bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances of Degradation Technologies Based on PROTAC Mechanism
Authors: Xiao Mingchao , Zhao Jiaojiao , Wang Qiang , Liu Jia , Ma Leina
Published: September 2022

PROTAC (proteolysis-targeting chimeras), which selectively degrades target proteins, has become the most popular technology for drug development in recent years. Here, we introduce the history of PROTAC, and summarize the recent advances in novel types of degradation technologies based on the PROTAC mechanism, including TF-PROTAC, Light-controllable PROTAC, PhosphoTAC, LYTAC, AUTAC, ATTEC, CMA, RNA-PROTAC and RIBOTACs. In addition, the clinical progress, current challenges and future prospects of degradation technologies based on PROTAC mechanism are discussed.
Public Transcriptomic Data Meta-Analysis Demonstrates TAAR6 Expression in the Mental Disorder-Related Brain Areas in Human and Mouse Brain
Authors: Vaganova Anastasia N. , Katolikova Nataliia V. , Murtazina Ramilya Z. , Kuvarzin Savelii R. , Gainetdinov Raul R.
Published: September 2022

G protein-coupled trace amine-associated receptors (TAAR) recognize different classes of amine compounds, including trace amines or other exogenous and endogenous molecules. Yet, most members of the TAAR family (TAAR2-TAAR9) are considered olfactory receptors involved in sensing innate odors. In this study, TAAR6 mRNA expression was evaluated in the brain transcriptomic datasets available in the GEO, Allen Brain Atlas, and GTEx databases. Transcriptomic data analysis demonstrated ubiquitous weak TAAR6 mRNA expression in the brain, especially in the prefrontal cortex and nucleus accumbens. RNA sequencing of isolated cells from the nucleus accumbens showed that the expression of TAAR6 in some cell populations may be more pronounced than in whole-tissue samples. Curiously, in D1 and D2 dopamine receptor-expressing medium spiny GABAergic neurons of the nucleus accumbens, TAAR6 expression was co-regulated with genes involved in G protein-coupled receptor signaling. However, in cholinergic interneurons of the nucleus accumbens, TAAR6 expression was not associated with the activation of any specific biological process. Finally, TAAR6 expression in the mouse prefrontal cortex was validated experimentally by RT-PCR analysis. These data demonstrated that TAAR6 is expressed at low levels in the human and mouse brain, particularly in limbic structures involved in the pathogenesis of mental disorders, and thus might represent a new pharmacotherapeutic target.
High Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Are Associated with a Higher Risk of Hemodialysis Vascular Access Failure
Authors: Pasqui Edoardo , de Donato Gianmarco , Lazzeri Elisa , Molino Cecilia , Galzerano Giuseppe , Giubbolini Michele , Palasciano Giancarlo
Published: September 2022

Our aim was to determine the predictive role of the preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in vascular access malfunctioning in patients who had undergone their first native arterio-venous fistula (AVF) for hemodialysis. Methods: This was a single-center retrospective observational study. All patients who underwent the procedure of the creation of a first native AVF for hemodialysis from January 2019 to December 2020 were considered eligible to be part of this study. Reinterventions for AVF malfunctioning were registered and the population was subdivided into two groups with respect to AVF malfunctioning. ROC curves were obtained to find the appropriate cut-off values for the NLR and PLR. A multivariate analysis was used to identify the independent predictors for an AVF malfunction. Kaplan–Meier curves were used to evaluate the AVF patency rates. A total of 178 patients were enrolled in the study, of them 70% (n = 121) were male. The mean age was 67.5 ± 12 years. Reinterventions for AVF malfunctioning were performed on 102 patients (57.3%). An NLR > 4.21 and a PLR > 208.8 was selected as the cut-off for AVF malfunctioning. The study population was divided into two groups depending on the NLR and PLR values of the individual. For the NLR < 4.21 group, the AVF patency rates were 90.7%, 85.3%, and 84% at the 3-, 6-, and 12-month follow-up, respectively, and 77.5%, 65.8%, and 39.3% at 3, 6, and 12 months for the NLR > 4.21 group, respectively (p < 0.0001). For the PLR < 208.8 group, the patency rates were 85.6%, 76.7%, and 67.7% at the 3-, 6-, and 12-month follow-up. For the PLR > 208.28 group, the patency rates were 80.8%, 71.2%, and 50.7% for the 3-, 6-, and 12-month follow-up, respectively (p = 0.014). The multivariate analysis highlighted that diabetes mellitus, the neutrophil count, the lymphocyte count, and the NLR were independent risk factors for an AVF failure. In our experience, the NLR and PLR are useful markers for the stratification of vascular access failure in hemodialysis patients. The inexpensive nature and ready availability of the values of these biomarkers are two points of strength for everyday clinical practice.
Stimulated Parotid Saliva Is a Better Method for Depression Prediction
Authors: Cui Yangyang , Zhang Hankun , Wang Song , Lu Junzhe , He Jinmei , Liu Lanlan , Liu Weiqiang
Published: September 2022

Background: Saliva cortisol is considered to be a biomarker of depression prediction. However, saliva collection methods can affect the saliva cortisol level. Objective: This study aims to determine the ideal saliva collection method and explore the application value of saliva cortisol in depression prediction. Methods: 30 depressed patients and 30 healthy controls were instructed to collect saliva samples in the morning with six collection methods. Simultaneous venous blood was collected. Enzyme-linked immunosorbent assay was used to determine the cortisol level. The 24-observerrated Hamilton depression rating scale (HAMD-24) was used to assess the severity of depression. Results: The significant differences in saliva cortisol levels depend on the saliva collection methods. The level of unstimulated whole saliva cortisol was most correlated with blood (r = 0.91). The stimulated parotid saliva cortisol can better predict depression. The area under the curve was 0.89. In addition, the saliva cortisol level of the depression patients was significantly higher than the healthy controls. The correlation between the cortisol level and the HAMD-24 score was highly significant. The higher the saliva cortisol level, the higher the HAMD-24 score. Conclusions: All the above findings point to an exciting opportunity for non-invasive monitoring of cortisol through saliva.
Relationship between Maternal Fever and Neonatal Sepsis: A Retrospective Study at a Medical Center
Authors: Huang Sheng-Hua , Chang Yu-Jun , Chen Lih-Ju , Lee Cheng-Han , Chen Hsiao-Neng , Chen Jia-Yuh , Hsiao Chien-Chou
Published: September 2022

Various risk factors are associated with neonatal sepsis; however, its relationship to maternal postpartum fever is unknown. This study aimed to determine the relationship between maternal postpartum fever and neonatal sepsis. Full-term and late preterm stable infants born from January 2019 to June 2021 and whose mothers developed intra- or post-partum fever were included in the study. After the newborns were transferred to the nursery, laboratory assessments were performed. Based on clinical conditions and data, the newborns were divided into unlikely sepsis and probable/proven sepsis groups. Maternal fever onset, duration, and maximum body temperature were recorded. We included 1059 newborns whose mothers developed fever intra-partum (n = 192), post-partum (n = 844), and intra- and post-partum (n = 23). The newborns were grouped into those with unlikely sepsis (n = 550) and those with probable/proven sepsis (n = 509). The incidence of intrapartum fever was higher in the probable/proven sepsis group than in the unlikely sepsis group (27.9% vs. 13.3%, p < 0.001). The incidence of postpartum fever was lower in the probable/proven sepsis group than in the unlikely sepsis group (74.7% vs. 88.5%, p < 0.001). Development of maternal fever within 1.8 h postpartum and a newborn respiratory rate of >60 breaths/min were positive predictors (91.6%) for neonatal probable/proven sepsis.
Investigating the Role of Circulating miRNAs as Biomarkers in Colorectal Cancer: An Epidemiological Systematic Review
Authors: Dansero Lucia , Ricceri Fulvio , De Marco Laura , Fiano Valentina , Nesi Ginevra , Padroni Lisa , Milani Lorenzo , Caini Saverio , Masala Giovanna , Agnoli Claudia , Sacerdote Carlotta
Published: September 2022

Colorectal cancer (CRC) is one of the most common cancers worldwide. Primary and secondary preventions are key to reducing the global burden. MicroRNAs (miRNAs) are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and to be related to cancer risk factors, such as obesity and inflammation. We conducted a systematic review and meta-analysis to identify circulating miRNAs related to CRC diagnosis that could be selected as biomarkers in a meet-in-the-middle analysis. Forty-four studies were included in the systematic review and nine studies in the meta-analysis. The pooled sensitivity and specificity of miR-21 for CRC diagnosis were 77% (95% CI: 69–84) and 82% (95% CI: 70–90), respectively, with an AUC of 0.86 (95% CI: 0.82–0.88). Several miRNAs were found to be dysregulated, distinguishing patients with CRC from healthy controls. However, little consistency was present across the included studies, making it challenging to identify specific miRNAs, which were consistently validated. Understanding the mechanisms by which miRNAs become biologically embedded in cancer initiation and promotion may help better understand cancer pathways to develop more effective prevention strategies and therapy approaches.
Disparate Roles of Oxidative Stress in Rostral Ventrolateral Medulla in Age-Dependent Susceptibility to Hypertension Induced by Systemic l-NAME Treatment in Rats
Authors: Chao Yung-Mei , Rauchová Hana , Chan Julie Y. H.
Published: September 2022

This study aims to investigate whether tissue oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, plays an active role in age-dependent susceptibility to hypertension in response to nitric oxide (NO) deficiency induced by systemic l-NAME treatment, and to decipher the underlying molecular mechanisms. Systolic blood pressure (SBP) and heart rate (HR) in conscious rats were recorded, along with measurements of plasma and RVLM level of NO and reactive oxygen species (ROS), and expression of mRNA and protein involved in ROS production and clearance, in both young and adult rats subjected to intraperitoneal (i.p.) infusion of l-NAME. Pharmacological treatments were administered by oral gavage or intracisternal infusion. Gene silencing of target mRNA was made by bilateral microinjection into RVLM of lentivirus that encodes a short hairpin RNA (shRNA) to knock down gene expression of NADPH oxidase activator 1 (Noxa1). We found that i.p. infusion of l-NAME resulted in increases in SBP, sympathetic neurogenic vasomotor activity, and plasma norepinephrine levels in an age-dependent manner. Systemic l-NAME also evoked oxidative stress in RVLM of adult, but not young rats, accompanied by augmented enzyme activity of NADPH oxidase and reduced mitochondrial electron transport enzyme activities. Treatment with L-arginine via oral gavage or infusion into the cistern magna (i.c.), but not i.c. tempol or mitoQ10, significantly offset the l-NAME-induced hypertension in young rats. On the other hand, all treatments appreciably reduced l-NAME-induced hypertension in adult rats. The mRNA microarray analysis revealed that four genes involved in ROS production and clearance were differentially expressed in RVLM in an age-related manner. Of them, Noxa1, and GPx2 were upregulated and Duox2 and Ucp3 were downregulated. Systemic l-NAME treatment caused greater upregulation of Noxa1, but not Ucp3, mRNA expression in RVLM of adult rats. Gene silencing of Noxa1 in RVLM effectively alleviated oxidative stress and protected adult rats against l-NAME-induced hypertension. These data together suggest that hypertension induced by systemic l-NAME treatment in young rats is mediated primarily by NO deficiency that occurs both in vascular smooth muscle cells and RVLM. On the other hand, enhanced augmentation of oxidative stress in RVLM may contribute to the heightened susceptibility of adult rats to hypertension induced by systemic l-NAME treatment.
Sixteen-Year Follow-Up in a Cavernous Sinus Hemangiopericytoma: Improved Outcomes over Radiotherapy Advances
Authors: Detti Beatrice , Bardoscia Lilia , Pisani Antonio Rosario , Cozzi Salvatore , Roghi Manuele , Mammucci Paolo , Sardaro Angela
Published: September 2022

Intracranial hemangiopericytomas are rare tumors, accounting for 1% of all central nervous system malignancies. This tumor is considered at high risk of local and also distant metastases. Surgical excision is the gold standard for treatment, but it is seldom curative by itself. Adjuvant radiotherapy is often recommended. We report an overview and update of the available literature on one such rare but aggressive mesenchymal tumor, using the case of a 46-year-old woman affected by hemangiopericytoma of the cavernous sinus surgically removed and treated with adjuvant radiotherapy at our institution. After seven years, the patient underwent a local recurrence and was treated with exeresis and Gamma Knife radiotherapy. Sixteen years after the initial diagnosis, she is still well with stable disease.
Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery
Authors: van der Noord Vera E. , van de Water Bob , Le Dévédec Sylvia E.
Published: September 2022

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC.
NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer
Authors: Goričar Katja , Dugar Franja , Dolžan Vita , Marinko Tanja
Published: September 2022

Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01–0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63–61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28–67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01–0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01–0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22–28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61–73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.
Association of Sentinel Node Biopsy and Pathological Report Completeness with Survival Benefit for Cutaneous Melanoma and Factors Influencing Their Different Uses in European Populations
Authors: Sant Milena , Magri Maria Chiara , Maurichi Andrea , Lillini Roberto , Bento Maria José , Ardanaz Eva , Guevara Marcela , Innos Kaire , Marcos-Gragera Rafael , Rubio-Casadevall Jordi , Sánchez Pérez Maria-José , Tumino Rosario , Rugge Massimo , Minicozzi Pamela ,   the Melanoma HR Study Working Group
Published: September 2022

Objectives: Standard care for cutaneous melanoma includes an accurate pathology report (PR) and sentinel lymph node biopsy (SLNB) for staging clinically node-negative >1 mm melanomas. We aimed to investigate the frequency of these indicators across European countries, also assessing consequences for survival. Methods: We analyzed 4245 melanoma cases diagnosed in six European countries in 2009–2013. Multivariable logistic regression was used to estimate the Odds Ratio (OR) of receiving complete PR with eight items or SLNB and model-based survival to estimate the five-year relative excess risks of death (RER). Results: Overall, 12% patients received a complete PR (range 2.3%, Estonia—20.1%, Italy); SLNB was performed for 68.8% of those with cN0cM0 stage (range 54.4%, Spain—81.7%, Portugal). The adjusted OR of receiving a complete PR was lower than the mean in Estonia (OR 0.11 (0.06–0.18)) and higher in Italy (OR 6.39 (4.90–8.34)) and Portugal (OR 1.39 (1.02–1.89)); it was higher for patients operated on in specialized than general hospitals (OR 1.42 (1.08–1.42)). In the multivariate models adjusted for age, sex, country and clinical-pathological characteristics, the RER resulted in being higher than the reference for patients not receiving a complete PR with eight items (RER 1.72 (1.08–2.72)), or for those not undergoing SLNB (RER 1.76 (1.26–2.47)) Patients with non-metastatic node-negative thickness >1 mm melanoma who did not undergo SLNB had a higher risk of death (RER (RER 1.69 (1.02–2.80)) than those who did. Conclusions: Accurate pathology profiling and SLNB carried survival benefit. Narrowing down between-countries differences in adhesion to guidelines might achieve better outcomes.
Moderately Prolonged QTc in Computer-Assessed ECG, Random Variation or Significant Risk Factor? A Literature Review
Authors: Hysing Jan , Gibbs Charlotte , Holla Øystein Lunde , Thalamus Jacob , Haugaa Kristina H.
Published: September 2022

Most ECGs in European hospitals are recorded with equipment giving computer measured intervals and interpretation of the recording. In addition to measurements of interval and QRS axis, this interpretation frequently provides the Bazett’s-corrected QTc time. The introduction of computer-corrected QTc revealed QTc prolongation to be a frequent condition among medical patients. Nevertheless, the finding is frequently overlooked by the treating physician. The authors combine experience from a local hospital with a review of the current literature in this field in order to elucidate the importance of this risk factor both as congenital long QT syndrome and as acquired QT prolongation.
Levels and Modifications of Both Lens Fiber Cell Connexins Are Affected in Connexin Mutant Mice
Authors: Jara Oscar , Minogue Peter J. , Berthoud Viviana M. , Beyer Eric C.
Published: September 2022

In the lens, cell homeostasis and transparency are supported by intercellular communication facilitated by the channels formed of connexin46 (Cx46) and connexin50 (Cx50). Mutations of these connexins are linked to inherited cataracts. We studied the levels and the variations in electrophoretic mobilities of the immunoreactive Cx46 and Cx50 bands between 1 and 21 days after birth in the lenses of wild-type mice and homozygous animals from two different mouse models of connexin-linked cataracts (Cx46fs380 and Cx50D47A). In Cx50D47A mice, the expression of the mutant Cx50 reduced the normal phosphorylation of the co-expressed wild-type Cx46. In both models, levels of the mutant connexin and the co-expressed wild-type connexin decayed more rapidly than in wild-type mice but with different time courses. In the Cx46fs380 mice, modeling suggested that Cx50 degradation could be explained by the mixing of mutant Cx46 with wild-type Cx50. However, in Cx50D47A mice, similar modeling suggested that mixing alone could not explain the decrease in Cx46 levels. These data highlight the complex influences between two connexin proteins expressed in the same cell, some of which occur through direct mixing, while others occur indirectly, as in Cx50D47A mice, where the expression of the mutant connexin causes endoplasmic reticulum stress and impaired differentiation.
SPHK/HIF-1α Signaling Pathway Has a Critical Role in Chrysin-Induced Anticancer Activity in Hypoxia-Induced PC-3 Cells
Authors: Han Hengmin , Lee Seon-Ok , Xu Yinzhu , Kim Jung-Eun , Lee Hyo-Jeong
Published: September 2022

Hypoxia, a typical feature of locally advanced solid tumors including prostate cancer, is a critical contributor to tumor progression and causes resistance to therapy. In this study, we investigated the effects of chrysin on tumor progression in hypoxic PC-3 cells. Chrysin exerted a significant inhibitory effect on 3D cell growth under normoxic and hypoxic conditions. It also decreased the hypoxia-induced vasculogenic mimicry and attenuated the expression of HIF-1α and VE-cadherin. Chrysin inhibited HIF-1α accumulation in a concentration- and time-dependent manner in hypoxic PC-3 cells, while also suppressing the expression of HIF-1α by inhibiting SPHK-1 in both CoCl2 and hypoxic PC-3 cells. At high concentrations of chrysin, there was a greater increase in apoptosis in the hypoxic cells compared to that in normoxic cells, which was accompanied by sub-G1 phase arrest. Chrysin-induced apoptosis inhibited VEGF and Bcl-2 and induced the cleavage of PARP and caspase-3. SPHK-1 knockdown induced apoptosis and inhibited epithelial–mesenchymal transition. Consistent with the in vitro data, 50 mg/kg of chrysin suppressed the tumor growth of PC-3 xenografts by 80.4% compared to that in the untreated control group. The immunohistochemistry of tumor tissues revealed decreased Ki-67, HIF-1α, and VEGF expression in the chrysin-treated group compared to an untreated control. Western blotting data for tumor tissues showed that chrysin treatment decreased SPHK-1, HIF-1α, and PARP expression while inducing caspase-3 cleavage. Overall, our findings suggest that chrysin exerts anti-tumor activity by inhibiting SPHK-1/HIF-1α signaling and thus represents a potent chemotherapeutic agent for hypoxia, which promotes cancer progression and is related to poor prognoses in prostate cancer patients.
Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats
Authors: Chamera Katarzyna , Curzytek Katarzyna , Kamińska Kinga , Trojan Ewa , Basta-Kaim Agnieszka
Published: September 2022

The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.
Demand Coupling Drives Neurodegeneration: A Model of Age-Related Cognitive Decline and Dementia
Authors: Turknett Josh , Wood Thomas R.
Published: September 2022

The societal burden of Alzheimer’s Disease (AD) and other major forms of dementia continues to grow, and multiple pharmacological agents directed towards modifying the pathological “hallmarks” of AD have yielded disappointing results. Though efforts continue towards broadening and deepening our knowledge and understanding of the mechanistic and neuropathological underpinnings of AD, our previous failures motivate a re-examination of how we conceptualize AD pathology and progression. In addition to not yielding effective treatments, the phenotypically heterogeneous biological processes that have been the primary area of focus to date have not been adequately shown to be necessary or sufficient to explain the risk and progression of AD. On the other hand, a growing body of evidence indicates that lifestyle and environment represent the ultimate level of causation for AD and age-related cognitive decline. Specifically, the decline in cognitive demands over the lifespan plays a central role in driving the structural and functional deteriorations of the brain. In the absence of adequate cognitive stimulus, physiological demand–function coupling leads to downregulation of growth, repair, and homeostatic processes, resulting in deteriorating brain tissue health, function, and capacity. In this setting, the heterogeneity of associated neuropathological tissue hallmarks then occurs as a consequence of an individual’s genetic and environmental background and are best considered downstream markers of the disease process rather than specific targets for direct intervention. In this manuscript we outline the evidence for a demand-driven model of age-related cognitive decline and dementia and why it mandates a holistic approach to dementia treatment and prevention that incorporates the primary upstream role of cognitive demand.
Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-β1-Dependent Mechanism
Authors: Bouchet Clément , Cardouat Guillaume , Douard Matthieu , Coste Florence , Robillard Paul , Delcambre Frédéric , Ducret Thomas , Quignard Jean-François , Vacher Pierre , Baudrimont Isabelle , Marthan Roger , Berger Patrick , Guibert Christelle , Freund-Michel Véronique
Published: September 2022

Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-β1 (TGF-β1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1β (IL-1β) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). TβRI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-β1 blockade (anti-TGF-β1 siRNA, TGF-β1 blocking antibodies, TβRI kinase, p38 or Smad3 inhibitors). TβRI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1β significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-β1 expression, binding to TβRI, TβRI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-β1 secretion by hPASMC and hPAEC. TGF-β1 may then act as an autocrine factor on these cells, increasing NGF secretion via TβRI activation. Since NGF and TGF-β1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.
Micropatterned Neurovascular Interface to Mimic the Blood–Brain Barrier’s Neurophysiology and Micromechanical Function: A BBB-on-CHIP Model
Authors: Singh Ajay Vikram , Chandrasekar Vaisali , Laux Peter , Luch Andreas , Dakua Sarada Prasad , Zamboni Paolo , Shelar Amruta , Yang Yin , Pandit Vaibhav , Tisato Veronica , Gemmati Donato
Published: September 2022

A hybrid blood–brain barrier (BBB)-on-chip cell culture device is proposed in this study by integrating microcontact printing and perfusion co-culture to facilitate the study of BBB function under high biological fidelity. This is achieved by crosslinking brain extracellular matrix (ECM) proteins to the transwell membrane at the luminal surface and adapting inlet–outlet perfusion on the porous transwell wall. While investigating the anatomical hallmarks of the BBB, tight junction proteins revealed tortuous zonula occludens (ZO-1), and claudin expressions with increased interdigitation in the presence of astrocytes were recorded. Enhanced adherent junctions were also observed. This junctional phenotype reflects in-vivo-like features related to the jamming of cell borders to prevent paracellular transport. Biochemical regulation of BBB function by astrocytes was noted by the transient intracellular calcium effluxes induced into endothelial cells. Geometry-force control of astrocyte–endothelial cell interactions was studied utilizing traction force microscopy (TFM) with fluorescent beads incorporated into a micropatterned polyacrylamide gel (PAG). We observed the directionality and enhanced magnitude in the traction forces in the presence of astrocytes. In the future, we envisage studying transendothelial electrical resistance (TEER) and the effect of chemomechanical stimulations on drug/ligand permeability and transport. The BBB-on-chip model presented in this proposal should serve as an in vitro surrogate to recapitulate the complexities of the native BBB cellular milieus.
Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy
Authors: Miao Ya-Ru , Liu Chun-Jie , Hu Hui , Yang Mei , Guo An-Yuan
Published: September 2022

Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74–0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research.
MicroRNAs Mediated Plant Responses to Salt Stress
Authors: Islam Waqar , Waheed Abdul , Naveed Hassan , Zeng Fanjiang
Published: September 2022

One of the most damaging issues to cultivatable land is soil salinity. While salt stress influences plant growth and yields at low to moderate levels, severe salt stress is harmful to plant growth. Mineral shortages and toxicities frequently exacerbate the problem of salinity. The growth of many plants is quantitatively reduced by various levels of salt stress depending on the stage of development and duration of stress. Plants have developed various mechanisms to withstand salt stress. One of the key strategies is the utilization of microRNAs (miRNAs) that can influence gene regulation at the post-transcriptional stage under different environmental conditions, including salinity. Here, we have reviewed the miRNA-mediated adaptations of various plant species to salt stress and other abiotic variables. Moreover, salt responsive (SR)-miRNAs, their targets, and corresponding pathways have also been discussed. The review article concludes by suggesting that the utilization of miRNAs may be a vital strategy to generate salt tolerant crops ensuring food security in the future.
Synthesis, Characterization of Magnetic Composites and Testing of Their Activity in Liquid-Phase Oxidation of Phenol with Oxygen
Authors: Dossumova Binara T. , Shakiyeva Tatyana V. , Muktaly Dinara , Sassykova Larissa R. , Baizhomartov Bedelzhan B. , Subramanian Sendilvelan
Published: September 2022

The development and improvement of methods for the synthesis of environmentally friendly catalysts based on base metals is currently an urgent and promising task of modern catalysis. Catalysts based on nanoscale magnetite and maghemite have fast adsorption–desorption kinetics and high chemical activity. The purpose of this work is to obtain magnetic composites, determine their physicochemical characteristics and verify their activity in the process of liquid-phase oxidation of phenol with oxygen. Magnetic nanocomposites were obtained by chemical co-deposition of salts of ferrous and trivalent iron. The synthesized magnetic composites were studied by X-ray diffractometry, energy dispersive X-ray fluorescence and Mössbauer spectroscopy, IR-Fourier spectroscopy and elemental analysis. To increase the catalytic activity in oxidative processes, the magnetite surfaces were modified using cobalt nitrate salt. Further, CoFe2O4 was stabilized by adding polyethylenimine (PEI) as a surfactant. Preliminary studies of the oxidation of phenol with oxygen, as the most typical environmental pollutant were carried out on the obtained Fe3O4, CoFe2O4, CoFe2O4/PEI catalysts. The spectrum of the reaction product shows the presence of CH in the aromatic ring and double C=C bonds, stretching vibrations of the C=O groups of carbonyl compounds; the band at 3059 cm−1 corresponds to the presence of double C=C bonds and the band at 3424 cm−1 to hydroquinone compounds. The band at 1678 cm−1 and the intense band at 1646 cm−1 refer to vibrations of the C=O bonds of the carbonyl group of benzoquinone. Peaks at 1366 cm−1 and 1310 cm−1 can be related to the vibrations of C–H and C–C bonds of the quinone ring. Thus, it was demonstrated that produced magnetic composites based on iron oxide are quite effective in the oxidation of phenol with oxygen.
Enhancing the Photocatalytic Activity of TiO2/Na2Ti6O13 Composites by Gold for the Photodegradation of Phenol
Authors: Permana Muhamad Diki , Noviyanti Atiek Rostika , Lestari Putri Rizka , Kumada Nobuhiro , Eddy Diana Rakhmawaty , Rahayu Iman
Published: September 2022

This study aims to synthesize Au/TiO2/Na2Ti6O13 composites to reduce the occurrence of recombination and increase photocatalytic activity in phenol degradation. Gold was used due to its high stability and strong surface plasmon resonance (SPR) properties which make it operate effectively in the visible light spectrum. The prepared composites were characterized using XRD, SEM, TEM, FTIR, and DRS. The results showed that the composite consisted of rutile TiO2 with a crystal size of 38–40 nm and Na2Ti6O13 with a crystal size of 25 nm. The gold in the composite has a crystallite size of 16–19 nm along with the percentage of gold added. Morphological analysis shows that the composite has the form of inhomogeneous spherical particles with gold spread among composites with sizes less than 20 nm. FTIR analysis showed the presence of Na–O and Ti–O–Ti bonds in the composite. The best composite was 3% Au/TiO2/Na2Ti6O13 which had high crystallinity, small particle size, and bandgap energy of 2.59 eV. Furthermore, it had an efficiency 205% better than without gold. After that, cost estimation is proposed as a large-scale application. This study describes the total cost, break-even analysis, and payback analysis for the commercialization needs of the designed photocatalytic catalyst.
Audiological Risk Factors, Referral Rates and Dropouts: 9 Years of Universal Newborn Hearing Screening in North Sardinia
Authors: De Luca Laura Maria , Malesci Rita , Gallus Roberto , Melis Andrea , Palmas Sara , Degni Emilia , Crescio Claudia , Piras Maria Lucia , Arca Sedda Maria Francesca , Canu Giovanna Maria , Rizzo Davide , Olzai Mauro Giorgio , Dessole Salvatore , Sotgiu Giovanni , Fetoni Anna Rita , Bussu Francesco
Published: September 2022

Background: Objectives of the present work were to analyze the prevalence of hearing loss in our population of screened newborns during the first 9 years of the universal newborn hearing screening (UNHS) program at University Hospital Sassari (Italy) (AOU Sassari), to analyze the risk factors involved, and to analyze our effectiveness in terms of referral rates and dropout rates. Methods: Monocentric retrospective study whose target population included all the newborns born or referred to our hospital between 2011 and 2019. Results: From 2011 to 2019, a total of 11,688 babies were enrolled in our screening program. In total, 3.9‰ of wellborn babies and 3.58% of neonatal intensive care unit (NICU) babies had some degree of hearing loss. The most frequently observed risk factors among non-NICU babies were family history of hearing loss (3.34%) and craniofacial anomalies (0.16%), among NICU babies were low birth weight (54.91%) and prematurity (24.33%). In the multivariate analysis, family history of hearing loss (p < 0.001), NICU (p < 0.001), craniofacial anomalies (p < 0.001), low birth weight (<1500 g) (p = 0.04) and HIV (p = 0.03) were confirmed as risk factors. Conclusions: Our data are largely consistent with the literature and most results were expected, one relevant exception being the possible role of NICU as a confounding factor and the limited number of risk factors confirmed in the multivariate analysis.
Circular Water Economy in the EU: Findings from Demonstrator Projects
Authors: Qtaishat Yahya , Hofman Jan , Adeyeye Kemi
Published: September 2022

Circular economy (CE) for water aims to maximise value derived from water, processes, and practices. As a result, the recovery of wastewater and renewable water resources is used to offset the exploitation and impact of abstracting new water resources. New regulations such as the new circular economy action plan by the European Commission are emerging to promote circularity within the Green Deal agenda. However, there is still a need for research and practical insights into the interaction and integration of CE for water within existing policies and regulations, and its practical application specifically at the project level. This paper presents findings from demonstrator cases used to explore the opportunities and constraints in the policy, process, and procedural frameworks that govern water circularity in important sectors in Europe. Desk reviews are used to examine and compare European legislation against national and regional legislative frameworks within the different member states. Interviews and demonstrator project feedback enabled the exploration of the policy and value constraints at the project level. The findings provide unique insights into the policy and legislative enablers for and barriers to implementing CE for water in key sectors and specifically at the project level. The paper concludes with a five-point route map for new and revised policies and regulations targeting improved uptake of circular water technologies in Europe.
Emerging Nanocomposite and Nanoarchitectonic Coatings for Biomedical Engineering
Authors: Liu Yang
Published: September 2022

Anti-bacterial, low-friction, superhydrophobic, and hydrophilic coatings are widely demanded in biomedical engineering for non-implantable and implantable devices, such as surgical tools, tubes, wires, rubber seals, and stents [...]
Capturing the Complexity of COVID-19 Research: Trend Analysis in the First Two Years of the Pandemic Using a Bayesian Probabilistic Model and Machine Learning Tools
Authors: De La Hoz-M Javier , Mendes Susana , Fernández-Gómez María José , González Silva Yolanda
Published: September 2022

Publications about COVID-19 have occurred practically since the first outbreak. Therefore, studying the evolution of the scientific publications on COVID-19 can provide us with information on current research trends and can help researchers and policymakers to form a structured view of the existing evidence base of COVID-19 and provide new research directions. This growth rate was so impressive that the need for updated information and research tools become essential to mitigate the spread of the virus. Therefore, traditional bibliographic research procedures, such as systematic reviews and meta-analyses, become time-consuming and limited in focus. This study aims to study the scientific literature on COVID-19 that has been published since its inception and to map the evolution of research in the time range between February 2020 and January 2022. The search was carried out in PubMed extracting topics using text mining and latent Dirichlet allocation modeling and a trend analysis was performed to analyze the temporal variations in research for each topic. We also study the distribution of these topics between countries and journals. 126,334 peer-reviewed articles and 16 research topics were identified. The countries with the highest number of scientific publications were the United States of America, China, Italy, United Kingdom, and India, respectively. Regarding the distribution of the number of publications by journal, we found that of the 7040 sources Int. J. Environ. Res. Public Health, PLoS ONE, and Sci. Rep., were the ones that led the publications on COVID-19. We discovered a growing tendency for eight topics (Prevention, Telemedicine, Vaccine immunity, Machine learning, Academic parameters, Risk factors and morbidity and mortality, Information synthesis methods, and Mental health), a falling trend for five of them (Epidemiology, COVID-19 pathology complications, Diagnostic test, Etiopathogenesis, and Political and health factors), and the rest varied throughout time with no discernible patterns (Therapeutics, Pharmacological and therapeutic target, and Repercussion health services).
Hybrid Organic-Inorganic Materials Used to Improve the Environment and Human Health
Authors: Raduly Florentina Monica , Fierăscu Radu Claudiu
Published: September 2022

The Special Issue on “Hybrid Organic-Inorganic Materials Used to Improve the Environment and Human Health” is a collection of 11 original articles (including one communication paper) dedicated to theoretical and experimental research works providing new insights and practical findings in the fields of the environmental protection and human health—related topics [...]
Synthesis and Magnetic Properties of Carbon Doped and Reduced SrTiO3 Nanoparticles
Authors: Makarova Marina V. , Prokhorov Andrey , Stupakov Alexander , Kopeček Jaromir , Drahokoupil Jan , Trepakov Vladimir , Dejneka Alexander
Published: September 2022

We report on the studies of the synthesis, structural, and magnetic properties of undoped SrTiO3 (STO), carbon-doped STO:C, and reduced STO STO:R nanoparticles. Fine (~20–30 nm) and coarse (~100 nm) nanoparticles with a single phase of cubic perovskite-type structure were sintered by thermal decomposition of SrTiO(C2O4)2. Magnetization loops of fine STO:C and STO:R nanoparticles at low temperatures and an almost linear decrease in magnetization with temperature indicate the realization of a soft, ferromagnetic state in them, with a pronounced disorder effect characteristic of doped dilute magnetic semiconductors. Oxidation and particle size increase suppress the magnetic manifestations, demonstrating the importance of surface-related defects and oxygen deficiency in the emergence of magnetism. It was found that oxygen vacancies and doping with carbon make similar contributions to the magnetization, while complementary electron paramagnetic resonance, together with magnetization measurement studies, show that the most probable state of oxygen vacancies, which determine the appearance of magnetic properties, are charged F+ oxygen vacancies and C-impurity centers, which tend to segregate on the surface of nanoparticles.
Practical Considerations for the Management of Cancer-Associated Venous Thromboembolism: A Guide for the General Oncology Practitioner
Authors: Harrigan Amye M. , Rioux Josée , Shivakumar Sudeep
Published: September 2022

Cancer-associated venous thromboembolism is a devastating complication of cancer and is associated with significant morbidity and mortality. The cornerstone of cancer-associated venous thromboembolism treatment is anticoagulation, and in recent years, there have been notable randomized clinical trials that have revealed insights into the efficacy and safety of direct oral anticoagulants and low-molecular-weight heparin in the treatment of cancer-associated thrombosis. Deciding on the ideal anticoagulation treatment plan for a patient with a cancer-associated thrombosis is a complex task that requires an understanding of clinical trial data, society guidelines, and, most importantly, consideration of many cancer-related, treatment-related, and patient-related factors. This article summarizes important factors to consider when deciding on anticoagulation therapy for a patient with cancer-associated thrombosis.
A Review of Current and Emerging Therapies for Advanced Hepatocellular Carcinoma
Authors: Singh Angelica , Zahid Sofia , Noginskiy Ilya , Pak Timothy , Usta Soeb , Barsoum Marina , Khan Uqba
Published: September 2022

Hepatocellular carcinoma remains a leading cause of cancer-related deaths worldwide. Liver disease including cirrhosis and viral hepatitis remains among the leading causes of hepatocellular carcinoma and despite increased screening, many patients are diagnosed in the advanced stages precluding them from locoregional therapy. Therapeutic agents for advanced hepatocellular carcinoma were limited to Sorafenib for several years; however, with the emergence of molecular targeted therapies including tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors, in addition to immunotherapies, the way hepatocellular carcinoma is treated has changed significantly. In this review, we summarize the key clinical trials that lead to the approval of these agents for systemic treatment of hepatocellular carcinoma and discuss the preferred sequence of treatment options as well as prospective studies for management of hepatocellular carcinoma.