bluuebunny/crossref_metadata_2025 huggingface dataset:
Repair of the Injured Spinal Cord by Schwann Cell Transplantation
Authors: Fu Haitao , Hu Die , Chen Jinli , Wang Qizun , Zhang Yingze , Qi Chao , Yu Tengbo
Published: February 2022

Spinal cord injury (SCI) can result in sensorimotor impairments or disability. Studies of the cellular response to SCI have increased our understanding of nerve regenerative failure following spinal cord trauma. Biological, engineering and rehabilitation strategies for repairing the injured spinal cord have shown impressive results in SCI models of both rodents and non-human primates. Cell transplantation, in particular, is becoming a highly promising approach due to the cells’ capacity to provide multiple benefits at the molecular, cellular, and circuit levels. While various cell types have been investigated, we focus on the use of Schwann cells (SCs) to promote SCI repair in this review. Transplantation of SCs promotes functional recovery in animal models and is safe for use in humans with subacute SCI. The rationales for the therapeutic use of SCs for SCI include enhancement of axon regeneration, remyelination of newborn or sparing axons, regulation of the inflammatory response, and maintenance of the survival of damaged tissue. However, little is known about the molecular mechanisms by which transplanted SCs exert a reparative effect on SCI. Moreover, SC-based therapeutic strategies face considerable challenges in preclinical studies. These issues must be clarified to make SC transplantation a feasible clinical option. In this review, we summarize the recent advances in SC transplantation for SCI, and highlight proposed mechanisms and challenges of SC-mediated therapy. The sparse information available on SC clinical application in patients with SCI is also discussed.
A Panel of Plasma Biomarkers for Differential Diagnosis of Parkinsonian Syndromes
Authors: Li Qi , Li Zhen , Han Xiaoxuan , Shen Xiao , Wang Fei , Bai Lipeng , Li Zhuo , Zhang Rui , Wang Yanlin , Zhu Xiaodong
Published: February 2022

Objective

The aim of our study is to explore the most reliable panel of plasma biomarkers for differential diagnosis of parkinsonian syndromes (PDSs). We selected five kinds of neurodegenerative proteins in plasma: neurofilament light chain (NfL), α-synuclein (α-syn), total tau, β-amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), and investigated the diagnostic value of these biomarkers.

Methods

A total of 99 plasma samples from patients with Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy, and age-matched healthy controls (HCs) were enrolled in our study. Plasma NfL, α-syn, total tau, Aβ42, and Aβ40 levels were quantified by ultrasensitive single molecule array immunoassay. We used logistic regression analyses to examine diagnostic accuracy of these plasma biomarkers. Disease severity was assessed by the modified Hoehn and Yahr staging scale, Unified Parkinson’s Disease Rating Scale part III (UPDRS III), and the Mini-Mental State Examination (MMSE), and subsequently, correlation analysis was performed.

Results

A combination of α-syn, Aβ42, Aβ40, Aβ42/40, and NfL could achieve a best diagnostic value in differentiating PDSs from HC and PD from HC, with an AUC of 0.983 and 0.977, respectively. By adding NfL to measurements of α-syn or Aβ42 or Aβ40 or Aβ42/40, the best discriminating panel was formed in differentiating atypical parkinsonian disorder (APD) and HC, and the discriminatory potential could reach a sensitivity of 100% and specificity of 100% (AUC = 1.000). For further distinguishing PD from APD, we found a combination of NfL, Aβ42, and total tau was the most reliable panel with equally high diagnostic accuracy. With respect to differentiating the subtypes of APD from one another, our results revealed that measurement of NfL, total tau, Aβ42, Aβ40, and Aβ42/40 was the best discriminating panel. Correlation analysis suggests that plasma Aβ42 levels were positively correlated to UPDRS part III scores in MSA. In terms of cognitive function, there was a relationship between plasma Aβ42/40 level and MMSE scores in patients with APD.

Conclusion

In our study, various combinations of plasma biomarkers have great potentialities in identifying PDSs, with important clinical utility in improving diagnostic accuracy. Plasma NfL may have added value to a blood-based biomarker panel for differentiating PDSs.
The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions
Authors: Cooke Jennifer , Molloy Ciara J. , Cáceres Antonia San José , Dinneen Thomas , Bourgeron Thomas , Murphy Declan , Gallagher Louise , Loth Eva
Published: February 2022

Synaptic gene conditions, i.e., “synaptopathies,” involve disruption to genes expressed at the synapse and account for between 0.5 and 2% of autism cases. They provide a unique entry point to understanding the molecular and biological mechanisms underpinning autism-related phenotypes. Phelan-McDermid Syndrome (PMS, also known as 22q13 deletion syndrome) and NRXN1 deletions (NRXN1ds) are two synaptopathies associated with autism and related neurodevelopmental disorders (NDDs). PMS often incorporates disruption to the SHANK3 gene, implicated in excitatory postsynaptic scaffolding, whereas the NRXN1 gene encodes neurexin-1, a presynaptic cell adhesion protein; both are implicated in trans-synaptic signaling in the brain. Around 70% of individuals with PMS and 43–70% of those with NRXN1ds receive a diagnosis of autism, suggesting that alterations in synaptic development may play a crucial role in explaining the aetiology of autism. However, a substantial amount of heterogeneity exists between conditions. Most individuals with PMS have moderate to profound intellectual disability (ID), while those with NRXN1ds have no ID to severe ID. Speech abnormalities are common to both, although appear more severe in PMS. Very little is currently known about the neurocognitive underpinnings of phenotypic presentations in PMS and NRXN1ds. The Synaptic Gene (SynaG) study adopts a gene-first approach and comprehensively assesses these two syndromic forms of autism. The study compliments preclinical efforts within AIMS-2-TRIALS focused on SHANK3 and NRXN1. The aims of the study are to (1) establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1ds, (2) to compare the clinical profile of PMS, NRXN1ds, and individuals with ‘idiopathic’ autism (iASD), (3) to identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles, and (4) investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles. In the current paper we describe our methodology for phenotyping the sample and our planned comparisons, with information on the necessary adaptations made during the global COVID-19 pandemic. We also describe the demographics of the data collected thus far, including 25 PMS, 36 NRXN1ds, 33 iASD, and 52 NTD participants, and present an interim analysis of autistic features and adaptive functioning.
The Effect and Mechanism of Transcranial Direct Current Stimulation on Episodic Memory in Patients With Mild Cognitive Impairment
Authors: Gu Jun , Li Da , Li Zhaohui , Guo Yuan , Qian Fuqiang , Wang Ying , Tang Li
Published: February 2022

Objective

This study aimed to investigate the efficacy of transcranial direct current stimulation (tDCS) on episodic memory in patients with mild cognitive impairment (MCI) and analyze the neural mechanism of tDCS therapy from the perspective of neuroelectrophysiological parameters.

Methods

Forty MCI patients were recruited and randomly divided into a sham group (n = 20) and a tDCS group (n = 20). Patients in the tDCS group were treated with a tDCS instrument for 20 min, once a day, for 5 days. Patients in the sham group were treated with sham stimulus. Montreal Cognitive Assessment Scale (MoCA), Wechsler Memory Scale (WMS), and event-related potential (ERP) (amplitude and latency of P300 wave) were comparatively assessed between the two groups at pre-treatment, 5 days and 4 weeks post-treatment points.

Results

The two groups showed no significant difference in any of the assessed parameters at pre-treatment (P > 0.05). At 5 days post-treatment, memory quotient (MQ) score in the tDCS group significantly increased (P < 0.05), scores of picture memory, visual regeneration, logical memory, memory span, visual regeneration-delay, and logical memory-delay were significantly increased compared to pre-treatment (P < 0.01). The P300 amplitude significantly increased, and its latency significantly shortened (P < 0.01). Four weeks post-treatment, the scores of MQ and visual regeneration-delay in the tDCS group increased, compared to pre-treatment (P < 0.05); picture memory, visual regeneration, logical memory, memory span, and logical memory-delay improved (P < 0.01); the P300 amplitude increased, and its latency shortened (P < 0.01). At 5 days and 4 weeks post-treatment points, the tDCS group, compared with the sham group (P < 0.01), exhibited greater scores of MQ, picture memory, visual regeneration, logical memory, memory span, visual regeneration-delay, and logical memory-delay, increased P300 amplitude, and shortened P300 latency. Similarly, the tDCS group showed higher MQ scores at 5 days post-treatment (P < 0.05) and 4 weeks post-treatment (P < 0.01). Before treatment and after 5 days of treatment, P300 amplitude and latency difference were positively correlated with MQ difference (P < 0.05).

Conclusion

tDCS improved episodic memory in MCI patients, and the effect lasted for 4 weeks. Changes in ERP (P300) suggested that tDCS could promote changes in brain function.
Longitudinal Serum Metabolomics in Extremely Premature Infants: Relationships With Gestational Age, Nutrition, and Morbidities
Authors: Nilsson Anders K. , Tebani Abdellah , Malmodin Daniel , Pedersen Anders , Hellgren Gunnel , Löfqvist Chatarina , Hansen-Pupp Ingrid , Uhlén Mathias , Hellström Ann
Published: February 2022

An increasing number of extremely premature infants survive the neonatal period and beyond. Little is known about the maturation of the preterm infant’s metabolome and its relation to the development of morbidities. Using 1H-NMR, we investigated the serum metabolic profile of 87 infants born at a gestational age (GA) <28 weeks [mean GA (SD) 25.4 (1.4) weeks] in samples longitudinally collected from birth to term equivalent age. The infant metabolome was analyzed in relation to GA, postnatal age, nutrition, and preterm morbidities. At postnatal day 1, low GA correlated with high levels of 3-hydroxyisobutyrate, acetate, acetoacetate, acetone, formate, glucose, and valine. Nearly all quantified metabolites displayed postnatal concentration changes. For example, the two phospholipid-related metabolites myo-inositol and ethanolamine displayed a similar decline from birth over the first weeks of life, irrespectively of GA. The proportion of enteral/parenteral energy intake in the first 28 days significantly correlated with mean levels of 52% of the analyzed metabolites. Low enteral energy intake was associated with high serum levels of 3-hydroxyisobutyrate, creatinine, glucose, glycerol, histidine, lactate, leucine, lysine, methionine, ornithine, phenylalanine, proline, threonine, and uridine. There were also significant correlations between high enteral intake and high serum levels of isoleucine and tyrosine. Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) outcomes were not significantly associated with metabolite levels in the neonatal period after correcting for multiple testing. In conclusion, the serum metabolome of extremely premature infants changes substantially in the neonatal period, largely driven by the gradual transfer from total parenteral nutrition to full enteral feeding. Further studies are needed to disentangle the intricate relationships between the metabolome, nutritional management, GA, and the development of preterm morbidities.
Deep Learning and Simulation for the Estimation of Red Blood Cell Flux With Optical Coherence Tomography
Authors: Stefan Sabina , Kim Anna , Marchand Paul J. , Lesage Frederic , Lee Jonghwan
Published: February 2022

We present a deep learning and simulation-based method to measure cortical capillary red blood cell (RBC) flux using Optical Coherence Tomography (OCT). This method is more accurate than the traditional peak-counting method and avoids any user parametrization, such as a threshold choice. We used data that was simultaneously acquired using OCT and two-photon microscopy to uncover the distribution of parameters governing the height, width, and inter-peak time of peaks in OCT intensity associated with the passage of RBCs. This allowed us to simulate thousands of time-series examples for different flux values and signal-to-noise ratios, which we then used to train a 1D convolutional neural network (CNN). The trained CNN enabled robust measurement of RBC flux across the entire network of hundreds of capillaries.
Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease
Authors: Sepúlveda Denisse , Cisternas-Olmedo Marisol , Arcos Javiera , Nassif Melissa , Vidal René L.
Published: February 2022

Parkinson’s disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.
Are Machine Learning Algorithms More Accurate in Predicting Vegetable and Fruit Consumption Than Traditional Statistical Models? An Exploratory Analysis
Authors: Côté Mélina , Osseni Mazid Abiodoun , Brassard Didier , Carbonneau Élise , Robitaille Julie , Vohl Marie-Claude , Lemieux Simone , Laviolette François , Lamarche Benoît
Published: February 2022

Machine learning (ML) algorithms may help better understand the complex interactions among factors that influence dietary choices and behaviors. The aim of this study was to explore whether ML algorithms are more accurate than traditional statistical models in predicting vegetable and fruit (VF) consumption. A large array of features (2,452 features from 525 variables) encompassing individual and environmental information related to dietary habits and food choices in a sample of 1,147 French-speaking adult men and women was used for the purpose of this study. Adequate VF consumption, which was defined as 5 servings/d or more, was measured by averaging data from three web-based 24 h recalls and used as the outcome to predict. Nine classification ML algorithms were compared to two traditional statistical predictive models, logistic regression and penalized regression (Lasso). The performance of the predictive ML algorithms was tested after the implementation of adjustments, including normalizing the data, as well as in a series of sensitivity analyses such as using VF consumption obtained from a web-based food frequency questionnaire (wFFQ) and applying a feature selection algorithm in an attempt to reduce overfitting. Logistic regression and Lasso predicted adequate VF consumption with an accuracy of 0.64 (95% confidence interval [CI]: 0.58–0.70) and 0.64 (95%CI: 0.60–0.68) respectively. Among the ML algorithms tested, the most accurate algorithms to predict adequate VF consumption were the support vector machine (SVM) with either a radial basis kernel or a sigmoid kernel, both with an accuracy of 0.65 (95%CI: 0.59–0.71). The least accurate ML algorithm was the SVM with a linear kernel with an accuracy of 0.55 (95%CI: 0.49–0.61). Using dietary intake data from the wFFQ and applying a feature selection algorithm had little to no impact on the performance of the algorithms. In summary, ML algorithms and traditional statistical models predicted adequate VF consumption with similar accuracies among adults. These results suggest that additional research is needed to explore further the true potential of ML in predicting dietary behaviours that are determined by complex interactions among several individual, social and environmental factors.
Molecular Mechanism Underlying the Regulatory Effect of Vine Tea on Metabolic Syndrome by Targeting Redox Balance and Gut Microbiota
Authors: Zhou Xixin , Song Ying , Zeng Chaoxi , Zhang Haowei , Lv Chenghao , Shi Meng , Qin Si
Published: February 2022

Metabolic syndrome (MS) is a metabolic disorder that arises from the increasing prevalence of obesity. The pathophysiology seems to be largely attributable to the imbalance of lipid and glucose metabolism, redox signaling pathways, and gut microbiota. The increased syndromes, such as type 2 diabetes and cardiovascular disease demands natural therapeutic attention for those at high risk. Vine tea, as a traditional medicinal and edible resource rich in flavonoids, especially for dihydromyricetin (DHM), exhibits promising health benefits on the intervention of MS, but the specific molecular mechanism has not been systematically elucidated. The present article aims to summarize the regulatory effects and biological targets of vine tea or DHM on MS, and analyze the underlying potential molecular mechanisms in cells, animals, and humans, mainly by regulating the redox associated signaling pathways, such as Nrf2, NF-κB, PI3K/IRS2/AKT, AMPK-PGC1α-SIRT1, SIRT3 pathways, and the crosstalk among them, and by targeting several key biomarkers. Moreover, vine tea extract or DHM has a positive impact on the modulation of intestinal microecology by upregulating the ratio of Firmicutes/Bacteroidetes (F/B) and increasing the relative abundance of Akkermansia muciniphila. Therefore, this review updated the latest important theoretical basis and molecular evidence for the development and application of vine tea in dietary functional products or drugs against MS and also imputed the future perspectives to clarify the deep mechanism among vine tea or DHM, redox associated signaling pathways, and gut microbiota.
Paclitaxel Restores Sensitivity to Chemotherapy in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma
Authors: Massa Annamaria , Peraldo-Neia Caterina , Vita Francesca , Varamo Chiara , Basiricò Marco , Raggi Chiara , Bernabei Paola , Erriquez Jessica , Sarotto Ivana , Leone Francesco , Marchiò Serena , Cavalloni Giuliana , Aglietta Massimo
Published: February 2022

The treatment of unresectable cholangiocarcinoma (CCA) is limited by the development of resistance to conventional first-line chemotherapy based on gemcitabine (GEM). In addition, a prior treatment with GEM frequently induces cross-resistance to other drugs employed in the second-line. Paclitaxel (PTX) is now emerging as an alternative option for the management of advanced/metastatic CCA. In the present work, we evaluate the antitumor activity of PTX in preclinical models of multidrug-resistant intrahepatic cholangiocarcinoma (iCCA). In vitro, PTX decreases tumor cell viability by affecting the cell cycle and inducing apoptosis and impairs the stem cell compartment. In vivo, a therapeutic regimen containing albumin-bound nanoparticle (Nab)-PTX overcomes drug resistance resulting in delayed tumor growth, impaired organization of the tumor vasculature, and reduced glucose uptake. Together, our results provide a rationale to consider PTX-based regimens in patients with iCCA who became refractory to conventional therapies.
Fertility-Sparing Treatment for Endometrial Cancer or Atypical Endometrial Hyperplasia Patients With Obesity
Authors: Chen Junyu , Cao Dongyan , Yang Jiaxin , Yu Mei , Zhou Huimei , Cheng Ninghai , Wang Jinhui , Zhang Ying , Peng Peng , Shen Keng
Published: February 2022

Objective

To evaluate the efficacy and prognosis of fertility-sparing treatment on endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) patients with BMI ≥ 30 kg/m2.

Methods

A total of 102 EC or AEH patients with obesity who received fertility-preserving therapy in the Department of Obstetrics and Gynecology, Peking Union Medical College Hospital were included in our study. All patients were followed up regularly. Clinical characteristics, treatment outcomes, adverse events, and reproductive outcomes were collected and analyzed.

Results

A total of 88 (86.3%) patients achieved complete response (CR), 92.5% in AEH and 82.3% in EC, with 6 months (3–12 months) median CR time. High remission rates were found in patients who received gonadotropin-releasing hormone agonist (GnRHa)-based regimen, were younger than 35 years old, and lost more than 10% of their weight. Fifteen (17.0%) women had developed recurrence with a median recurrence time of 26 (8–52) months. Patients who received GnRHa regimen, lost more than 10% weight, received maintenance therapy, or conceived during the follow-up period had a low probability of recurrence. Of the patients with CR, 57 women attempted to get pregnant and 16 (28.1%) patients became pregnant, 7 (12.3%) of them successfully delivered and 4 (7.0%) were in pregnancy, while 5 (8.8%) of them miscarried.

Conclusion

For obese patients with EC and AEH, fertility-preserving treatment can still achieve a promising response. Weight loss of more than 10% has a positive influence on response, recurrence, as well as pregnancy rates. GnRHa could be an option for obese women due to less effect on weight gain compared to progestin therapy.
Efficacy of Daratumumab-Containing Regimens Among Patients With Multiple Myeloma Progressing on Lenalidomide Maintenance: Retrospective Analysis
Authors: Mian Hira , Eisfeld Christine , Venner Christopher P. , Masih-Khan Esther , Kardjadj Moustafa , Jimenez-Zepeda Victor H. , Khandanpour Cyrus , Lenz Georg , McCurdy Arleigh , Sebag Michael , Song Kevin , LeBlanc Richard , White Darrell , Stakiw Julie , Reiman Anthony , Louzada Martha , Aslam Muhammad , Kotb Rami , Gul Engin , Reece Donna
Published: February 2022

Background

Daratumumab, a monoclonal antibody directed against CD38 is a recent class of drugs introduced into the multiple myeloma therapeutic landscape. While clinical trial data have shown a remarkable impact on outcomes, the efficacy of daratumumab combination therapies in specific clinically relevant subgroups including among patients refractory to lenalidomide maintenance remains unknown.

Methods

In this study, retrospective data were reviewed from the Canadian Myeloma Research Group and the German Munster Myeloma databases to identify patients that received daratumumab in combination with pomalidomide (DPd), lenalidomide (DRd), and bortezomib (DVd) in a population that had relapsed on lenalidomide maintenance postautologous stem cell transplant. The primary aim of the study was to look at outcomes of these patients in different daratumumab combinations.

Results

A total of 73 patients were identified. The median age of the patients at the time of daratumumab initiation was 60 (38-72) and 64.4% (n = 47) were men. In the selected cohort, 43.8% (n = 32) were treated with DRd, 31.5% (n = 23) with DVd, and 24.7% (n = 18) with DPd regimen. The median progression-free survival (PFS) of the entire cohort was 15.8 months (95% CI, 12.9–37.1 months). The median PFS of the individual regimens was as follows: DPd 18.9 months (95% CI, 13.7-not reached), DRd 21.7 months (95% CI, 11.6-not reached), and DVd 12.9 months (95% CI, 3.1-not reached).

Conclusions

Daratumumab-containing therapies are effective regimens in patients progressing on lenalidomide maintenance. Additional studies are required to decide the optimal regimen post-lenalidomide maintenance.
Whole-Body MRI Is an Effective Imaging Modality for Hematological Malignancy Treatment Response Assessment: A Systematic Review and Meta-Analysis
Authors: Lin Guisen , Zong Xiaodan , Li Yaowen , Tan Weiting , Sun Weisheng , Zhang Siqi , Gan Yungen , Zeng Hongwu
Published: February 2022

Objectives

To evaluate the diagnostic accuracy of whole-body MRI (WB-MRI) for assessment of hematological malignancies’ therapeutic response.

Methods

PubMed, Embase, and Web of Science were searched up to August 2021 to identify studies reporting the diagnostic performance of WB-MRI for the assessment of hematological malignancies’ treatment response. A bivariate random-effects model was applied for the generation of the pooled diagnostic performance.

Results

Fourteen studies with 457 patients with lymphoma, multiple myeloma, and sarcoma (very small proportion) were analyzed. Overall pooled sensitivity and specificity of WB-MRI were 0.88 (95% CI: 0.73–0.95) and 0.86 (95% CI: 0.73–0.93), respectively. Studies using whole-body diffusion-weighted imaging (WB-DWI) showed higher sensitivity than those that did not (0.94 vs. 0.55, p = 0.02). The pooled concordance rate of WB-MRI to assess hematological malignancies’ treatment response with reference standard was 0.78 (95% CI: 0.59–0.96). WB-MRI and PET/CT showed similar diagnostic performance (sensitivity [0.83 vs. 0.92, p = 0.11] and specificity [0.87 vs. 0.76, p = 0.73]).

Conclusion

WB-MRI has high diagnostic performance for hematological malignancies’ treatment response assessment. The adding of WB-DWI is strongly associated with increased sensitivity.
Diagnostic Workup of Acute Myeloid Leukemia: What Is Really Necessary? An Italian Survey
Authors: Voso Maria Teresa , Ferrara Felicetto , Galimberti Sara , Rambaldi Alessandro , Venditti Adriano
Published: February 2022

Acute myeloid leukemia (AML) is a heterogeneous disease with a wide variety of clinical presentations, morphological features, and immunophenotypes. The diagnostic approaches to AML that are adopted in Italy have been explored using an online Delphi-based process to expand the global discussion on mandatory tests for the correct diagnosis and, consequently, for optimal management of AML in clinical practice. The final results of the panel of Italian hematologists involved in this work highlight the importance of genetic evaluation for classification and risk stratification and firmly establish that karyotyping, fluorescence in situ hybridization in cases with non-evaluable karyotype, and molecular tests must be performed in every case of AML, regardless of age. Obtaining clinically relevant genetic data at diagnosis is the basis for the success of patient-tailored therapy. The Italian specialists also confirm the role of multidisciplinary diagnostics for AML, now mandatory and expected to become more important in the future context of “precision” medicine.
Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1
Authors: Bukhari Amirali B. , Chan Gordon K. , Gamper Armin M.
Published: February 2022

Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy. The key regulator of the G2/M checkpoint, the cyclin-dependent kinase 1 (CDK1), is tightly controlled, including by its phosphorylation state. This posttranslational modification, which is determined by the opposing activities of the phosphatase cdc25 and the kinase Wee1, allows for a more rapid response to cellular stress than via the synthesis or degradation of modulatory interacting proteins, such as p21 or cyclin B. Reducing Wee1 activity results in ectopic activation of CDK1 activity and drives premature entry into mitosis with unrepaired or under-replicated DNA and causing mitotic catastrophe. Here, we review efforts to use small molecule inhibitors of Wee1 for therapeutic purposes, including strategies to combine Wee1 inhibition with genotoxic agents, such as radiation therapy or drugs inducing replication stress, or inhibitors of pathways that show synthetic lethality with Wee1. Furthermore, it become increasingly clear that Wee1 inhibition can also modulate therapeutic immune responses. We will discuss the mechanisms underlying combination treatments identifying both cell intrinsic and systemic anti-tumor activities.
5-Aminolevulinic Acid False-Positive Rates in Newly Diagnosed and Recurrent Glioblastoma: Do Pseudoprogression and Radionecrosis Play a Role? A Meta-Analysis
Authors: Ricciardi Luca , Sturiale Carmelo Lucio , Scerrati Alba , Stifano Vito , Somma Teresa , Ius Tamara , Trungu Sokol , Acqui Michele , Raco Antonino , Miscusi Massimo , Della Pepa Giuseppe Maria
Published: February 2022

Background

Several studies have confirmed the impact of 5-aminolevulinic acid (5-ALA) on the extent of resection in newly diagnosed glioblastoma (GBM). However, there are controversies on the 5-ALA fluorescence status in recurrent GBM surgery, with specific reference to pseudoprogression or radionecrosis; therefore, the safety and accuracy of surgical planning in 5-ALA-assisted procedures in the recurrent context are still unclear.

Materials and Methods

This is a systematic review and meta-analysis of comparative studies on the use of 5-ALA in newly diagnosed and recurrent GBM, consistently conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data on fluorescence status and correlation between fluorescence and histological findings were collected. We performed a meta-analysis of proportions to estimate the pooled rates of each outcome.

Results

Three online medical databases (PubMed, Scopus, Cochrane Library) were screened, 448 articles were evaluated, and 3 papers were finally included for data analysis. Fluorescence rate was not different between newly diagnosed and recurrent GBM [p = 0.45; odds ratio (OR): 1.23; 95% CI: 0.72–2.09; I2 = 0%], while the rate of 5-ALA fluorescence-positive areas not associated with histological findings of GBM cells was higher in recurrent GBM (p = 0.04; OR: 0.24; 95% CI: 0.06–0.91; I2 = 19%). Furthermore, there were no cases of radionecrosis in false-positive samples, while inflammation and signs of pseudoprogression were found in 81.4% of the cases.

Discussion and Conclusions

Therefore, a robust awareness of 5-ALA potentialities and pitfalls in recurrent GBM surgery should be considered for a cognizant surgical strategy. Further clinical trials could confirm the results of the present meta-analysis.
A Case Report of a 3-Year-Old Child With Anaphylactic Shock After a Diclofenac Suppository Confirmed by Serial Tryptase and a Basophil Activation Test
Authors: Huang Wun-Yan , Chiu Tsu-Man , Kuo Su-Feng , Chung Wen-Hung , Tsai Yi-Giien
Published: February 2022

Diclofenac is one of the most commonly used non-steroidal anti-inflammatory drug (NSAID) agents for fever management by general practitioners. Anaphylaxis due to suppository of diclofenac sodium (Voltaren) is extremely rare in children. We report the case of a 3-year-old girl with anaphylactic shock after a diclofenac suppository with confirmation by serial tryptase and a basophil activation test.
Case Report: Identification and Functional Analysis of a Homozygous Synonymous Variant in the PLOD1 Gene in a Chinese Neonatal With the Ehlers–Danlos Syndrome
Authors: Yan Xiaodan , Shu Jianbo , Nie Yanyan , Zhang Ying , Wang Ping , Zhou Weiwei , Cui Xiaoyu , Liu Yang
Published: February 2022

Background

Kyphoscoliotic Ehlers–Danlos syndrome (kEDS; OMIM225400) is a rare autosomal recessive genetic disease caused by variants in the PLOD1 gene. This research was conducted to verify the disease-causing gene in a Chinese neonatal family with the EDS.

Methods

We recruited a Han Chinese neonate with PLOD1-related kEDS without kyphoscoliosis. Detailed clinical examination and laboratory tests were performed and whole exome sequencing (WES) was used to detect the pathogenic genes of the proband. In vivo experiments (reverse-transcription PCR, quantitative real-time PCR) and in vitro experiments (minigene analysis) were used to verify the function of variants suspected of affecting the splicing process. The effect of the splice site variant on the PLOD1 transcript was analyzed using splice prediction programs NetGene2 and Alternative Splice Site Predictor (ASSP).

Results

A homozygous synonymous variant c.1095C>T (p.Gly365, rs1032781250) in the PLOD1 gene was found and verified in the family with kEDS. This splicing variant resulted in a premature termination codon of exon 10 and affected the expression of the four bases GCGC.

Conclusion

Our research showed that the homozygous synonymous variant in PLOD1 was the pathogenic cause in the proband. The combined application of WES and functional studies verified the effect of uncertain gene variants on splicing, upgrading pathogenicity evidence, and determining the cause of disease. This is helpful for the early diagnosis and treatment of kEDS.
Levistilide A Promotes Expansion of Human Umbilical Cord Blood Hematopoietic Stem Cells by Enhancing Antioxidant Activity
Authors: He Mei , Xu Hui , Liu Guangju , Yang Ming , Zhang Wenshan , Li Yafang , Zhang Hexiao , Wang Chaoqun , Zhang Yiran , Liu Xiaolei , Xu Shiqi , Ding Yahui , Li Yinghui , Gao Yingdai , Zhang Quan
Published: February 2022

Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs ex vivo. An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.
Dihydroartemisinin Inhibits Laser-Induced Choroidal Neovascularization in a Mouse Model of Neovascular AMD
Authors: Li Xun , Gao Sheng , Zhang Yun , Xin Mei , Zuo Cheng , Yan Naihong , Xia Qingjie , Zhang Meixia
Published: February 2022

Purpose: Choroidal neovascularization (CNV) is the main pathogenic process and a leading cause of severe vision loss in neovascular age-related macular degeneration (AMD). We investigated the antiangiogenic efficacy of dihydroartemisinin (DHA) in an experimental laser-induced CNV mouse model.

Methods: After fluorescein angiography confirmed that CNV was induced by laser photocoagulation in C57BL/6J mice, DHA or vehicle was given by intragastric administration once a day. On day 6 and day 12, fluorescein angiography, optic coherence tomography, and flat-mounting analysis were performed to grade CNV leakage, measure CNV thickness and evaluate CNV areas, respectively. Immunofluorescence staining and Western blot analysis were performed to evaluate the expression of NF-κB, VEGF, and VEGFR2. To confirm the safety of intragastric DHA application, changes in retinal morphology and neural cell apoptosis were tested by histopathological examination and TUNEL assay, and retinal function was determined by electroretinogram (ERG).

Results: Intragastric administration of DHA significantly suppressed CNV leakage and CNV formation in both thickness and area. Immunofluorescence showed that DHA suppressed VEGFR2 and NF-κB p65 expression in laser-induced lesions. Compared to the normal group, the protein expression of VEGF, VGFER2, NF-κB p65, and NF-κB1 p50 increased significantly in the vehicle group after laser photocoagulation, while it was profoundly inhibited by DHA treatment. In addition, histopathological examination, TUNEL analysis, and ERG test showed no obvious evidence of retinal toxicity caused by DHA.

Conclusion: Systemic administration of DHA can effectively inhibit laser-induced CNV formation in mice, which might be due to the suppression of the classic NF-κB signaling pathway and downregulation of VEGFR2 and VEGF expression. The current results suggest that DHA could be a natural potential alternative therapeutic strategy for neovascular AMD.
Unequal Bandpass Filtering Power Divider Based on Hybrid HMSIW-SSPP Modes
Authors: Pan Bai Cao , Yu Ping , Guo Ben Jian , Qian Ya Hui , Luo Guo Qing
Published: February 2022

This letter presents a novel unequal bandpass filtering power divider based on hybrid-mode of half mode substrate integrated waveguide (HMSIW) and spoof surface plasmon polaritons (SSPPs). Bandpass response is achieved by combining the transmission properties of HMSIW and SSPPs simultaneously. The operating bandwidth can be designed in a wide range by simply optimizing the dimensions of HMSIW and SSPPs. In addition, defected ground structures (DGSs) are etched on the bottom of the substrate to improve out-of-band suppression. The power division ratio of the proposed unequal power divider is finally optimized to 1:3. The measured results agree with the simulated one. Such design provides a stable power division within wide frequency range from 6.5 to 9.5 GHz.
Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs
Authors: Renzini Alessandra , D’Onghia Marco , Coletti Dario , Moresi Viviana
Published: February 2022

Skeletal muscle plays a major role in controlling body mass and metabolism: it is the most abundant tissue of the body and a major source of humoral factors; in addition, it is primarily responsible for glucose uptake and storage, as well as for protein metabolism. Muscle acts as a metabolic hub, in a crosstalk with other organs and tissues, such as the liver, the brain, and fat tissue. Cytokines, adipokines, and myokines are pivotal mediators of such crosstalk. Many of these circulating factors modulate histone deacetylase (HDAC) expression and/or activity. HDACs form a numerous family of enzymes, divided into four classes based on their homology to their orthologs in yeast. Eleven family members are considered classic HDACs, with a highly conserved deacetylase domain, and fall into Classes I, II, and IV, while class III members are named Sirtuins and are structurally and mechanistically distinct from the members of the other classes. HDACs are key regulators of skeletal muscle metabolism, both in physiological conditions and following metabolic stress, participating in the highly dynamic adaptative responses of the muscle to external stimuli. In turn, HDAC expression and activity are closely regulated by the metabolic demands of the skeletal muscle. For instance, NAD+ levels link Class III (Sirtuin) enzymatic activity to the energy status of the cell, and starvation or exercise affect Class II HDAC stability and intracellular localization. SUMOylation or phosphorylation of Class II HDACs are modulated by circulating factors, thus establishing a bidirectional link between HDAC activity and endocrine, paracrine, and autocrine factors. Indeed, besides being targets of adipo-myokines, HDACs affect the synthesis of myokines by skeletal muscle, altering the composition of the humoral milieu and ultimately contributing to the muscle functioning as an endocrine organ. In this review, we discuss recent findings on the interplay between HDACs and circulating factors, in relation to skeletal muscle metabolism and its adaptative response to energy demand. We believe that enhancing knowledge on the specific functions of HDACs may have clinical implications leading to the use of improved HDAC inhibitors for the treatment of metabolic syndromes or aging.
Dysregulated Immunity in Pulmonary Hypertension: From Companion to Composer
Authors: Funk-Hilsdorf Teresa C. , Behrens Felix , Grune Jana , Simmons Szandor
Published: February 2022

Pulmonary hypertension (PH) represents a grave condition associated with high morbidity and mortality, emphasizing a desperate need for innovative and targeted therapeutic strategies. Cumulative evidence suggests that inflammation and dysregulated immunity interdependently affect maladaptive organ perfusion and congestion as hemodynamic hallmarks of the pathophysiology of PH. The role of altered cellular and humoral immunity in PH gains increasing attention, especially in pulmonary arterial hypertension (PAH), revealing novel mechanistic insights into the underlying immunopathology. Whether these immunophysiological aspects display a universal character and also hold true for other types of PH (e.g., PH associated with left heart disease, PH-LHD), or whether there are unique immunological signatures depending on the underlying cause of disease are points of consideration and discussion. Inflammatory mediators and cellular immune circuits connect the local inflammatory landscape in the lung and heart through inter-organ communication, involving, e.g., the complement system, sphingosine-1-phosphate (S1P), cytokines and subsets of, e.g., monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and T- and B-lymphocytes with distinct and organ-specific pro- and anti-inflammatory functions in homeostasis and disease. Perivascular macrophage expansion and monocyte recruitment have been proposed as key pathogenic drivers of vascular remodeling, the principal pathological mechanism in PAH, pinpointing toward future directions of anti-inflammatory therapeutic strategies. Moreover, different B- and T-effector cells as well as DCs may play an important role in the pathophysiology of PH as an imbalance of T-helper-17-cells (TH17) activated by monocyte-derived DCs, a potentially protective role of regulatory T-cells (Treg) and autoantibody-producing plasma cells occur in diverse PH animal models and human PH. This article highlights novel aspects of the innate and adaptive immunity and their interaction as disease mediators of PH and its specific subtypes, noticeable inflammatory mediators and summarizes therapeutic targets and strategies arising thereby.
Insights in the Effect of Fluctuating Female Hormones on Injury Risk—Challenge and Chance
Authors: Legerlotz Kirsten , Nobis Tina
Published: February 2022

It is time to take on the challenge of investigating the complex effect of fluctuating female hormones on injury risk as this offers a chance to improve female athletes’ health and performance. During the recent decade, the body of knowledge on female hormones and injury risk has largely been increased. New insights have been offered regarding the association of certain phases of the menstrual cycle and injury prevalence as well as regarding relationships between hormone levels and musculoskeletal changes such as, for example, ligamentous stiffness and knee laxity. However, current research often follows the theme of a causal relationship between estrogen levels and musculoskeletal function or injury and thus—one might argue—further enhances a rather simplistic approach, instead of uncovering complex relationships which could help in establishing more nuanced ways of preventing female injuries. To uncover real effects and to truly understand the physiological responses, we suggest to reflect on potential bias regarding research questions and current approaches. It may enhance future studies to apply a more nuanced approach to causation, to include multidimensional perspectives and to implement an interdisciplinary methodology.
Changes in Cytokines Concentration Following Long-Distance Running: A Systematic Review and Meta-Analysis
Authors: Alves Micael Deivison de Jesus , Silva Devisson dos Santos , Pereira Erika Vitoria Moura , Pereira Danielle Dutra , de Sousa Fernandes Matheus Santos , Santos Dayane Franciely Conceição , Oliveira Davi Pereira Monte , Vieira-Souza Lucio Marques , Aidar Felipe J. , de Souza Raphael Fabricio
Published: February 2022

Long-distance running is an exhausting effort for the whole organism. Prolonged aerobic exercise induces changes in inflammatory markers. However, predicting muscle damage in response has limitations in terms of selecting biomarkers used to measure inflammatory status. The present study conducts a systematic review and meta-analysis of articles focusing in ultra-marathon, marathon, and half-marathon and levels of cytokines. The search was conducted in PubMed, Web of Science, and Scopus databases, resulting in the inclusion of 76 articles. IL-6 was highlighted, evaluated in 62 studies and show increase in the standard mean difference (SMD): half-marathon (SMD −1.36; IC 95%: −1.82, −0.89, Ch2:0.58; tau2:0.00;p< 0.0001), marathon (SMD −6.81; IC 95%: −9.26, −4.37; Ch2:481.37 tau2:11.88;p< 0.0001) and ultra-marathon (SMD −8.00 IC 95%: −10.47, −5.53; Ch2:328.40; tau2:14.19;p< 0.0001). In contrast meta-regression analysis did not show relationship to the running distance (p = 0.864). The meta-analysis evidenced increase in the concentration of IL-1ra (p< 0.0001), IL-1B (p< 0.0001), IL-8 (p< 0.0001), IL-10 (p< 0.0001) and TNF-α (p< 0.0001). Reduction in IL-2 (p< 0.0001) and INF-y (p< 0.03) and no change in the IL-4 (p< 0.56). The number of studies evaluating the effect of adipokines was limited, however Leptin and Resistin were recurrent. The effects of an acute bout of prolonged aerobic exercise will protect against chronic systemic inflammation. The time to return to baseline values showed a substantial and dose-dependent relationship with run volume. The concentration of IL-6 was robustly studied and the marathon running was the most explored. Network of endocrine interactions in which circulating factors, released in extreme exercises, interplay through inter-organ crosstalk and physiologic changes were expressed. The running volume variability was able to modulate compounds that play a fundamental role in the maintenance of homeostasis and cell signaling.
Reproductive Biology of Rheum webbianum Royle, a Vulnerable Medicinal Herb From Alpines of North-Western Himalaya
Authors: Wani Ishfaq Ahmad , Verma Susheel , Ahmad Parvaiz , El-Serehy Hamed A. , Hashim Maha J.
Published: February 2022

Information on reproductive biology and pollination ecology studies of threatened plants are essential to develop strategies for their sustainable utilization and effective conservation. As such, these studies were conducted on Rheum webbianum, a high-value “vulnerable” medicinal herb of the north-western Himalaya. This species presents a unique mode of reproductive behavior through the involvement of different floral events, including the movement of reproductive organs. The plants survive extremely cold conditions through underground perennating rhizomes that sprout into juvenile shoots with the onset of the favorable climatic conditions. The peduncle arises from the axils of the radical leaves, bearing a globular collection of densely arranged hermaphrodite flowers with temporally separated male and female phases; the male phase precedes the female phase (protandry). Anther dehiscence and stigma receptivity is post-anthesis. Anthers dehisce longitudinally along margins, liberating a large mass of spherical and tricolpate pollen with spinulose exine. Pollen viability decreased to < 10% on day 9. Pistil is tristylous, with each style terminating into a fan-shaped stigma lobe. The pollen receptive surface of each stigmatic lobe remains incurved at an angle of 360° and shows upward movement after anthesis, forming a funnel-like structure at an angle of 180° with respect to the ovary. Pollination syndrome is ambophilous. Spontaneous autogamy or geitonogamy to a certain extent is achieved in this species due to the arrangement of flowers in the inflorescence and overlapping of male and female reproductive phases among them. Incurved stigmatic lobes and outward movement of stamens too facilitate outcrossing. Pollen/ovule ratio estimates, results of pollination experiments on breeding behavior, outcrossing, and self-compatibility indices demonstrated that plants are self-compatible and cross-fertile.