bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Age on Beta-Amyloid1–42 Plasma Levels in Healthy Subjects
Authors: Zecca Chiara , Pasculli Giuseppe , Tortelli Rosanna , Dell’Abate Maria Teresa , Capozzo Rosa , Barulli Maria Rosaria , Barone Roberta , Accogli Miriam , Arima Serena , Pollice Alessio , Brescia Vincenzo , Logroscino Giancarlo
Published: September 2021

Beta-amyloid (Aβ) plaques have been observed in the brain of healthy elderlies with frequencies strongly influenced by age. The aim of the study is to evaluate the role of age and other biochemical and hematological parameters on Aβ1–42 plasma levels in cognitively and neurologically normal individuals. Two-hundred and seventy-five normal subjects stratified by age groups (<35 years, 35–65 years, and >65 years) were included in the study. Aβ1–42 plasma levels significantly correlated with age (rs = 0.27; p < 0.0001) in the whole sample, inversely correlated with age in the first age group (rs = −0.25, p = 0.01), positively correlated in the second group (rs = 0.22, p = 0.03), while there was no significant correlation in the older group (rs = 0.02, p = 0.86). Both age (β-estimate = 0.08; p < 0.001) and cholesterol (β-estimate = 0.03; p = 0.009) were significantly associated with Aβ1–42 plasma level in multivariable analysis. However, only the association with age survived post hoc adjustment for multiple comparisons. The different effects of age on the Aβ level across age groups should be explored in further studies to better understand the age-dependent variability. This could better define the value of plasma Aβ as a biomarker of the Alzheimer neuropathology.
Influence of Dietary Nutrient Intake on Episodic Memory Across the Adult Life Span
Authors: Cansino Selene , Torres-Trejo Frine , Estrada-Manilla Cinthya , Flores-Mendoza Adriana , Ramírez-Pérez Gerardo , Ruiz-Velasco Silvia
Published: September 2021

The aim of the study was to identify nutrients that have the ability to impact brain functioning and, as a consequence, influence episodic memory. In particular, we examined recollection, the ability to recall details of previous experiences, which is the episodic memory process most affected as age advances. A sample of 1,550 healthy participants between 21 and 80 years old participated in the study. Nutritional intake was examined through a food frequency questionnaire and software developed to determine the daily consumption of 64 nutrients based on food intake during the last year. Recollection was measured through a computerized source memory paradigm. First, we identified which nutrients influence recollection across the entire adult life span. Then, moderator analyses were conducted by dividing the sample into young (21–40 years old), middle-aged (41–60 years old) and older (61–80 years old) adults to establish in which life stage nutrients influence episodic memory. Across the adult life span, recollection accuracy was shown to benefit from the intake of sodium, heme, vitamin E, niacin, vitamin B6, cholesterol, alcohol, fat, protein, and palmitic, stearic, palmitoleic, oleic, gadoleic, alpha-linoleic and linoleic acid. The effects of energy, maltose, lactose, calcium and several saturated fatty acids on recollection were modulated by age; in older adults, the consumption of these nutrients negatively influenced episodic memory performance, and in middle-aged adults, only lactose had negative effects. Several brain mechanisms that support episodic memory were influenced by specific nutrients, demonstrating the ability of food to enhance or deteriorate episodic memory.
Chronic Exposure to Alcohol Inhibits New Myelin Generation in Adult Mouse Brain
Authors: Guo Feng , Zhang Yi-Fan , Liu Kun , Huang Xu , Li Rui-Xue , Wang Shu-Yue , Wang Fei , Xiao Lan , Mei Feng , Li Tao
Published: September 2021

Chronic alcohol consumption causes cognitive impairments accompanying with white matter atrophy. Recent evidence has shown that myelin dynamics remain active and are important for brain functions in adulthood. For example, new myelin generation is required for learning and memory functions. However, it remains undetermined whether alcohol exposure can alter myelin dynamics in adulthood. In this study, we examine the effect of chronic alcohol exposure on myelin dynamics by using genetic approaches to label newly generated myelin (NG2-CreERt; mT/mG). Our results indicated that alcohol exposure (either 5% or 10% in drinking water) for 3 weeks remarkably reduced mGFP + /NG2- new myelin and mGFP + /CC1 + new oligodendrocytes in the prefrontal cortex and corpus callosum of 6-month-old NG2-CreERt; mT/mG mice as compared to controls without changing the mGFP + /NG2 + oligodendrocyte precursor cells (OPCs) density, suggesting that alcohol exposure may inhibit oligodendrocyte differentiation. In support with these findings, the alcohol exposure did not significantly alter apoptotic cell number or overall MBP expression in the brains. Further, the alcohol exposure decreased the histone deacetylase1 (HDAC1) expression in mGFP + /NG2 + OPCs, implying epigenetic mechanisms were involved in the arrested OPC differentiation. Together, our results indicate that chronic exposure to alcohol can inhibit myelinogenesis in the adult mouse brain and that may contribute to alcohol-related cognitive impairments.
Analysis of Heritability Across the Clinical Phenotypes of Frontotemporal Dementia and the Frequency of the C9ORF72 in a Colombian Population
Authors: López-Cáceres Andrea , Velasco-Rueda María , Garcia-Cifuentes Elkin , Zarante Ignacio , Matallana Diana
Published: September 2021

Frontotemporal dementia (FTD) is a highly heritable condition. Up to 40% of FTD is familial and an estimated 15% to 40% is due to single-gene mutations. It has been estimated that the G4C2 hexanucleotide repeat expansions in the C9ORF72 gene can explain up to 37.5% of the familial cases of FTD, especially in populations of Caucasian origin. The purpose of this paper is to evaluate hereditary risk across the clinical phenotypes of FTD and the frequency of the G4C2 expansion in a Colombian cohort diagnosed with FTD.

Methods: A total of 132 FTD patients were diagnosed according to established criteria in the behavioral variant FTD, logopenic variant PPA, non-fluent agrammatic PPA, and semantic variant PPA. Hereditary risk across the clinical phenotypes was established in four categories that indicate the pathogenic relationship of the mutation: high, medium, low, and apparently sporadic, based on those proposed by Wood and collaborators. All subjects were also examined for C9ORF72 hexanucleotide expansion (defined as >30 repetitions).

Results: There were no significant differences in the demographic characteristics of the patients between the clinical phenotypes of FTD. The higher rate phenotype was bvFTD (62.12%). In accordance with the risk classification, we found that 72 (54.4%) complied with the criteria for the sporadic cases; for the familial cases, 23 (17.4%) fulfilled the high-risk criteria, 23 (17.4%) fulfilled the low risk criteria, and 14 (10.6%) fulfilled the criteria to be classified as subject to medium risk. C9ORF72 expansion frequency was 0.76% (1/132).

Conclusion: The FTD heritability presented in this research was very similar to the results reported in the literature. The C9ORF72 expansion frequency was low. Colombia is a triethnic country, with a high frequency of genetic Amerindian markers; this shows consistency with the present results of a low repetition frequency. This study provides an initial report of the frequency for the hexanucleotide repeat expansions in C9ORF72 in patients with FTD in a Colombian population and paves the way for further study of the possible genetic causes of FTD in Colombia.
Association of Preoperative Cerebrospinal Fluids Parameters With Early Shunt Obstruction in Patients With Post-hemorrhagic Hydrocephalus Treated by Lumboperitoneal Shunt
Authors: Sun Tong , Cui Wenyao , Chen Siyang , Yuan Yikai , Yang Jingguo , Zhou Yicheng , Li Xuepei , Yu Hang , You Chao , Guan Junwen
Published: September 2021

Background: Early shunt obstruction (SO) remains the most common cause of lumboperitoneal shunt (LPS) failure. Although there is anecdotal evidence that the level of cerebrospinal fluid (CSF) parameters might affect shunt performance, its association with early LPS obstruction in adults with post-hemorrhagic hydrocephalus (PHH) is unclear.

Methods: The retrospective study was performed by reviewing the adults with PHH treated by LPS from years 2014 to 2018. We included patients with CSF samples analyzed within 1 week prior to shunt insertion or at the time of shunt insertion. Baseline characteristics of each patient were collected. The primary outcomes were the incidence rate and associated factors of SO occurring within 3 months of shunt placement. The secondary outcomes included scores on the National Institute of Health Stroke Scale (NIHSS) and Evans Index at discharge.

Results: A total of 76 eligible patients were analyzed, of whom 61 were obstruction-free and 15 were early SO. The overall rate of early SO was 15.6%. The RBCs count and nucleated cells count in preoperative CSF were actually higher in patients with early SO, compared to patients in the control group. Multivariate analysis identified RBC elevation (>0 × 106/L; OR: 10.629, 95% CI: 1.238–91.224, p = 0.031) as a dependent risk factor for early SO. NIHSS dramatically decreased at discharge while the alteration of ventricular size was not observed.

Conclusions: This study suggested that the presence of RBCs in preoperative CSF was associated with early SO in patients with PHH treated by LPS.
Physical Activity and Health-Related Quality of Life in Adults With a Neurologically-Related Mobility Disability During the COVID-19 Pandemic: An Exploratory Analysis
Authors: Nightingale Tom E. , Heneghan Nicola R. , Fenton Sally A. M. , Veldhuijzen van Zanten Jet J. C. S. , Jutzeler Catherine R.
Published: September 2021

Background: During the coronavirus-19 (COVID-19) pandemic various containment strategies were employed. Their impact on individuals with neurological conditions, considered vulnerable to COVID-19 complications, remains to be determined.

Objective: To investigate associations between physical activity and health-related quality of life outcomes in individuals with a neurological condition during government mandated COVID-19 restrictions.

Methods: An e-survey assessing fear of COVID-19, physical activity level and health-related quality of life outcomes (functional disability and pain, anxiety and depression, loneliness, fatigue, and vitality) was distributed to individuals with a neurologically-related mobility disability living in the United Kingdom. Open-ended questions were also included to contextualize barriers and facilitators to engage in physical activity during the COVID-19 pandemic. Gamma-weighted generalized linear models and tree-structured regression models were employed to determine the associations between physical activity and health-related quality of life.

Results: Of 199 responses, 69% reported performing less physical activity compared to pre-pandemic. Tree-structured regression models revealed that lower leisure-time physical activity was significantly associated (p ≤ 0.009) with higher depression and fatigue, but lower vitality. The closure of leisure facilities and organized sport (27%) was the most commonly cited barrier to engage in physical activity, while 31% of participants mentioned concerns around their physical and mental health as a facilitator.

Conclusion: Our analysis identified homogenous subgroups for depression, fatigue, and vitality based specifically on leisure-time physical activity cut points, irrespective of additional demographic or situational characteristics. Findings highlight the importance of and need to safely promote leisure-time physical activity during the COVID-19 pandemic in this at-risk population to help support health-related quality of life.
Aging With Cerebral Palsy: A Photovoice Study Into Citizenship
Authors: van Heijningen Vera G. , Cardol Mieke , van Heijningen-Tousain Heidi J. M. , Oosterveer Daniëlla M. , van Markus-Doornbosch Frederike , Sattoe Jane N. T. , van der Holst Menno , Hilberink Sander R.
Published: September 2021

Background: Adults with cerebral palsy (CP) may experience an increasing impact of their disability on daily life and this may interfere with their citizenship. Citizenship is a layered construct. Next to formal and theoretical significations, and civil rights acts such as the UN Convention on the Rights for Persons with Disabilities (CRPD), the meaning of citizenship is formed by the person themselves. The present study aimed to gain insight into what citizenship means for adults with CP 40 years or older and what is needed to support and pursue their citizenship to improve person-centered rehabilitation which can facilitate this process.

Methods: Adults with CP (>40 years) without intellectual disability were recruited from medical records of a large rehabilitation center to participate in a qualitative study using the photovoice method. Participants were asked to take photos of objects or life situations that constituted citizenship for them; these photos were then the prompts for the semi-structured interviews that were held face-to-face at their homes. Background and clinical characteristics were gathered using a short face-to-face questionnaire. Data were analyzed through inductive thematic analysis.

Results: Nineteen adults participated [mean age (SD) 57.8 (9.4) years (range 44–79), six men]. From the analysis four themes emerged: (a) Meanings of citizenship; (b) Citizenship: Facilitator and barriers; (c) Paradoxes of support and participation; and (d) Future. Furthermore, next to the ability to participate in society without restrictions, sense of belonging was reported to be an important aspect of “meanings of citizenship.” The physiotherapist was perceived as an important health professional to maintain physical activity and deal with the impact of aging with CP on daily activities. Complex healthcare and support services regulations and aging affected citizenship negatively.

Conclusion: Middle-aged and older adults with CP view citizenship as the ability to participate and belong in society. To optimize their citizenship the challenges and individual needs must be seen and supported by person-centered rehabilitation and support services. Simplification of complex healthcare and services regulations can further improve citizenship.
Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation
Authors: Kandić Mina , Moliadze Vera , Andoh Jamila , Flor Herta , Nees Frauke
Published: September 2021

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.
Update on the Neuroimaging and Electroencephalographic Biomarkers of Epileptogenesis: A Literature Review
Authors: Chen Guihua , Zhang Zheyu , Wang Meiping , Geng Yu , Jin Bo , Aung Thandar
Published: September 2021

Epilepsy is one of the most common debilitating neurological disorders that lead to severe socio-cognitive dysfunction. While there are currently more than 30 antiseizure medications available for the treatment and prevention of seizures, none address the prevention of epileptogenesis that leading to the development of epilepsy following a potential brain insult. Hence, there is a growing need for the identification of accurate biomarkers of epileptogenesis that enable the prediction of epilepsy following a known brain insult. Although recent studies using various neuroimages and electroencephalography have found promising biomarkers of epileptogenesis, their utility needs to be further validated in larger clinical trials. In this literature review, we searched the Medline, Pubmed, and Embase databases using the following search algorithm: “epileptogenesis” and “biomarker” and “EEG” or “electroencephalography” or “neuroimaging” limited to publications in English. We presented a comprehensive overview of recent innovations in the role of neuroimaging and EEG in identifying reliable biomarkers of epileptogenesis.
The Higher Parietal Cortical Thickness in Abstinent Methamphetamine Patients Is Correlated With Functional Connectivity and Age of First Usage
Authors: Yang Ru , He Lei , Zhang Zhixue , Zhou Wenming , Liu Jun
Published: September 2021

Aim

This study aimed to explore the changes of cortical thickness in abstinent methamphetamine (MA) patients compared with healthy controls.

Materials and Methods

Three-tesla structural and functional magnetic resonance imaging (MRI) was obtained from 38 abstinent methamphetamine-dependent (AMD) patients and 32 demographically equivalent healthy controls. The cortical thickness was assessed using FreeSurfer software. General linear model was used to get brain regions with significant different cortical thickness between groups (p < 0.05, Monte Carlo simulation corrected). The mean cortical thickness value and functional connectivity with all other brain regions was extracted from those significant regions. Moreover, correlation coefficients were calculated in the AMD group to assess the relations between the mean cortical thickness, functional connectivity and age when they first took MA and the duration of both MA use and abstinence.

Results

The AMD group showed significant cortical thickness increase in one cluster located in the parietal cortex, including right posterior central gyrus, supramarginal gyrus, and superior parietal lobule. In addition, cortical thickness values of those regions were all significant and negatively correlated with the age when patients first used MA. The cortical thickness of right posterior gyrus were positively correlated with its functional connectivities with left middle frontal gyrus and both left and right medial orbitofrontal gyrus.

Conclusion

The higher cortical thickness in the parietal cortex of the AMD group is in agreement with findings in related studies of increased glucose metabolism and gray matter volume. Importantly, the negative correlation between parietal cortical thickness and age of first MA suggested that adolescent brains are more vulnerable to MA’s neurotoxic effect.
Affective Contagion: How Attitudes Expressed by Others Influence Our Perception of Actions
Authors: Di Cesare Giuseppe , Pelosi Annalisa , Aresta Silvia Maria , Lombardi Giada , Sciutti Alessandra
Published: September 2021

Vitality forms represent a fundamental aspect of social interactions by characterizing how actions are performed and how words are pronounced on the basis of the attitude of the agent. Same action, such as a handshake, may have a different impact on the receiver when it is performed kindly or vigorously, and similarly, a gentle or rude tone of voice may have a different impact on the listener. In the present study, we carried out two experiments that aimed to investigate whether and how vocal requests conveying different vitality forms can influence the perception of goal-directed actions and to measure the duration of this effect over time. More specifically, participants were asked to listen to the voice of an actor pronouncing “give me” in a rude or gentle way. Then, they were asked to observe the initial part of a rude or a gentle passing action, continue it mentally, and estimate the time of its completion. Results showed that the perception of different vitality forms expressed by vocal requests influenced the estimation of action duration. Moreover, we found that this effect was limited to a certain time interval (800 ms), after which it started to decay.
Update on the Relationship Between Depression and Neuroendocrine Metabolism
Authors: Qiu Wenxin , Cai Xiaodan , Zheng Chenhui , Qiu Shumin , Ke Hanyang , Huang Yinqiong
Published: September 2021

Through the past decade of research, the correlation between depression and metabolic diseases has been noticed. More and more studies have confirmed that depression is comorbid with a variety of metabolic diseases, such as obesity, diabetes, metabolic syndrome and so on. Studies showed that the underlying mechanisms of both depression and metabolic diseases include chronic inflammatory state, which is significantly related to the severity. In addition, they also involve endocrine, immune systems. At present, the effects of clinical treatments of depression is limited. Therefore, exploring the co-disease mechanism of depression and metabolic diseases is helpful to find a new clinical therapeutic intervention strategy. Herein, focusing on the relationship between depression and metabolic diseases, this manuscript aims to provide an overview of the comorbidity of depression and metabolic.
A Multivariate Assessment of Age-Related Cognitive Impairment in Octodon degus
Authors: Rivera Daniela S. , Lindsay Carolina B. , Oliva Carolina A. , Bozinovic Francisco , Inestrosa Nibaldo C.
Published: September 2021

Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.
Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD
Authors: Arnold Madeline L. , Saijo Kaoru
Published: September 2021

Interestingly, more males are diagnosed with autism spectrum disorder (ASD) than females, yet the mechanism behind this difference is unclear. Genes on the sex chromosomes and differential regulation by sex steroid hormones and their receptors are both candidate mechanisms to explain this sex-dependent phenotype. Nuclear receptors (NRs) are a large family of transcription factors, including sex hormone receptors, that mediate ligand-dependent transcription and may play key roles in sex-specific regulation of immunity and brain development. Infection during pregnancy is known to increase the probability of developing ASD in humans, and a mouse model of maternal immune activation (MIA), which is induced by injecting innate immune stimulants into pregnant wild-type mice, is commonly used to study ASD. Since this model successfully recaptures the behavioral phenotypes and male bias observed in ASD, we will discuss the potential role of sex steroid hormones and their receptors, especially focusing on estrogen receptor (ER)β, in MIA and how this signaling may modulate transcription and subsequent inflammation in myeloid-lineage cells to contribute to the etiology of this neurodevelopmental disorder.
Activation of Rac1 Has an Opposing Effect on Induction and Maintenance of Long-Term Potentiation in Hippocampus by Acting on Different Kinases
Authors: Cui Dongyang , Jiang Xiaodong , Chen Ming , Sheng Huan , Shao Da , Yang Li , Guo Xinli , Wang Yingqi , Lai Bin , Zheng Ping
Published: September 2021

Rac1 is a small GTPase of the Rho family. A previous study showed that the activation of Rac1 had an opposing effect on induction and maintenance of long-term potentiation (LTP) in the hippocampus. However, the molecular mechanism underlying this opposing effect remains to be addressed. In the present work, we find that the activation of Rac1 during the induction of LTP leads to an activation of PKCι/λ by phosphatidylinositol-3-kinase (PI3K), whereas the activation of Rac1 during the maintenance of LTP leads to the inhibition of PKMζ by LIM_kinase (LIMK) in the hippocampus. This result suggests that during different stages of LTP, the activation of Rac1 can modulate different signaling pathways, which leads to an opposing effect on the induction and maintenance of LTP in the hippocampus.
A Nutraceutical Formula Is Effective in Raising the Circulating Vitamin and Mineral Levels in Healthy Subjects: A Randomized Trial
Authors: Nenseth Hatice Zeynep , Sahu Aparna , Saatcioglu Fahri , Osguthorpe Steven
Published: September 2021

Low levels of nutrient intake are common in industrialized countries. This has negative implications on health and is associated with chronic diseases. Supplementation of vitamins, minerals, and key nutrients to optimal levels may, therefore, be beneficial for individual health and for the health economy. Although the use of supplements has become very common, due to a lack of monitoring, there is very limited data on the efficacy of supplementation with different formulas. In this study, we present the results of a randomized controlled study on the efficacy of a novel formulated nutraceutical, N247, in 250 healthy volunteers aged 26–75 years and a placebo control group (n = 35). The broad-spectrum formulation of N247 includes essential vitamins, minerals, and trace elements that are adequately balanced in regard to synergies and related metabolic functions. Moreover, tolerance, safety, and nutrient availability is an important aspect of daily, long-term use of N247. After 3 months of regular N247 use, levels of vitamins and minerals in serum were significantly increased in the N247 group compared with the control group and a placebo group, with excellent compliance rates. Coupled with additional natural ingredients that aim to increase the potency of the nutrients, N247 may represent a novel and beneficial supplement for individuals with nutritional deficiencies.

Clinical Trial Registration:https://clinicaltrials.gov/, identifier: NCT04054505.
Effects of Fermented Radix puerariae Residue on Nutrient Digestibility and Reproductive Performance of Sows
Authors: Luo Zhenfu , Zhao Yuanyuan , Zeng Liming , Yin Jie , Zeng Qinghua , Li Xilong , He Jianhua , Wang Jing , Tan Bi'e
Published: September 2021

This study was conducted to investigate the effect of fermented Radix puerariae residue (FRPR) on reproductive performance, apparent total tract digestibility (ATTD) of nutrients, and fecal short-chain fatty acid (SCFA) contents of sows. A total of 36 landrace × large white multiparous sows were randomly arranged into three treatments, representing supplementation with 0, 2, and 4% FRPR to a corn-soybean meal and wheat bran-based diet during the whole gestation period. The results showed that dietary FRPR had no effects on litter size and the number of total alive piglets (P > 0.05), and that the number of weaned piglets and weaning weight of litter were increased in sows with 4% FRPR treatment compared with control treatment (P < 0.05). Dietary 4% FRPR significantly decreased constipation rate, improved the ATTD of dry matter and organics, and fecal contents of acetate, propionate, and total SCFAs (P < 0.05). In the offspring piglets, serum concentrations of total protein, alkaline phosphatase, IgG, IL-10, and TGF-β were increased, but blood urea nitrogen content was decreased with 4% FRPR treatment (P < 0.05). There were no significant differences in all determined indexes except for fecal acetic acid and total SCFAs between control and 2% FRPR treatment (P > 0.05). These findings indicated that FRPR used in the diets of sows showed positive effects on fecal characteristics, utilization of nutrients, and reproductive performance. Maternal supplementation with 4% FRPR is recommended for improving immune responses, weaning litter size, and litter weight of offspring piglets, which provide useful information for the application of residues of R. puerariae.
Management of Large Cell Neuroendocrine Carcinoma
Authors: Corbett Virginia , Arnold Susanne , Anthony Lowell , Chauhan Aman
Published: September 2021

Background

Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease.

Methods

We performed a PubMed search for “Large cell neuroendocrine carcinoma” and “High grade neuroendocrine carcinoma.” All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC.

Results

Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential.

Discussion

LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.
miR-9-5p Mediates ABCC1 to Elevate the Sensitivity of Glioma Cells to Temozolomide
Authors: Chen Xiang-Rui , Zhang Yan-Guo , Wang Qiang
Published: September 2021

Chemotherapy combined with surgery is an important clinical treatment for glioma, but endogenous or acquired temozolomide (TMZ) resistance can lead to poor prognosis. microRNA (miR)-9-5p acts in biological function of glioma, but the drug resistance of miR-9-5p in glioma is under exploration. The study intended to test the molecular mechanism of miR-9-5p in glioma cells. MTT assay was applied to investigate the chemosensitivity enhancement of miR-9-5p on TMZ in glioma cells U87-TMZ and U251-TMZ, and in vivo experiments confirmed its role on tumor growth in nude mice. The results of double luciferase reporter gene assay, qRT-PCR and WB indicated that miR-9-5p directly targeted ABCC1 (ATP binding cassette subfamily C member 1) to reduce its expressions. MTT and flow cytometry indicated that elevation of miR-9-5p or down-regulation of ABCC1 could inhibit proliferation-induced apoptosis of drug-resistant cells, and the decrease of miR-9-5p could reverse the reduction of ABCC1 on proliferation-induced apoptosis of drug-resistant cells. In vivo experiments showed that miR-9-5p could promote the anti-tumor role of TMZ. To sum up, the increase of miR-9-5p directly targets ABCC1 and may make glioma cells sensitive to TMZ.
Comprehensive Analysis of circRNA Expression Profiles During Cervical Carcinogenesis
Authors: Luo Haixia , Li Yuanxing , Zhao Yueyang , Chang Jingjing , Zhang Xiu , Zou Binbin , Gao Lifang , Wang Wei
Published: September 2021

Circular RNAs (circRNAs) are regulatory molecules that participate in the occurrence, development and progression of tumors. To obtain a complete blueprint of cervical carcinogenesis, we analyzed the temporal transcriptomic landscapes of mRNAs and circRNAs. Microarrays were performed to identify the circRNA and mRNA expression profiles of cervical squamous cell carcinoma (CSCC) and high-grade squamous intraepithelial lesion (HSIL) patients compared with normal controls (NC). Short time-series expression miner (STEM) was utilized to characterize the time-course expression patterns of circRNAs and mRNAs from NC to HSIL and CSCC. A total of 3 circRNA profiles and 3 mRNA profiles with continuous upregulated patterns were identified and selected for further analysis. Furthermore, functional annotation showed that the mRNAs were associated with DNA repair and cell division. The protein-protein interaction (PPI) network analysis revealed that the ten highest-degree genes were considered to be hub genes. Subsequently, a competing endogenous RNA (ceRNA) network analysis and real-time PCR validation indicated that hsa_circ_0001955/hsa-miR-6719-3p/CDK1, hsa_circ_0001955/hsa-miR-1277-5p/NEDD4L and hsa_circ_0003954/hsa-miR-15a-3p/SYCP2 were highly correlated with cervical carcinogenesis. Silencing of hsa_circ_0003954 inhibited SiHa cell proliferation and perturb the cell cycle in vitro. This study provides insight into the molecular events regulating cervical carcinogenesis, identifies functional circRNAs in CSCC, and improves the understanding of the pathogenesis and molecular biomarkers of CSCC and HSIL.
BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer
Authors: Demerlé Clemence , Gorvel Laurent , Olive Daniel
Published: September 2021

Lung cancer is the leading cause of cancer deaths worldwide. Immunotherapies (IT) have been rapidly approved for lung cancer treatment after the spectacular results in melanoma. Responses to the currently used checkpoint inhibitors are strikingly good especially in metastatic diseases. However, durable responses are observed in only 25% of cases. Consequently, there is an urgent need for new immunotherapy targets. Among the multiple checkpoints involved in the tumor immune escape, the BTLA-HVEM couple appears to be a promising target. BTLA (B- and T- Lymphocyte Attenuator) is a co-inhibitory receptor mainly expressed by B and T cells, repressing the activation signal transduction. BTLA shares similarities with other immune checkpoints such as PD-1 and CTLA-4 which are the targets of the currently used immunotherapies. Furthermore, BTLA expression points out terminally exhausted and dysfunctional lymphocytes, and correlates with lung cancer progression. The ligand of BTLA is HVEM (Herpes Virus Entry Mediator) which belongs to the TNF receptor family. Often described as a molecular switch, HVEM is constitutively expressed by many cells, including cells from tumor and healthy tissues. In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies.
Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment
Authors: Wei Jun , Gilboa Eli , Calin George A. , Heimberger Amy B.
Published: September 2021

Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.
Prognostic Signature of Hepatocellular Carcinoma and Analysis of Immune Infiltration Based on m6A-Related lncRNAs
Authors: Guo Ting , He Kun , Wang Yifei , Sun Jingjing , Chen Yong , Yang Zelong
Published: September 2021

The relationship between m6A-related lncRNAs and prognosis in hepatocellular carcinoma (HCC) is not yet clear. We used Lasso regression to establish a prognostic signature based on m6A-related lncRNAs using a training set from TCGA, and then verified the signature efficacy in a test set. Fluorescence quantitative real-time PCR (qPCR), Survival analysis, clinical risk difference analysis, immune-related analysis, and drug-sensitivity analysis were conducted. The results revealed that 1,651 lncRNAs were differentially expressed in HCC tissues, among which, 163 were m6A-related. Univariate analysis showed that 87 lncRNAs were associated with the overall survival. Six differential m6A-related lncRNAs were validated and selected via Lasso regression to construct a prognostic signature which demonstrated a satisfactory predictive efficacy. In the clinically relevant pathologic stage, histologic grade, and T stage, the risk scores obtained based on this signature showed a statistically significant difference. The high- and low-risk groups exhibited a difference in the tumor immune infiltrating cells, immune checkpoint gene expression, and sensitivity to chemotherapy. In summary, the prognostic signature based on the m6A-related lncRNAs can effectively predict the prognosis of patients and might provide a new vista for the chemotherapy and immunotherapy of HCC.
Systemic Sequential Therapy of CisGem, Tislelizumab, and Lenvatinib for Advanced Intrahepatic Cholangiocarcinoma Conversion Therapy
Authors: Ding Yuan , Han Xin , Sun Zhongquan , Tang Jinlong , Wu Yingsheng , Wang Weilin
Published: September 2021

Intrahepatic cholangiocarcinoma (CCA), always diagnosed at an advanced stage in recent years, is of high aggression and poor prognosis. There is no standard treatment beyond first-line chemotherapy and no molecular-targeted agents or immune checkpoint inhibitors approved for advanced intrahepatic CCA. Hence, we firstly report an original therapeutic strategy for a 60-year-old patient diagnosed with intrahepatic CCA categorized as Stage IIIB (T3N1M0) by the American Joint Committee on Cancer staging system. After histopathological examination and next-generation sequencing, the patient was treated with four courses of novel systemic sequential therapy (intravenous gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8; oral lenvatinib 8 mg/day from days 1 to 21; intravenous tislelizumab 200 mg on day 15). Then, the patient achieved partial response and was operated on right hemihepatectomy, cholecystectomy, and abdominal lymph node dissection. Without any perioperative complications, the patient was discharged from our hospital in perfect condition. Thereafter, the patient continued to use this new regimen 1 month after surgery for adjuvant therapy and was confirmed without recurrence when we followed up. In a word, we found an effective therapeutic regimen for preoperative advanced intrahepatic CCA conversion therapy, which may become a new approach in cancer treatment in the future.
Polymorphism of MUC1 Gene in Vietnamese Gastric Cancer Patients: A Multicenter Case–Control Study
Authors: Nguyen Ngoc-Lan Thi , Dang Ngoc-Dzung Thi , Dang Quang-Huy , Tran Van-Chuc , Vo Hoang-Long , Yamaguchi Masamitsu , Ta Thanh-Van
Published: September 2021

Background

A few studies revealed that the polymorphisms of Mucin 1 gene have a role and significance as a susceptible factor contributing to gastric cancer. To better understand the roles of two MUC1 genotype polymorphisms of rs4072037 and rs2070803 in the development of gastric cancer in Vietnamese population, a multicenter, large-sample, case–control study was conducted to investigate the potential association of these single-nucleotide polymorphisms (SNPs) of MUC1 gene with gastric cancer risk and to evaluate the combination factors in relation with these SNPs.

Methods

This case–control study included 302 gastric cancer patients and 304 controls at four national medical hospitals between 2016 and 2018. All participants were interviewed for sociodemographic characteristics, smoking and drinking status, and personal and family history of gastric diseases. Genotyping was done using polymerase chain reaction–restriction fragment length polymorphism analysis. The association of SNPs with gastric cancer was explored using logistic regression models.

Results

AA genotype for rs4072037 was significantly associated with increased gastric cancer. Those with AA genotype had higher gastric cancer risk than had patients with AG (OR: 2.09, 95% CI: 1.48–2.96) and a combination of AG+GG (OR: 1.85, 95% CI: 1.33–2.56). In rs2070803, GG genotype increased gastric cancer risk when compared with AG (OR: 1.97, 95% CI: 1.39–2.80) and AG+AA (OR: 1.71, 95% CI: 1.23–2.39). AG genotypes in both SNPs decreased gastric cancer risk when compared with homogenous genotype, more specifically AA (OR: 0.51, 95% CI: 0.35–0.72) and GG (OR: 0.58, 95% CI: 0.35–0.97). These genotypes in combination with above-60-year-old age, male gender, alcoholism, and personal history of gastric disease were also significantly elevated risk factors for gastric cancer.

Conclusions

rs4072037 and rs2070803 of Mucin 1 genes are two genotypic risk factors for gastric cancer. Those in combination with gender, family history, smoking, and drinking habits significantly increase the risk of gastric cancer.
Comparison of Multiple Clinical Testing Modalities for Assessment of NPM1-Mutant AML
Authors: Lopez Amanda , Patel Sanjay , Geyer Julia T. , Racchumi Joelle , Chadburn Amy , Simonson Paul , Ouseph Madhu M. , Inghirami Giorgio , Mencia-Trinchant Nuria , Guzman Monica L. , Gomez-Arteaga Alexandra , Lee Sangmin , Desai Pinkal , Ritchie Ellen K. , Roboz Gail J. , Tam Wayne , Kluk Michael J.
Published: September 2021

Background

NPM1 mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant NPM1 is increasing in order to detect residual disease in AML, alongside flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant NPM1 in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms.

Methods

Peripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC.

Results

RT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (<0.5% NCN by RT-PCR). Nevertheless, the positive predictive value of NGS, IHC and FC were each ≥ 80% indicating that positive results by those assays are typically associated with RT-PCR positivity. IHC, unlike bulk methods (RT-PCR, NGS and FC), is able provide information regarding cellular/architectural context of disease in biopsies. FC did not identify any NPM1-mutated residual disease not already detected by RT-PCR, NGS or IHC.

Conclusion

Overall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for “deep-sequencing” NGS panels for NGS-based monitoring of residual disease in NPM1-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for NPM1-mutated AML. Together, these findings can help inform future clinical testing algorithms.
Immune Checkpoint Inhibitor in First-Line Treatment of Metastatic Renal Cell Carcinoma: A Review of Current Evidence and Future Directions
Authors: Tung Iris , Sahu Arvind
Published: September 2021

The incidence of renal cell carcinoma (RCC) is rising and metastatic RCC carries a very poor prognosis. The treatment paradigm for metastatic RCC has shifted dramatically in the last decade with multi-targeted tyrosine kinase inhibitors (TKI) previously used as first-line treatment but its utility is limited by short-lived efficacy and rapid disease progression. The dysregulation of immune cells in the tumour microenvironment contributes to unregulated growth of RCC. Thus, the use of immune checkpoint inhibitors has become first-line treatment for metastatic RCC and has offered dramatic improvement in clinical benefit and survival. Treatment with immune checkpoint inhibitor in combination with TKI appears to be promising in offering even greater response rates. The treatment for metastatic RCC continues to evolve and ongoing advances with new targeted agents and biomarkers are needed to continue to improve prognosis in the future.