bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental and Mechanical Evaluation of Blended Cements With High Mineral Admixture Content
Authors: Rodrigues Anna Luiza Macachero Victor , Mendes Álvaro Ávila Franklin , Gomes Vanessa , Battagin Arnaldo Forti , Saade Marcella Ruschi Mendes , Da Silva Maristela Gomes
Published: July 2022

The synergistic effect of combining supplementary cementitious materials (SCMs) as partial substitutes for clinker improves cement properties and reduces its clinker factor and, hence, its carbon footprint. Limestone-calcined clay cement (LC3)—a family of clinker, calcined clay, and limestone filler mixes—is studied worldwide for its properties equivalent to those of Portland cement. Although slag and fly ash are no longer sufficient to keep up with current commercial blended cements, in the long run, these SCMs can support the development of optimized formulations for the future. By relating the environmental and the mechanical performances, the GHG emission intensity offers a broader assessment and selection perspective. In this article, 13 blended cements were evaluated: ternary, quaternary, and multi-admixture (i.e., OPC plus 4 SCMs) blends with clinker factor between 40 and 50%, composed of—in addition to calcined clay and limestone filler—blast furnace slag and fly ash. Compressive strength was measured at 3, 7, 28, 91, and 365 days. The greenhouse gas (GHG) emissions were estimated through life cycle assessment and related to the blends’ compressive strength unit. Quaternary and multi-addition cements consistently outperformed after 3 days of age, demonstrating the benefits of the synergistic effect between SCMs jointly on GHG emissions and compressive strength. Such an effect enables reducing not only the clinker factor and carbon footprint but also the GHG emission intensity, which relates both. This study showed that the formulated cements, particularly those composed of multi-additions (Series D), are potential alternatives for reducing the GHG emissions, whilst preserving mechanical performance demanded by construction market practices. From a multidisciplinary analysis standpoint, durability assessments are necessary to complement the reported findings, as low clinker contents can affect the pH of the concrete’s pore solution and carbonation which ultimately lead to deterioration.
Insights Into the Role of Platelet-Derived Growth Factors: Implications for Parkinson’s Disease Pathogenesis and Treatment
Authors: Li Dan , Huang Le-Tian , Zhang Cheng-pu , Li Qiang , Wang Jia-He
Published: July 2022

Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, commonly occurs in the elderly population, causing a significant medical and economic burden to the aging society worldwide. At present, there are few effective methods that achieve satisfactory clinical results in the treatment of PD. Platelet-derived growth factors (PDGFs) and platelet-derived growth factor receptors (PDGFRs) are important neurotrophic factors that are expressed in various cell types. Their unique structures allow for specific binding that can effectively regulate vital functions in the nervous system. In this review, we summarized the possible mechanisms by which PDGFs/PDGFRs regulate the occurrence and development of PD by affecting oxidative stress, mitochondrial function, protein folding and aggregation, Ca2+homeostasis, and cell neuroinflammation. These modes of action mainly depend on the type and distribution of PDGFs in different nerve cells. We also summarized the possible clinical applications and prospects for PDGF in the treatment of PD, especially in genetic treatment. Recent advances have shown that PDGFs have contradictory roles within the central nervous system (CNS). Although they exert neuroprotective effects through multiple pathways, they are also associated with the disruption of the blood–brain barrier (BBB). Our recommendations based on our findings include further investigation of the contradictory neurotrophic and neurotoxic effects of the PDGFs acting on the CNS.
Cognitive Assessment in SARS-CoV-2 Patients: A Systematic Review
Authors: Biagianti Bruno , Di Liberto Asia , Nicolò Edoardo Aiello , Lisi Ilaria , Nobilia Letizia , de Ferrabonc Giulia Delor , Zanier Elisa R. , Stocchetti Nino , Brambilla Paolo
Published: July 2022

Background

Patients with post-infective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often show both short- and long-term cognitive deficits within the dysexecutive/inattentive spectrum. However, little is known about which cognitive alterations are commonly found in patients recovered from SARS-CoV-2, and which psychometric tools clinicians should consider when assessing cognition in this population. The present work reviewed published studies to provide a critical narrative of neuropsychological (NPs) deficits commonly observed after SARS-CoV-2 infection and the tests most suited for detecting such cognitive sequelae depending on illness severity.

Methods

This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was pre-registered on Prospective Register of Systematic Reviews (PROSPERO) (CRD42021253079). Observational studies quantitatively assessing cognition in patients with post-infective SARS-CoV-2 were considered. From 711 retrieved articles, 19 studies conducted on patients with SARS-CoV-2 without medical comorbidities were included and stratified by disease severity.

Results

The majority of studies (N = 13) adopted first-level tests. The most frequently administered screeners were the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE)—with the former more likely to detect mild, and the latter moderate/severe deficits. Among second-level tests, those assessing attention and executive functions (EFs) were highly represented. Remotely-delivered tests yielded lower percentages of cognitive impairment. Overall, cognitive domains often found to be impaired were EFs, attention, and memory.

Conclusion

Cognitive sequelae in patients with post-infective SARS-CoV-2 can be detected with NPs testing. Depending on the psychometric test features, the likelihood of observing cognitive deficits can vary. Further studies on larger sample sizes are needed to investigate the clinical usefulness of second-level tools. The primary goal of preventative health services should be the early detection and intervention of emerging cognitive deficits.
Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer’s Disease Pathology, Constitute a Potential Object for Early Diagnosis
Authors: Lopez-Toledo Gustavo , Silva-Lucero Maria-del-Carmen , Herrera-Díaz Jorge , García David-Erasmo , Arias-Montaño José-Antonio , Cardenas-Aguayo Maria-del-Carmen
Published: July 2022

Alzheimer’s disease (AD), a neurodegenerative disorder that can occur in middle or old age, is characterized by memory loss, a continuous decline in thinking, behavioral and social skills that affect the ability of an individual to function independently. It is divided into sporadic and familial subtypes. Early-onset familial AD (FAD) is linked to mutations in genes coding for the amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2), which lead to alterations in AβPP processing, generation of the Amyloid-β peptide and hyperphosphorylation of tau protein. Identification of early biomarkers for AD diagnosis represents a challenge, and it has been suggested that molecular changes in neurodegenerative pathways identified in the brain of AD patients can be detected in peripheral non-neural cells derived from familial or sporadic AD patients. In the present study, we determined the protein expression, the proteomic and in silico characterization of skin fibroblasts from FAD patients with PS1 mutations (M146L or A246E) or from healthy individuals. Our results shown that fibroblasts from AD patients had increased expression of the autophagy markers LC3II, LAMP2 and Cathepsin D, a significant increase in total GSK3, phosphorylated ERK1/2 (Thr202/Tyr204) and phosphorylated tau (Thr231, Ser396, and Ser404), but no difference in the phosphorylation of Akt (Ser473) or the α (Ser21) and β (Ser9) GSK3 isoforms, highlighting the relevant role of abnormal protein post-translational modifications in age-related neurodegenerative diseases, such as AD. Both 2-DE gels and mass spectrometry showed significant differences in the expression of the signaling pathways associated with protein folding and the autophagic pathway mediated by chaperones with the expression of HSPA5, HSPE1, HSPD1, HSP90AA1, and HSPE1 and reticular stress in the FAD samples. Furthermore, expression of the heat shock proteins HSP90 and HSP70 was significantly higher in the cells from AD patients as confirmed by Western blot. Taken together our results indicate that fibroblasts from patients with FAD-PS1 present alterations in signaling pathways related to cellular stress, autophagy, lysosomes, and tau phosphorylation. Fibroblasts can therefore be useful in modeling pathways related to neurodegeneration, as well as for the identification of early AD biomarkers.
Application of Cognitive Bias Testing in Neuropsychiatric Disorders: A Mini-Review Based on Animal Studies
Authors: Zhang Yu-Han , Wang Ning , Lin Xiao-Xiao , Wang Jin-Yan , Luo Fei
Published: July 2022

Cognitive biases can arise from cognitive processing under affective states and reflect the impact of emotion on cognition. In animal studies, the existing methods for detecting animal emotional state are still relatively limited, and cognitive bias test has gradually become an important supplement. In recent years, its effectiveness in animal research related to neuropsychiatric disorders has been widely verified. Some studies have found that cognitive bias test is more sensitive than traditional test methods such as forced swimming test and sucrose preference test in detecting emotional state. Therefore, it has great potential to become an important tool to measure the influence of neuropsychiatric disorder-associated emotions on cognitive processing. Moreover, it also can be used in early drug screening to effectively assess the potential effects or side effects of drugs on affective state prior to clinical trials. In this mini-review, we summarize the application of cognitive bias tests in animal models of neuropsychiatric disorders such as depression, anxiety, bipolar disorder, and pain. We also discussed its critical value in the identification of neuropsychiatric disorders and the validation of therapeutic approaches.
Optimal Technique for Introducing Schwann Cells Into Peripheral Nerve Repair Sites
Authors: Errante Emily L. , Diaz Anthony , Smartz Taylor , Khan Aisha , Silvera Risset , Brooks Adriana E. , Lee Yee-Shuan , Burks S. Shelby , Levi Allan D.
Published: July 2022

Peripheral nerve injury (PNI) is found in a relatively large portion of trauma patients. If the injury is severe, such as with the presence of a long segmental gap, PNI can present a challenge for treatment. The current clinical standard of nerve harvest for the repair of long segmental gap PNI can lead to many potential complications. While other methods have been utilized, recent evidence indicates the relevance of cell therapies, particularly through the use of Schwann cells, for the treatment of PNI. Schwann cells (SCs) are integral in the regeneration and restoration of function following PNI. SCs are able to dedifferentiate and proliferate, remove myelin and axonal debris, and are supportive in axonal regeneration. Our laboratory has demonstrated that SCs are effective in the treatment of severe PNI when axon guidance channels are utilized. However, in order for this treatment to be effective, optimal techniques for cellular placement must be used. Thus, here we provide relevant background information, preclinical, and clinical evidence for our method in the treatment of severe PNI through the use of SCs and axon guidance channels.
The Impact of Sleep Pattern in School/Work Performance During the COVID-19 Home Quarantine in Patients With Narcolepsy
Authors: Zhao Mengke , Zhang Baokun , Tang Jiyou , Zhang Xiao
Published: July 2022

Objectives

Narcolepsy patients were observed improvements in their academic performance during the COVID-19 home quarantine. Therefore, we aim to investigate the influence of sleep behavioral changes on school/work performance in narcolepsy patients during the home quarantine.

Methods

Patients admitted to Shandong Provincial Qianfoshan Hospital from Jan 1, 2017 to Jan 1, 2021 who were diagnosed with narcolepsy were studied by online questionnaires in two different periods (during and 1 year after the COVID-19 home quarantine), including five aspects: (1) changes in school/work performance (percentile ranking in class/Sheehan Disability Scale 1, SDS1); (2) daytime functions; (3) clinical symptoms; (4) psychological moods; (5) medication situations.

Results

A total of 46 narcolepsy patients 34 (73.9%) narcolepsy type 1, 12 (26.1%) narcolepsy type 2 with average age of 20.76 ± 8.99 years and an equal number of age and gender matched control subjects were enrolled. During the COVID-19 home quarantine, the narcolepsy patients were found that they altered sleep patterns, including later get up time (P < 0.001), longer total sleep time (TST, P = 0.001), better sleep quality (PSQI, P = 0.001), and lower anxiety level (P = 0.005). Their school/work performance improved parallelly [with better percentile ranking (P = 0.001) and lower SDS1 scores (P = 0.002)]. The results of multiple linear stepwise regression analysis showed a linear regression relationship between TST [efficient (95%) −7.356 (−13.570 to 1.143)], SDS1 score [efficient (95%) 6.580 (2.346–10.815), P = 0.004] and the percentile ranking after adjusting for potential effects. Both the improvements of sleep behavior and school/work performance disappeared after the end of COVID-19 home quarantine. No similar fluctuation was found in the control group.

Discussion

Changes in sleep pattern during the COVID-19 home quarantine, such as longer sleep time and later wake-up time, can reduce the degree of daytime sleepiness and increase the degree of daytime wakefulness of narcolepsy patients, which can alleviate the impact of the disease on school/work performance.
Quantifying the Cerebral Hemometabolic Response to Blood Transfusion in Pediatric Sickle Cell Disease With Diffuse Optical Spectroscopies
Authors: Lee Seung Yup , Brothers Rowan O. , Turrentine Katherine B. , Quadri Ayesha , Sathialingam Eashani , Cowdrick Kyle R. , Gillespie Scott , Bai Shasha , Goldman-Yassen Adam E. , Joiner Clinton H. , Brown R. Clark , Buckley Erin M.
Published: July 2022

Red blood cell transfusions are common in patients with sickle cell disease who are at increased risk of stroke. Unfortunately, transfusion thresholds needed to sufficiently dilute sickle red blood cells and adequately restore oxygen delivery to the brain are not well defined. Previous work has shown that transfusion is associated with a reduction in oxygen extraction fraction and cerebral blood flow, both of which are abnormally increased in sickle patients. These reductions are thought to alleviate hemometabolic stress by improving the brain's ability to respond to increased metabolic demand, thereby reducing susceptibility to ischemic injury. Monitoring the cerebral hemometabolic response to transfusion may enable individualized management of transfusion thresholds. Diffuse optical spectroscopies may present a low-cost, non-invasive means to monitor this response. In this study, children with SCD undergoing chronic transfusion therapy were recruited. Diffuse optical spectroscopies (namely, diffuse correlation spectroscopy combined with frequency domain near-infrared spectroscopy) were used to quantify oxygen extraction fraction (OEF), cerebral blood volume (CBV), an index of cerebral blood flow (CBFi), and an index of cerebral oxygen metabolism (CMRO2i) in the frontal cortex immediately before and after transfusion. A subset of patients receiving regular monthly transfusions were measured during a subsequent transfusion. Data was captured from 35 transfusions in 23 patients. Transfusion increased median blood hemoglobin levels (Hb) from 9.1 to 11.7 g/dL (p < 0.001) and decreased median sickle hemoglobin (HbS) from 30.9 to 21.7% (p < 0.001). Transfusion decreased OEF by median 5.9% (p < 0.001), CBFi by median 21.2% (p = 0.020), and CBV by median 18.2% (p < 0.001). CMRO2i did not statistically change from pre-transfusion levels (p > 0.05). Multivariable analysis revealed varying degrees of associations between outcomes (i.e., OEF, CBFi, CBV, and CMRO2i), Hb, and demographics. OEF, CBFi, and CBV were all negatively associated with Hb, while CMRO2i was only associated with age. These results demonstrate that diffuse optical spectroscopies are sensitive to the expected decreases of oxygen extraction, blood flow, and blood volume after transfusion. Diffuse optical spectroscopies may be a promising bedside tool for real-time monitoring and goal-directed therapy to reduce stroke risk for sickle cell disease.
Multiplexed Visualization Method to Explore Complete Targeting Regulatory Relationships Among Circadian Genes for Insomnia Treatment
Authors: Li Tao , Liu Zhenyu , Wang Yitong , Zuo Dongshi , Wang Shenyuan , Ju Haitao , Wang Shichao , Xing Yanping , Ling Yu , Liu Chunxia , Zhang Yanru , Zhou Huanmin , Yin Jun , Cao Junwei , Gao Jing
Published: July 2022

Understanding the complete map of melatonin synthesis, the information transfer network among circadian genes in pineal gland, promises to resolve outstanding issues in endocrine systems and improve the clinical diagnosis and treatment level of insomnia, immune disease and hysterical depression. Currently, some landmark studies have revealed some genes that regulate circadian rhythm associated with melatonin synthesis. However, these studies don't give a complete map of melatonin synthesis, as transfer information among circadian genes in pineal gland is lost. New biotechnology, integrates dynamic sequential omics and multiplexed imaging method, has been used to visualize the complete process of melatonin synthesis. It is found that there are two extremely significant information transfer processes involved in melatonin synthesis. In the first stage, as the light intensity decreased, melatonin synthesis mechanism has started, which is embodied in circadian genes, Rel, Polr2A, Mafk, and Srbf1 become active. In the second stage, circadian genes Hif1a, Bach1, Clock, E2f6, and Per2 are regulated simultaneously by four genes, Rel, Polr2A, Mafk, and Srbf1 and contribute genetic information to Aanat. The expeditious growth in this technique offer reference for an overall understanding of gene-to-gene regulatory relationship among circadian genes in pineal gland. In the study, dynamic sequential omics and the analysis process well provide the current state and future perspectives to better diagnose and cure diseases associated with melatonin synthesis disorder.
Identification of Prefrontal Cortex and Amygdala Expressed Genes Associated With Sevoflurane Anesthesia on Non-human Primate
Authors: Cheng Yanyong , Liu Siyu , Zhang Lei , Jiang Hong
Published: July 2022

Clinical trials and animal studies have indicated that long-term use or multiple administrations of anesthesia may lead to fine motor impairment in the developing brain. Most studies on anesthesia-induced neurotoxicity have focused on the hippocampus and prefrontal cortex (PFC); however, the role of other vital encephalic regions, such as the amygdala, is still unclear. Herein, we focused on sevoflurane, the most commonly used volatile anesthetic in infants, and performed a transcriptional analysis of the PFC and amygdala of macaques after multiple exposures to the anesthetic by RNA sequencing. The overall, overlapping, and encephalic region-specific transcriptional patterns were separately analyzed to reveal their functions and differentially expressed gene sets that were influenced by sevoflurane. Specifically, functional, protein–protein interaction, neighbor gene network, and gene set enrichment analyses were performed. Further, we built the basic molecular feature of the amygdala by comparing it to the PFC. In comparison with the amygdala’s changing pattern following sevoflurane exposure, functional annotations of the PFC were more enriched in glial cell-related biological functions than in neuron and synapsis development. Taken together, transcriptional studies and bioinformatics analyses allow for an improved understanding of the primate PFC and amygdala.
Sex as a Biological Factor in the Changes in Disease Patients During Ramadan Intermittent Fasting: A Systematic Review
Authors: Roky Rachida , Aadil Nadia , Krami Al Mehdi , Benaji Brahim , Errabih Ikram , Abdelrahim Dana N. , Faris MoezAlIslam Ezzat
Published: July 2022

Background

During Ramadan, many patients with diabetes, renal, cardiovascular, gastrointestinal diseases, headaches, and epilepsy choose to fast even against their doctor's advice. The impact of this intermittent fasting on health and disease could be different in men and women. The aim of this study was to determine the effect of sex as a factor in diseases outcomes of patients who opt to fast during Ramadan.

Main Body

The articles included in this study reported data on six diseases: diabetes, renal, cardiovascular, gastrointestinal diseases, headaches, and epilepsy. A systematic search was performed on PubMed and Scopus for observational and clinical studies mentioning Ramadan, diabetes, renal, cardiovascular, gastrointestinal diseases, headaches, and epilepsy in both men and women. Data was extracted by two independent reviewers using a standardized data-collection form. From 381 original articles, 38 studies were selected, including 25,023 patients of which 44.4% were women. Sex-based differences were reported by 18 studies for several variables such as body mass index, blood glucose, the frequency of hypoglycemia, renal colic, mortality, thrombosis, and gastrointestinal diseases in patients fasting during Ramadan. Most of the differences between men and women were reported both in the baseline period before Ramadan and during Ramadan. Indeed, during the period outside Ramadan, the frequency of renal colic, cardiovascular, gastrointestinal diseases, were higher in men; while body mass index, Thrombosis, and headache were higher in women. In the remaining 21 studies, it was reported that the sex factor was not associated with the effect of Ramadan fasting in the frequency and other outcomes of these diseases.

Conclusion

Currently, small attention is paid to sex as a determinant factor in patients while fasting during Ramadan. There appeared to be differences in the frequency and incidence of diseases in men and women during Ramadan. Closer attention to sex differences regarding the frequency and the progression of the diseases during fasting may help to improve patient care, especially to benefit those patients willing to fast during Ramadan.
Research Review of Thermal Ablation in the Treatment of Papillary Thyroid Carcinoma
Authors: Ou Di , Chen Chen , Jiang Tian , Xu Dong
Published: July 2022

Background

Minimally invasive treatment of thyroid tumors has become increasingly common, but has mainly focused on benign thyroid tumors, whereas thermal ablation of thyroid cancer remains controversial. Clinical studies analyzing the efficacy of thermal ablation of papillary thyroid carcinoma (PTC) have been conducted in several countries to verify its safety. Here, we screened and reviewed recent studies on the efficacy and safety of thermal ablation of PTC as well as psychological assessment, patient prognosis, recurrence, and factors affecting ablation.

The most significant controversy surrounding ablative treatment of PTC centers on its effectiveness and safety, and >40 studies have been conducted to address this issue. The studies include papillary thyroid microcarcinoma (PTMC) and non-PTMC, single PTC and multiple PTC, and controlled studies of ablative therapy and surgical treatment. In general, ablation techniques can be carefully performed and promoted under certain conditions and with active follow-up of postoperative patients. Ablation is a promising alternative treatment especially in patients who are inoperable.

Conclusions

Clinical studies on PTC ablation have provided new perspectives on local treatment. However, because PTC grows very slowly, it is an indolent tumor; therefore, studies with larger sample sizes and extended post-procedure follow-ups are necessary to confirm the investigators’ hypotheses.
The Risk Factors, Incidence and Prognosis of Postpartum Breast Cancer: A Nationwide Study by the SMARTSHIP Group
Authors: Park Sungmin , Lee Ji Sung , Yoon Jae Sun , Kim Nam Hyoung , Park Seho , Youn Hyun Jo , Lee Jong Won , Lee Jung Eun , Lee Jihyoun , Hur Ho , Jeong Joon , Kim Kweon-Cheon , Bae Soo Youn
Published: July 2022

The term ‘pregnancy-associated breast cancer’ is no longer used as it has been consistently reported that breast cancer during pregnancy and breast cancer after delivery (postpartum breast cancer) have different characteristics and prognosis. The purpose of this study is to define postpartum breast cancer by analyzing the incidence rate, related factors, and prognosis according to the timing of breast cancer. Data from the Korean National Health Insurance Service were used to analyze 1,292,727 women aged 20-49 years who birthed their first child between 2007 and 2012. The annual incidence rate of breast cancer after delivery increased every year (7.7 per 10,000 person-years after 5 years, 19.36 per 10,000 person-years after 10 years). The risk of breast cancer was significantly higher (hazard ratio 1.15, 95% CI 1.05-1.27, P=0.0037) in women diagnosed with gestational diabetes, but that was not associated with overall survival (OS). Patients diagnosed with breast cancer within 5 years of delivery had a poorer prognosis than those diagnosed later (5-year OS, <5 years: 91.1% vs. 5-10 years: 96.0%). In multivariate analysis of OS, the hazard ratio of patients diagnosed within 5 years after delivery was twice as high as of patients diagnosed between 5 and 10 years. Women diagnosed with gestational diabetes had an increased risk of breast cancer. Breast cancer patients diagnosed within 5 years of delivery had a poorer prognosis than those diagnosed later. In this regard, careful screening for early diagnosis of high-risk patients and intensive research on new treatment strategies are needed.
Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis
Authors: Kuttikrishnan Shilpa , Masoodi Tariq , Sher Gulab , Bhat Ajaz A. , Patil Kalyani , El-Elimat Tamam , Oberlies Nicholas H. , Pearce Cedric J. , Haris Mohmmad , Ahmad Aamir , Alali Feras Q. , Uddin Shahab
Published: July 2022

Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.
Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease
Authors: Forster Stefan , Radpour Ramin
Published: July 2022

Multiple myeloma (MM) is the most common malignant monoclonal disease of plasma cells. Aside from classical chemotherapy and glucocorticoids, proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are used in the current treatment scheme of MM. The tumor microenvironment (TME) plays a fundamental role in the development and progression of numerous solid and non-solid cancer entities. In MM, the survival and expansion of malignant plasma cell clones heavily depends on various direct and indirect signaling pathways provided by the surrounding bone marrow (BM) niche. In a number of MM patients, single plasma cell clones lose their BM dependency and are capable to engraft at distant body sites or organs. The resulting condition is defined as an extramedullary myeloma (EMM). EMMs are highly aggressive disease stages linked to a dismal prognosis. Emerging literature demonstrates that the dynamic interactions between the TME and malignant plasma cells affect myeloma dissemination. In this review, we aim to summarize how the cellular and non-cellular BM compartments can promote plasma cells to exit their BM niche and metastasize to distant intra-or extramedullary locations. In addition, we list selected therapy concepts that directly target the TME with the potential to prevent myeloma spread.
Dose-Dependent Antidepressant-Like Effects of Cannabidiol in Aged Rats
Authors: Hernández-Hernández Elena , García-Fuster M. Julia
Published: July 2022

Aging predisposes to late-life depression and since antidepressants are known to change their efficacy with age, novel treatment options are needed for our increased aged population. In this context, the goal of the present study was to evaluate the potential antidepressant-like effect of cannabidiol in aged rats. For this purpose, 19–21-month-old Sprague–Dawley rats were treated for 7 days with cannabidiol (dose range: 3–30 mg/kg) and scored under the stress of the forced-swim test. Hippocampal cannabinoid receptors and cell proliferation were evaluated as potential molecular markers underlying cannabidiol’s actions. The main results of the present study demonstrated that cannabidiol exerted a dose-dependent antidepressant-like effect in aged rats (U-shaped, effective at the intermediate dose of 10 mg/kg as compared to the other doses tested), without affecting body weight. None of the molecular markers analyzed in the hippocampus were altered by cannabidiol’s treatment. Overall, this study demonstrated a dose-dependent antidepressant-like response for cannabidiol at this age-window (aged rats up to 21 months old) and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.
Assessment of the Anti-Inflammatory, Antibacterial and Anti-Aging Properties and Possible Use on the Skin of Hydrogels Containing Epilobium angustifolium L. Extracts
Authors: Nowak Anna , Zagórska-Dziok Martyna , Perużyńska Magdalena , Cybulska Krystyna , Kucharska Edyta , Ossowicz-Rupniewska Paula , Piotrowska Katarzyna , Duchnik Wiktoria , Kucharski Łukasz , Sulikowski Tadeusz , Droździk Marek , Klimowicz Adam
Published: July 2022

Epilobium angustifolium L. is an ethnomedicinal plant known as a medicinal plant in many regions of the world, among others, in various skin diseases. Despite the great interest in this plant, there are still few reports of biological activity of ready-made dermatological or cosmetical preparations containing the E. angustifolium extracts. The antioxidant, anti-ageing, anti-inflammatory, antibacterial properties and toxicity, wound healing, and skin permeation of topical hydrogels containing E. angustifolium extracts (HEas) was assessed. First, the plant extracts were prepared using three solvents: 70% (v/v) ethanol, 70% (v/v) isopropanol and water, next by preparing hydrogels witch by dry extracts (HEa-EtOH), (HEa-iPrOH) and (HEa-WA), respectively. Finally, the content of selected phenolic acids in the HEas was evaluated by high-performance liquid chromatography (HPLC). All the HEas were characterized by high antioxidant activity. The most increased antibacterial activity was observed for a strain of Streptococcus pneumoniae ATCC 49619, Escherichia coli, Enterococcus faecalis ATCC 29212, Enterococcus faecium, Sarcina lutea ATCC 9341 and Bacillus pseudomycoides, while the strains of Streptococcus epidermidis, Bacillus subtilis, and Staphylococcus aureus were the least sensitive. All the HEas showed a reduction in the activity of lipoxygenase enzymes, proteases, and inhibition of protein denaturation. The HEa-EtOH and HEa-iPrOH also enhanced the wound healing activity of HDF cells. Additionally, in vitro penetration studies were performed using the Franz diffusion cells. These studies showed that the active ingredients contained in E. angustifolium penetrate through human skin and accumulate in it. Furthermore, the hydrogels containing E. angustifolium extracts showed a broad spectrum of activity. Therefore, they can be considered as an interesting alternative for dermatologic and cosmetic preparations.
Chemotherapy Combined With Immunotherapy as a First-Line Treatment Brings Benefits to Patients With Lung Squamous Cell Carcinoma but Different Risks of Adverse Reactions: A Systematic Review and Meta-Analysis
Authors: Chen Qian , Zhang Zhen , Li Xiaoli , Bu Lingbiao
Published: July 2022

Objective To explore the efficacy and safety of chemotherapy combined with immunotherapy as the first-line treatment of advanced or metastatic squamous NSCLC.

Methods Two researchers independently searched PubMed, the Cochrane Library, EMBASE, CNKI, Wanfang Data, and other databases by using a computer, collected the clinical trials or randomized controlled trials published by April 2022 about immunotherapy combined with chemotherapy as the first-line treatment of advanced or metastatic squamous NSCLC, screened the literature, and extracted the data according to the nanodischarge criteria. We used Revman5.4 for statistical analysis of the included studies, and publication bias was analyzed with Egger’s test in Stata12.

Results A total of seven clinical trials were included, including 1,510 cases in the chemotherapy combined with the immunotherapy group and 1,519 cases in the chemotherapy group. In terms of effectiveness, compared with the chemotherapy group, chemotherapy combined with immunotherapy for advanced or metastatic squamous NSCLC had longer overall survival (HR = 1.59, 95% CI: 1.46–1.72, p < 0.00001) and progression-free survival (HR = 1.84, 95% CI: 1.66–2.03, p < 0.00001). In terms of safety, the chemotherapy combined with immunotherapy group has a higher risk of adverse reactions at any level and above three levels of hematotoxicity, gastrointestinal abnormalities, and liver dysfunction than the chemotherapy group. Egger’s test has minor publication bias.

Conclusion Chemotherapy combined with immunotherapy is effective as the first-line treatment for advanced or metastatic squamous NSCLC, but the risk of adverse reactions is relatively high. If there are adverse reactions in clinical application, it should be treated in time.
Efficacy, Safety and Mechanism of Jinzhen Oral Liquid in the Treatment of Acute Bronchitis in Children: A Randomized, Double-Blind, Multicenter Clinical Trial Protocol
Authors: Cui Xin , Liang Long , Geng Hongjiao , Liu Yi , Xi Junyu , Wang Junhong , Ching Tee Bee , Bee Eow Gaik , Chai Yan , Wu ShengXian , Jin De , Xie YanMing
Published: July 2022

Background: Acute bronchitis (AB) is a common disease in pediatrics. Prolonged AB may develop into chronic bronchitis. Bronchitis caused by the influenza virus can lead to severe hypoxia or insufficient ventilation, causing great harm to patients and increasing the burden on children and society. Presently, there is no specific treatment for AB except symptomatic supportive treatment. It is urgent to find an effective treatment for AB. Jinzhen Oral Liquid (JZOL) has been found to have a broad spectrum of anti-inflammatory and antiviral effects in previous clinical and basic studies and has a good effect on AB in children. However, the large-sample, randomized, double-blind, head-to-head, evidence-based studies are lacking. The purpose of this protocol is to evaluate the efficacy, safety, and mechanism of JZOL in the treatment of AB in children.

Methods: This is a randomized, double-blind, parallel-controlled multi-center clinical trial. The sample size is 500 participants in the intervention group and the control group respectively, with a total of 1000 participants. They will be recruited by 10 hospitals in China. The Intervention group takes JZOL and Ambroxol Hydrochloride and Clenbuterol Hydrochloride Oral Solution (AHCHOS) placebo, while the control group receives AHCHOS and JZOL placebo. The dosage of the two drugs varies according to age and weight. The medication lasts for 7 days. The disappearance time of cough is adopted as the primary outcome. Quality control will be carried out at every stage of data management and processing to ensure that all data are reliable and processed correctly. SAS is used for statistical analysis. Intention-to-treat analysis will be carried out in this trial. All statistical tests are conducted using a two-sided test, and p <0.05 would be considered statistically significant.

Discussion: We hypothesized that children with AB could get good health benefits from JZOL. This study not only evaluates the clinical efficacy and safety of JZOL but also conducts metagenomics analysis and metabolomics analysis of feces and saliva of participants to study the mechanism of JZOL against AB. Therefore, this protocol evaluates the efficacy, safety, and mechanism of JZOL from a comprehensive perspective, so as to obtain a more solid evidence chain, which will enhance the credibility of the evidence. If successful, this study will provide a high-level evidence-based reference for the treatment of AB in children and future relevant studies.
Nation-Wide Survey Assessing the Knowledge and Attitudes of Romanian Pharmacists Concerning Pharmacogenetics
Authors: Pop Cristina , Cristina Anamaria , Iaru Irina , Popa Stefan L. , Mogoșan Cristina
Published: July 2022

Background: Pharmacogenetics (PGx) is an important component of personalized medicine that has the potential to improve medicines’ effectiveness and safety. However, despite progress in technology and availability, PGx testing application into patient-care in Eastern Europe countries, has been slow.

Objectives: Our aim was to describe knowledge and attitudes of Romanian pharmacists concerning PGx, and identify potential factors limiting PGx implementation.

Method: An anonymous, web-based questionnaire was distributed to Romanian pharmacists registered in the National Pharmacists’ Association (NPA) via an official e-mail sent by NPA representatives.

Results: A total of 1,058 pharmacists completed the questionnaires, resulting in a response rate of 7.6%. Pharmacists were predominantly female (90.1%), younger than 49 years (87.5%) and mostly worked in community pharmacies (80.2%). Most pharmacists (64.8%) had a knowledge score between 30 and 49 points out of 60, and (75.4%) had attitude scores between 9 and 7 out of 10. Attitude and knowledge scores positively correlated.

Conclusion: Despite performing fairly well on general questions regarding PGx, Romanian pharmacists may lack in-depth knowledge, which can affect their readiness to discuss PGx information with patients or other healthcare professionals. High pricing was considered an important impediment in PGx implementation.
On the Entropy Projection and the Robustness of High Order Entropy Stable Discontinuous Galerkin Schemes for Under-Resolved Flows
Authors: Chan Jesse , Ranocha Hendrik , Rueda-Ramírez Andrés M. , Gassner Gregor , Warburton Tim
Published: July 2022

High order entropy stable schemes provide improved robustness for computational simulations of fluid flows. However, additional stabilization and positivity preserving limiting can still be required for variable-density flows with under-resolved features. We demonstrate numerically that entropy stable Discontinuous Galerkin (DG) methods which incorporate an “entropy projection” are less likely to require additional limiting to retain positivity for certain types of flows. We conclude by investigating potential explanations for this observed improvement in robustness.
Impact of Comorbid Prematurity and Congenital Anomalies: A Review
Authors: Gunn-Charlton Julia K.
Published: July 2022

Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also more likely to be born preterm than those without congenital anomalies. Moreover, the comorbid impact of prematurity and congenital anomalies is more than cumulative. Multiple common factors increase the risk of brain injury and neurodevelopmental impairment in both preterm babies and those born with congenital anomalies. These include prolonged hospital length of stay, feeding difficulties, nutritional deficits, pain exposure and administration of medications including sedatives and analgesics. Congenital heart disease provides a well-studied example of the impact of comorbid disease with prematurity. Impaired brain growth and maturity is well described in the third trimester in this population; the immature brain is subsequently more vulnerable to further injury. There is a colinear relationship between degree of prematurity and outcome both in terms of mortality and neurological morbidity. Both prematurity and relative brain immaturity independently increase the risk of subsequent neurodevelopmental impairment in infants with CHD. Non-cardiac surgery also poses a greater risk to preterm infants despite the expectation of normal in utero brain growth. Esophageal atresia, diaphragmatic hernia and abdominal wall defects provide examples of congenital anomalies which have been shown to have poorer neurodevelopmental outcomes in the face of prematurity, with associated increased surgical complexity, higher relative cumulative doses of medications, longer hospital and intensive care stay and increased rates of feeding difficulties, compared with infants who experience either prematurity or congenital anomalies alone.
Myosin 5a in the Urinary Bladder: Localization, Splice Variant Expression, and Functional Role in Neurotransmission
Authors: Carew Josephine A. , Cristofaro Vivian , Dasari Suhas P. , Carey Sean , Goyal Raj K. , Sullivan Maryrose P.
Published: July 2022

Dysregulation of neurotransmission is a feature of several prevalent lower urinary tract conditions, but the mechanisms regulating neurotransmitter release in the bladder are not completely understood. The unconventional motor protein, Myosin 5a, transports neurotransmitter-containing synaptic vesicles along actin fibers towards the varicosity membrane, tethering them at the active zone prior to reception of a nerve impulse. Our previous studies indicated that Myosin 5a is expressed and functionally relevant in the peripheral nerves of visceral organs such as the stomach and the corpora cavernosa. However, its potential role in bladder neurotransmission has not previously been investigated. The expression of Myosin 5a was examined by quantitative PCR and restriction analyses in bladders from DBA (dilute-brown-nonagouti) mice which express a Myosin 5a splicing defect and in control mice expressing the wild-type Myosin 5a allele. Functional differences in contractile responses to intramural nerve stimulation were examined by ex vivo isometric tension analysis. Data demonstrated Myosin 5a localized in cholinergic nerve fibers in the bladder and identified several Myosin 5a splice variants in the detrusor. Full-length Myosin 5a transcripts were less abundant and the expression of splice variants was altered in DBA bladders compared to control bladders. Moreover, attenuation of neurally-mediated contractile responses in DBA bladders compared to control bladders indicates that Myosin 5a facilitates excitatory neurotransmission in the bladder. Therefore, the array of Myosin 5a splice variants expressed, and the abundance of each, may be critical parameters for efficient synaptic vesicle transport and neurotransmission in the urinary bladder.
Strigolactones and Cytokinin Interaction in Buds in the Control of Rice Tillering
Authors: Zha Manrong , Zhao Yanhui , Wang Yan , Chen Bingxian , Tan Zecheng
Published: July 2022

Shoot branching is among the most crucial morphological traits in rice (Oryza sativa L.) and is physiologically modulated by auxins, cytokinins (CKs), and strigolactones (SLs) cumulatively in rice. A number of studies focused on the interplay of these three hormones in regulating rice tiller extension. The present study primarily aimed at determining the impact of different treatments, which were used to regulate rice tiller and axillary bud development on node 2 at the tillering stage and full heading stage, respectively. Transcription levels of several genes were quantified through qRT-PCR analysis, and an endogenous auxin and four types of CKs were determined through LC-MS/MS. Both nutrient deficiency and exogenous SL supply were found to inhibit rice tiller outgrowth by reducing the CK content in the tiller buds. Furthermore, supplying the inhibitor of both exogenous SLs and endogenous SL synthesis could also affect the expression level of OsCKX genes but not the OsIPT genes. Comparison of OsCKX gene expression pattern under exogenous SL and CK supply suggested that the induction of OsCKX expression was most likely via a CK-induced independent pathway. These results combined with the expression of CK type-A RR genes in bud support a role for SLs in regulating bud outgrowth through the regulation of local CK levels. SL functioned antagonistically with CK in regulating the outgrowth of buds on node 2, by promoting the OsCKX gene expression in buds.