outcomes in Lupus Nephritis and IgA Nephropathy
Authors: Yang Xiaoqian , Yuan Yanhong , Shao Xinghua , Pang Huihua , Che Xiajing , Cao Liou , Zhang Minfang , Xu Yao , Ni Zhaohui , Qi Chaojun , Wang Qin , Mou Shan
Published: January 2022

Background

As an indispensable marker of complement cascades activation, C4d was confirmed of its crucial role in the pathogenesis of both lupus nephritis (LN) and IgA nephropathy (IgAN). While the studies directly comparing the diagnostic value, and outcomes predicting function of C4d between LN and IgAN are still absent.

Methods

A cohort of 120 LN patients, 120 IgAN patients who were diagnosed by renal biopsy between January 2015 and December 2017 and 24 healthy age matched controls were prospectively analyzed. The patients were followed till December 2020. The outcomes were adverse disease treatment response (disease relapse) and kidney disease progression event (decline of estimated glomerular filtration rate by more than 20% or end-stage kidney disease). The renal C4d deposition proportion and pattern were compared between IgAN and LN patients. In addition, the relationship between renal C4d deposition and disease subtypes, disease relapse as well as disease progression for LN and IgAN patients were also analyzed.

Results

The LN, IgAN patients and healthy controls were well matched in ages. The follow-up period was 38.5 (30.3–60.8) months for LN patients and 45.0 (30.5–57.0) months for IgAN patients. 78 patients (65.0%) with LN had renal C4d deposition, compared with only 39 IgAN patients (32.5%) with C4d deposition in renal tissues (P < 0.001). The LN patients shared different renal C4d distribution patterns with IgAN patients. Compared with IgAN patients, the C4d deposition in LN patients was significantly more in renal glomerulus (P < 0.001) and less in renal tubules (P = 0.003). For disease subtypes, renal C4d deposition was especially strong in class V membranous LN and IgAN with tubulointerstitial fibrosis (T1/T2) lesions. Renal C4d deposition was independently correlated with the disease relapse of LN patients (HR = 1.007, P = 0.040), and acted as an independent predictor of disease progression during the follow-up period for IgAN patients (HR = 1.821, P = 0.040).

Conclusions

Renal C4d distribution proportion and pattern differed between LN and IgAN patients. The presence of C4d in renal tissue acted as an independent predictor of relapse for LN patients and disease progression for IgAN patients.
Overexpression and Biochemical Properties of a GH46 Chitosanase From Marine Streptomyces hygroscopicus R1 Suitable for Chitosan Oligosaccharides Preparation
Authors: Wang Jianrong , Wang Ping , Zhu Mujin , Chen Wei , Yu Si , Zhong Bin
Published: January 2022

Due to the various biological activities of chitosan oligosaccharides (COSs), they have great potential value for use in many areas. Chitosanase plays an important role in enzymatic preparation of COSs. Herein, a gene encoding a chitosanase (ShCsn46) from marine Streptomyces hygroscopicus R1 was cloned and the sequences encoding ShCsn46 without signal peptide were optimized based on the codon usage of Pichia pastoris (P. pastoris). In addition, the optimized gene was ligated to pPICZαA and transformed to P. pastoris X33. After screening, a recombinant strain named X33-Sh33 with the highest activity was isolated from 96 recombinant colonies. The maximum activity and total protein concentration of the recombinant strain ShCsn46 were 2250 U/ml and 3.98 g/l, respectively. The optimal pH and temperature of purified ShCsn46 were 5.5 and 55°C, respectively. Meanwhile, ShCsn46 was stable from pH 5.0 to 10.0 and 40 to 55°C, respectively. The purified ShCsn46 was activated by Mn2+ and inhibited by Cu2+, Fe2+, and Al3+. In addition, substrate specificity of the purified ShCsn46 showed highest activity toward colloidal chitosan with 95% degree of deacetylation. Furthermore, the purified ShCsn46 exhibited high efficiency to hydrolyze 4% colloidal chitosan to prepare COSs. COSs with degree of polymerization of 2–6, 2–5, and 2–4 were controllably produced by adjusting the reaction time. This study provides an excellent chitosanase for the controllable preparation of COSs with a desirable degree of polymerization.
Current Perspectives on Gastrointestinal Models to Assess Probiotic-Pathogen Interactions
Authors: Anjum Mehreen , Laitila Arja , Ouwehand Arthur C. , Forssten Sofia D.
Published: January 2022

There are different models available that mimic the human intestinal epithelium and are thus available for studying probiotic and pathogen interactions in the gastrointestinal tract. Although, in vivo models make it possible to study the overall effects of a probiotic on a living subject, they cannot always be conducted and there is a general commitment to reduce the use of animal models. Hence, in vitro methods provide a more rapid tool for studying the interaction between probiotics and pathogens; as well as being ethically superior, faster, and less expensive. The in vitro models are represented by less complex traditional models, standard 2D models compromised of culture plates as well as Transwell inserts, and newer 3D models like organoids, enteroids, as well as organ-on-a-chip. The optimal model selected depends on the research question. Properly designed in vitro and/or in vivo studies are needed to examine the mechanism(s) of action of probiotics on pathogens to obtain physiologically relevant results.
Schwann Cell-Derived Exosomes Induce the Differentiation of Human Adipose-Derived Stem Cells Into Schwann Cells
Authors: Zhou Nan , Xu Zhao , Li Xiang , Ren Sen , Chen Jing , Xiong Hewei , Wang Cheng , Guo Jiahe , Kang Yu , Chen Zhenbing , Li Wenqing , Yang Xiaofan , Zhang Xing , Xu Xiang
Published: January 2022

Adipose-derived stem cells (ADSCs) can differentiate into Schwann cells (SCs) at the site of nerve injury, where Schwann cell-derived exosomes (SC-Exos) are suspected to exert an induction effect. Our study aimed to induce the differentiation of ADSCs in vitro using SC-Exos and to investigate the mechanisms involved through miRNA sequencing. Subcutaneous fat was used to extract ADSCs. Exosomes were extracted from Schwann cell lines (RSC96) using ultracentrifugation and were able to be taken up by human ADSCs. After 8 days of induction of ADSCs by SC-Exos, phenotypic characteristics were observed by examining the expression of SC markers (S100ß, NGFR, MPZ, GFAP) through RT-qPCR, Western blot and immunofluorescence. The RNA and protein expression levels of S100ß, NGFR, MPZ, and GFAP were found to be significantly higher in the SC-Exo induction group than in the uninduced group, which was also consistent with the immunofluorescence results. Additionally, miRNA sequencing was performed on exosome-induced ADSCs, followed by bioinformatic analysis and validation of the results. According to the sequencing results, there were a total of 94 differentially expressed miRNAs. Bioinformatics analysis indicated that 3506 Gene Ontology terms and 98 Kyoto Encyclopedia of Genes and Genomes pathways were significantly enriched. Ten miRNAs, 5 target mRNAs and elevated expression of the PIK3CD/Akt pathway were validated by RT-qPCR or Western blot, which is consistent with the sequencing results. Our study demonstrates that the utility of SC-Exos is effective in inducing the differentiation of ADSCs into SCs, in which these validated differentially expressed miRNAs exert a vital effect. This work provides a new paradigm via rationally applying Schwann cell-derived exosomes as a promising therapeutic option for repairing peripheral nerve injury.
Longitudinal Trajectories of Participant- and Study Partner-Rated Cognitive Decline, in Relation to Alzheimer’s Disease Biomarkers and Mood Symptoms
Authors: Munro Catherine E. , Buckley Rachel , Vannini Patrizia , DeMuro Carla , Sperling Reisa , Rentz Dorene M. , Johnson Keith , Gatchel Jennifer R. , Amariglio Rebecca
Published: January 2022

Whereas discrepancies between participant- and study partner-reported cognitive concerns on the Alzheimer’s disease (AD) continuum have been observed, more needs to be known regarding the longitudinal trajectories of participant- vs. study partner-reported concerns, particularly their relationship to AD biomarkers and mood symptomology. Additionally, it is unclear whether years of in-clinic data collection are needed to observe relationships with AD biomarkers, or whether more frequent, remote assessments over shorter periods of time would suffice. This study primarily sought to examine the relationships between longitudinal trajectories of participant- and study partner-rated cognitive decline and baseline biomarker levels [i.e., amyloid and tau positron emission tomography (PET)], in addition to how mood symptomatology may alter these trajectories of concerns over a 2-year period. Baseline mood was associated with longitudinal participant-rated concerns, such that participants with elevated depression and anxiety scores at baseline had decreasing concerns about cognitive decline over time (fixed estimate = −0.17, 95% CI [−0.29 to −0.05], t = −2.75, df = 457, adj. p = 0.012). A significant interaction between baseline amyloid (fixed estimate = 4.07, 95% CI [1.13–7.01], t = 2.72, df = 353, adj. p = 0.026) and tau (fixed estimate = 3.50, 95% CI [0.95–6.06], t = 2.70, df = 331, adj. p = 0.030) levels was associated with increasing study partner concerns, but not participant concerns, over time. The interaction between amyloid and study partner concerns remained significant when utilizing only the first year of concern-related data collection. Overall, these results suggest that frequent, remote assessment of study partner-reported concerns may offer additional insight into the AD clinical spectrum, as study partners appear to more accurately update their concerns over time with regard to pathology, with these concerns less influenced by participants’ mood symptomatology.
Deletion of β-Neurexins in Mice Alters the Distribution of Dense-Core Vesicles in Presynapses of Hippocampal and Cerebellar Neurons
Authors: Ferdos Shima , Brockhaus Johannes , Missler Markus , Rohlmann Astrid
Published: January 2022

Communication between neurons through synapses includes the release of neurotransmitter-containing synaptic vesicles (SVs) and of neuromodulator-containing dense-core vesicles (DCVs). Neurexins (Nrxns), a polymorphic family of cell surface molecules encoded by three genes in vertebrates (Nrxn1–3), have been proposed as essential presynaptic organizers and as candidates for cell type-specific or even synapse-specific regulation of synaptic vesicle exocytosis. However, it remains unknown whether Nrxns also regulate DCVs. Here, we report that at least β-neurexins (β-Nrxns), an extracellularly smaller Nrxn variant, are involved in the distribution of presynaptic DCVs. We found that conditional deletion of all three β-Nrxn isoforms in mice by lentivirus-mediated Cre recombinase expression in primary hippocampal neurons reduces the number of ultrastructurally identified DCVs in presynaptic boutons. Consistently, colabeling against marker proteins revealed a diminished population of chromogranin A- (ChrgA-) positive DCVs in synapses and axons of β-Nrxn-deficient neurons. Moreover, we validated the impaired DCV distribution in cerebellar brain tissue from constitutive β-Nrxn knockout (β-TKO) mice, where DCVs are normally abundant and β-Nrxn isoforms are prominently expressed. Finally, we observed that the ultrastructure and marker proteins of the Golgi apparatus, responsible for packaging neuropeptides into DCVs, seem unchanged. In conclusion, based on the validation from the two deletion strategies in conditional and constitutive KO mice, two neuronal populations from the hippocampus and cerebellum, and two experimental protocols in cultured neurons and in the brain tissue, this study presented morphological evidence that the number of DCVs at synapses is altered in the absence of β-Nrxns. Our results therefore point to an unexpected contribution of β-Nrxns to the organization of neuropeptide and neuromodulator function, in addition to their more established role in synaptic vesicle release.
Knock-In Mouse Models to Investigate the Functions of Opioid Receptors in vivo
Authors: Degrandmaison Jade , Rochon-Haché Samuel , Parent Jean-Luc , Gendron Louis
Published: January 2022

Due to their low expression levels, complex multi-pass transmembrane structure, and the current lack of highly specific antibodies, the assessment of endogenous G protein-coupled receptors (GPCRs) remains challenging. While most of the research regarding their functions was performed in heterologous systems overexpressing the receptor, recent advances in genetic engineering methods have allowed the generation of several unique mouse models. These animals proved to be useful to investigate numerous aspects underlying the physiological functions of GPCRs, including their endogenous expression, distribution, interactome, and trafficking processes. Given their significant pharmacological importance and central roles in the nervous system, opioid peptide receptors (OPr) are often referred to as prototypical receptors for the study of GPCR regulatory mechanisms. Although only a few GPCR knock-in mouse lines have thus far been generated, OPr are strikingly well represented with over 20 different knock-in models, more than half of which were developed within the last 5 years. In this review, we describe the arsenal of OPr (mu-, delta-, and kappa-opioid), as well as the opioid-related nociceptin/orphanin FQ (NOP) receptor knock-in mouse models that have been generated over the past years. We further highlight the invaluable contribution of such models to our understanding of the in vivo mechanisms underlying the regulation of OPr, which could be conceivably transposed to any other GPCR, as well as the limitations, future perspectives, and possibilities enabled by such tools.
Prediction of Communication Impairment in Children With Bilateral Cerebral Palsy Using Multivariate Lesion- and Connectome-Based Approaches: Protocol for a Multicenter Prospective Cohort Study
Authors: Hu Jie , Zhang Jingjing , Yang Yanli , Liang Ting , Huang Tingting , He Cheng , Wang Fuqin , Liu Heng , Zhang Tijiang
Published: January 2022

Background

Bilateral cerebral palsy (BCP) is the most common type of CP in children and is often accompanied by different degrees of communication impairment. Several studies have attempted to identify children at high risk for communication impairment. However, most prediction factors are qualitative and subjective and may be influenced by rater bias. Individualized objective diagnostic and/or prediction methods are still lacking, and an effective method is urgently needed to guide clinical diagnosis and treatment. The aim of this study is to develop and validate an objective, individual-based model for the prediction of communication impairment in children with BCP by the time they enter school.

Methods

A multicenter prospective cohort study will be conducted in four Chinese hospitals. A total of 178 children with BCP will undergo advanced brain magnetic resonance imaging (MRI) at baseline (corrected age, before the age of 2 years). At school entry, communication performance will be assessed by a communication function classification system (CFCS). Three-quarters of children with BCP will be allocated as a training cohort, whereas the remaining children will be allocated as a test cohort. Multivariate lesion- and connectome-based approaches, which have shown good predictive ability of language performance in stroke patients, will be applied to extract features from MR images for each child with BCP. Multiple machine learning models using extracted features to predict communication impairment for each child with BCP will be constructed using data from the training cohort and externally validated using data from the test cohort. Prediction accuracy across models in the test cohort will be statistically compared.

Discussion

The findings of the study may lead to the development of several translational tools that can individually predict communication impairment in children newly diagnosed with BCP to ensure that these children receive early, targeted therapeutic intervention before they begin school.

Trial registration

The study has been registered with the Chinese Clinical Trial Registry (ChiCTR2100049497).
Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications
Authors: Angstadt Shantel , Zhu Qingfeng , Jaffee Elizabeth M. , Robinson Douglas N. , Anders Robert A.
Published: January 2022

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.
Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment
Authors: Pelizzaro Filippo , Haxhi Selion , Penzo Barbara , Vitale Alessandro , Giannini Edoardo G. , Sansone Vito , Rapaccini Gian Ludovico , Di Marco Maria , Caturelli Eugenio , Magalotti Donatella , Sacco Rodolfo , Celsa Ciro , Campani Claudia , Mega Andrea , Guarino Maria , Gasbarrini Antonio , Svegliati-Baroni Gianluca , Foschi Francesco Giuseppe , Olivani Andrea , Masotto Alberto , Nardone Gerardo , Raimondo Giovanni , Azzaroli Francesco , Vidili Gianpaolo , Brunetto Maurizia Rossana , Trevisani Franco , Farinati Fabio
Published: January 2022

Background

Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy.

Methods

Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment.

Results

The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC).

Conclusions

Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis.
Imaging Glioblastoma With 18F-Fluciclovine Amino Acid Positron Emission Tomography
Authors: Scarpelli Matthew L. , Healey Debbie R. , Mehta Shwetal , Quarles C. Chad
Published: January 2022

Introduction

Conventional methods of imaging brain tumors fail to assess metabolically active tumor regions, which limits their capabilities for tumor detection, localization, and response assessment. Positron emission tomography (PET) with 18F-fluciclovine (fluciclovine) provides regional assessment of amino acid uptake in tumors that could overcome some of the limitations of conventional imaging. However, the biological basis of enhanced fluciclovine uptake is insufficiently characterized in brain tumors, which confounds clinical interpretation and application. This study sought to address this gap by correlating multiple biologic quantities with fluciclovine PET uptake across a range of human glioblastoma xenograft models.

Methods

Thirty-one rats underwent orthotopic implantations with one of five different human glioblastoma cell lines. After tumors were established, fluciclovine PET and magnetic resonance imaging (MRI) scans were performed. The fluciclovine tumor-to-normal-brain (TN) uptake ratio was used to quantify fluciclovine uptake. MRI scans were used to assess tumor volume and gadolinium enhancement status. Histologic assessments quantified tumor cell proliferation, tumor cell density, and tumor cell amino acid transporters (LAT1 and ASCT2). Multivariate linear regression models related fluciclovine uptake with the other measured quantities.

Results

Within the multivariate regression, the fluciclovine TN uptake ratio (measured 15 to 35 minutes after fluciclovine injection) was most strongly associated with tumor ASCT2 levels (β=0.64; P=0.001). The fluciclovine TN uptake ratio was also significantly associated with tumor volume (β=0.45; P=0.001) and tumor enhancement status (β=0.40; P=0.01). Tumor cell proliferation, tumor cell density, and LAT1 levels were not significantly associated with fluciclovine uptake in any of the multivariate models. In general, both enhancing and non-enhancing tumors could be visualized on fluciclovine PET images, with the median TN uptake ratio across the five tumor lines being 2.4 (range 1.1 to 8.9).

Conclusions

Increased fluciclovine PET uptake was associated with increased levels of the amino acid transporter ASCT2, suggesting fluciclovine PET may be useful for assessing brain tumor amino acid metabolism. Fluciclovine PET uptake was elevated in both enhancing and non-enhancing tumors but the degree of uptake was greater in larger tumors and tumors with enhancement, indicating these variables could confound fluciclovine metabolic measurements if not accounted for.
Andersen–Tawil Syndrome With Novel Mutation in KCNJ2: Case Report
Authors: Yim Jisook , Kim Kyoung Bo , Kim Minsun , Lee Gun Dong , Kim Myungshin
Published: January 2022

Andersen–Tawil syndrome (ATS) is a rare autosomal dominant disorder characterized by a classic symptom triad: periodic paralysis, ventricular arrhythmias associated with prolonged QT interval, and dysmorphic skeletal and facial features. Pathogenic variants of the inwardly rectifying potassium channel subfamily J member 2 (KCNJ2) gene have been linked to the ATS. Herein, we report a novel KCNJ2 causative variant in a proband and her father showing different ATS-associated symptoms. A 15-year-old girl was referred because of episodic weakness and periodic paralysis in both legs for 2–3 months. The symptoms occurred either when she was tired or after strenuous exercise. These attacks made walking or climbing stairs difficult and lasted from one to several days. She had a short stature (142 cm, <3rd percentile) and weighed 40 kg. The proband also showed orbital hypertelorism, dental crowding, mandibular hypoplasia, fifth-digit clinodactyly, and small hands. Scoliosis in the thoracolumbar region was detected by chest X-ray. Since she was 7 years old, she had been treated for arrhythmia-associated long QT interval and underwent periodic echocardiography. Brain MRI revealed cerebrovascular abnormalities indicating absence or hypoplasia of bilateral internal carotid arteries, and compensation of other collateral vessels was observed. There were no specific findings related to intellectual development. The proband's father also had a history of periodic paralysis similar to the proband. He did not show any cardiac symptoms. Interestingly, he was diagnosed with hyperthyroidism during an evaluation for paralytic symptoms. Clinical exome sequencing revealed a novel heterozygous missense variant: Chr17(GRCh37):g.68171593A>T, NM_000891.2:c.413A>T, p.(Glu138Val) in KCNJ2 in the proband and the proband's father.
Type III Monteggia Injury With Ipsilateral Distal Forearm Fracture in a Child: A Case Report
Authors: Gao Chao , Sun Jing Hua , Zheng Hua Jiang , Wu Yong Yao , Cao Jin
Published: January 2022

Monteggia fracture refers to breakage of the upper third of the ulna combined with dislocation of the radial head. It often occurs in children and adolescents and represents a combined injury. Fracture of the distal forearm is among the most common trauma suffered by children. However, distal forearm fractures have rarely been reported as having an association with Monteggia fractures. We report on a 9-year-old boy diagnosed with a type III Monteggia fracture combined with a distal forearm fracture. He underwent surgery and received rehabilitation training 1 month later. He was followed-up for 1 year. The affected limb functioned well with no sign of radial head dislocation.
The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features
Authors: Golshiri Keivan , Ataabadi Ehsan Ataei , Jüttner Annika A. , Snyder Gretchen L. , Davis Robert E , Lin Amy , Zhang Lei , de Vries René , Garrelds Ingrid M , Leijten Frank P. J. , Danser A. H. Jan , Roks Anton J. M.
Published: January 2022

Age-related cardiovascular diseases (CVDs) remain among the leading global causes of death, and vascular smooth muscle cell (VSMC) remodeling plays an essential role in its pathology. Reduced NO-cGMP pathway signaling is a major feature and pathogenic mechanism underlying vasodilator dysfunction. Recently, we identified phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides cAMP and cGMP, and thereby provides a potential treatment target for restoring age-related vascular dysfunction due to aging of VSMC. Based on this hypothesis, we here tested the effects of PDE1 inhibition in a model of SMC-specific accelerated aging mice. SMC-KO and their WT littermates received either vehicle or the PDE1 inhibitor lenrispodun for 8 weeks. Vascular function was measured both in vivo (Laser Doppler technique) and ex vivo (organ bath). Moreover, we deployed UV irradiation in cell culture experiments to model accelerated aging in an in vitro situation. SMC-KO mice display a pronounced loss of vasodilator function in the isolated aorta, the cutaneous microvasculature, and mesenteric arteries. Ex vivo, in isolated vascular tissue, we found that PDE1 inhibition with lenrispodun improves vasodilation, while no improvement was observed in isolated aorta taken from mice after chronic treatment in vivo. However, during lenrispodun treatment in vivo, an enhanced microvascular response in association with upregulated cGMP levels was seen. Further, chronic lenrispodun treatment decreased TNF-α and IL-10 plasma levels while the elevated level of IL-6 in SMC-KO mice remained unchanged after treatment. PDE1 and senescence markers, p16 and p21, were increased in both SMC-KO aorta and cultured human VSMC in which DNA was damaged by ultraviolet irradiation. This increase was lowered by chronic lenrispodun. In contrast, lenrispodun increased the level of PDE1A in both situations. In conclusion, we demonstrated that PDE1 inhibition may be therapeutically useful in reversing aspects of age-related VSMC dysfunction by potentiating NO-cGMP signaling, preserving microvascular function, and decreasing senescence. Yet, after chronic treatment, the effects of PDE1 inhibition might be counteracted by the interplay between differential PDE1A and C expression. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment.
A Cryogenic Hydrogen Ribbon for Laser Driven Proton Acceleration at Hz-Level Repetition Rate
Authors: Chagovets T. , Viswanathan J. , Tryus M. , Grepl F. , Velyhan A. , Stancek S. , Giuffrida L. , Schillaci F. , Cupal J. , Koubikova L. , Garcia D. , Manzagol J. , Bonnay P. , Souris F. , Chatain D. , Girard A. , Margarone D.
Published: January 2022

We report on recent progress in deploying a continuous solid hydrogen ribbon as a debris-free and renewable laser-driven source of pure proton beams generated by a 30-fs laser with ∼1-J laser energy focused on target at relativistic intensities of ∼1019 W/cm2 and repetition rate of 0.1 Hz. The stability of the ribbon position versus the laser interaction point and maximum repetition rate was tested up to 3.3 Hz. The acceleration of protons with cut-off energies up to 1.5 MeV is demonstrated using a 100-μm thick hydrogen ribbon as proof-of-principle capability of the relatively thick target delivery system. The laser-target geometry presented demonstrates an experimental technique that can potentially enables the operation of a laser–plasma source at Hz-level repetition rate.
Motif Transition Intensity: A Novel Network-Based Early Warning Indicator for Financial Crises
Authors: Wang Ze , Liu Siyao , Han Chengyuan , Huang Shupei , Gao Xiangyun , Tang Renwu , Di Zengru
Published: January 2022

Financial crisis, rooted in a lack of system resilience and robustness, is a particular type of critical transition that may cause grievous economic and social losses and should be warned against as early as possible. Regarding the financial system as a time-varying network, researchers have identified early warning signals from the changing dynamics of network motifs. In addition, network motifs have many different morphologies that unveil high-order correlation patterns of a financial system, whose synchronous change represents the dramatic shift in the financial system’s functionality and may indicate a financial crisis; however, it is less studied. This paper proposes motif transition intensity as a novel method that quantifies the synchronous change of network motifs in detail. Applying this method to stock networks, we developed three early warning indicators. Empirically, we conducted a horse race to predict ten global crises during 1991–2020. The results show evidence that the proposed indicators are more efficient than the VIX and the other 39 network-based indicators. In a detailed analysis, the proposed indicators send sensitive and comprehensible warning signals, especially for the U.S. subprime mortgage crisis and the European sovereign debt crisis. Furthermore, the proposed method provides a new perspective to detect critical signals and may be extended to predict other crisis events in natural and social systems.
Skeletal Muscle Hyperemia: A Potential Bridge Between Post-exercise Hypotension and Glucose Regulation
Authors: Pellinger Thomas K. , Emhoff Chi-An W.
Published: January 2022

For both healthy individuals and patients with type 2 diabetes (T2D), the hemodynamic response to regular physical activity is important for regulating blood glucose, protecting vascular function, and reducing the risk of cardiovascular disease. In addition to these benefits of regular physical activity, evidence suggests even a single bout of dynamic exercise promotes increased insulin-mediated glucose uptake and insulin sensitivity during the acute recovery period. Importantly, post-exercise hypotension (PEH), which is defined as a sustained reduction in arterial pressure following a single bout of exercise, appears to be blunted in those with T2D compared to their non-diabetic counterparts. In this short review, we describe research that suggests the sustained post-exercise vasodilation often observed in PEH may sub-serve glycemic regulation following exercise in both healthy individuals and those with T2D. Furthermore, we discuss the interplay of enhanced perfusion, both macrovascular and microvascular, and glucose flux following exercise. Finally, we propose future research directions to enhance our understanding of the relationship between post-exercise hemodynamics and glucose regulation in healthy individuals and in those with T2D.
Exogenous Melatonin Promotes the Salt Tolerance by Removing Active Oxygen and Maintaining Ion Balance in Wheat (Triticum aestivum L.)
Authors: Zhang Zhihui , Liu Liantao , Li Hongye , Zhang Shaocong , Fu Xiaoyi , Zhai Xiuzhen , Yang Na , Shen Jiaming , Li Ruiqi , Li Dongxiao
Published: January 2022

Melatonin (MT) is a small molecule indole hormone that plays an important role in the regulation of biological processes and abiotic stress resistance. Previous studies have confirmed that MT promotes the normal development of plants under stress by mediating physiological regulation mechanisms. However, the physiological mechanism of exogenous MT regulating seed germination and seedling growth of wheat under salt stress is still unclear. In this study, NaCl stress decreased germination rate and inhibited seedling growth of wheat, but shoot length, root length, and plant weight of SM15 did not change significantly. The addition of 300 μM MT in the cultivation solution directly promoted the germination rate of SM15 and ZM18, and lateral root production, but decreased the germination rate of JM22 and inhibited the length of germ and radicle of three varieties under salt stress. For wheat seedling, application of MT could increase proline content, soluble protein, soluble sugar, Ca2+content, and vital amino acid content in leaves to keep high water content, low level of H2O2content, and low [K+]/[Na+] ratio. MT increased root vigor and [K+]/[Na+] ratio and decreased H2O2content in root induced by salt stress. In conclusion, MT enhanced salt tolerance in wheat seeds and seedlings by regulating the synthesis of soluble protein and sugar, ion compartmentation in roots and leaves, enhancement of enzymatic systems, and changes in amino acid levels. Salt resistance varied with different varieties under the same environmental condition. SM15 was a higher salt-resistant variety and JM22 was a salt-sensitive one. In wheat production, the application of exogenous MT should consider the differences among varieties of wheat during the sowing and seedling stages.
Organelle Phylogenomics and Extensive Conflicting Phylogenetic Signals in the Monocot Order Poales
Authors: Wu Hong , Yang Jun-Bo , Liu Jing-Xia , Li De-Zhu , Ma Peng-Fei
Published: January 2022

The Poales is one of the largest orders of flowering plants with significant economic and ecological values. Reconstructing the phylogeny of the Poales is important for understanding its evolutionary history that forms the basis for biological studies. However, due to sparse taxon sampling and limited molecular data, previous studies have resulted in a variety of contradictory topologies. In particular, there are three nodes surrounded by incongruence: the phylogenetic ambiguity near the root of the Poales tree, the sister family of Poaceae, and the delimitation of the xyrid clade. We conducted a comprehensive sampling and reconstructed the phylogenetic tree using plastid and mitochondrial genomic data from 91 to 66 taxa, respectively, representing all the 16 families of Poales. Our analyses support the finding of Bromeliaceae and Typhaceae as the earliest diverging groups within the Poales while having phylogenetic relationships with the polytomy. The clade of Ecdeiocoleaceae and Joinvilleaceae is recovered as the sister group of Poaceae. The three families, Mayacaceae, Eriocaulaceae, and Xyridaceae, of the xyrid assembly diverged successively along the backbone of the Poales phylogeny, and thus this assembly is paraphyletic. Surprisingly, we find substantial phylogenetic conflicts within the plastid genomes of the Poales, as well as among the plastid, mitochondrial, and nuclear data. These conflicts suggest that the Poales could have a complicated evolutionary history, such as rapid radiation and polyploidy, particularly allopolyploidy through hybridization. In sum, our study presents a new perspicacity into the complex phylogenetic relationships and the underlying phylogenetic conflicts within the Poales.