bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging Detection Techniques for Large Vessel Occlusion Stroke: A Scoping Review
Authors: Nicholls Jennifer K. , Ince Jonathan , Minhas Jatinder S. , Chung Emma M. L.
Published: January 2022

Background: Large vessel occlusion (LVO) is the obstruction of large, proximal cerebral arteries and can account for up to 46% of acute ischaemic stroke (AIS) when both the A2 and P2 segments are included (from the anterior and posterior cerebral arteries). It is of paramount importance that LVO is promptly recognised to provide timely and effective acute stroke management. This review aims to scope recent literature to identify new emerging detection techniques for LVO. As a good comparator throughout this review, the commonly used National Institutes of Health Stroke Scale (NIHSS), at a cut-off of ≥11, has been reported to have a sensitivity of 86% and a specificity of 60% for LVO.

Methods: Four electronic databases (Medline via OVID, CINAHL, Scopus, and Web of Science), and grey literature using OpenGrey, were systematically searched for published literature investigating developments in detection methods for LVO, reported from 2015 to 2021. The protocol for the search was published with the Open Science Framework (10.17605/OSF.IO/A98KN). Two independent researchers screened the titles, abstracts, and full texts of the articles, assessing their eligibility for inclusion.

Results: The search identified 5,082 articles, in which 2,265 articles were screened to assess their eligibility. Sixty-two studies remained following full-text screening. LVO detection techniques were categorised into 5 groups: stroke scales (n = 30), imaging and physiological methods (n = 15), algorithmic and machine learning approaches (n = 9), physical symptoms (n = 5), and biomarkers (n = 3).

Conclusions: This scoping review has explored literature on novel and advancements in pre-existing detection methods for LVO. The results of this review highlight LVO detection techniques, such as stroke scales and biomarkers, with good sensitivity and specificity performance, whilst also showing advancements to support existing LVO confirmatory methods, such as neuroimaging.
Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature
Authors: Nanetti Lorenzo , Di Bella Daniela , Magri Stefania , Fichera Mario , Sarto Elisa , Castaldo Anna , Mongelli Alessia , Baratta Silvia , Fenu Silvia , Moscatelli Marco , Bonati Maria Teresa , Martinuzzi Andrea , Mariotti Caterina , Taroni Franco
Published: January 2022

A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon—Holmes, Boucher—Neuhauser, Oliver—Mc Farlane, and Laurence—Moon syndromes. These syndromes present variable and overlapping clinical symptoms, encompassing cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy, spastic paraplegia, muscle wasting, peripheral neuropathy, and cognitive impairment. In the present study, we performed a wide genetic screening in 292 patients presenting with ataxia or spastic paraplegia using a probe-based customized gene panel, covering >200 genes associated with spinocerebellar diseases. We identified six novel and four recurrent PNPLA6 gene variants in eight patients (2.7%). Six patients presented an infantile or juvenile onset (age <18), and two patients had an adult onset. Cerebellar ataxia was observed in seven patients and spastic paraplegia in one patient. Progression of cerebellar symptoms was slow in all patients, who retained ambulation even after a mean disease duration of 15 years. Brain MRI showed cerebellar atrophy in 6/8 patients, more pronounced in superior and dorsal vermis lobules (I to VII). Additional clinical features included hypogonadotropic hypogonadism (5/8), growth hormone deficiency (2/8), peripheral axonal neuropathy (4/8), cognitive impairment (3/8), chorioretinal dystrophy (2/8), and bilateral vestibular areflexia with a reduced visual vestibule-ocular reflex (1/8). In accordance with previous studies, chorioretinal dystrophy was the most frequent presenting symptom in early onset patients, hypogonadotropic hypogonadism in juvenile onset cases, and cerebellar ataxia in adult patients. One patient had an initial clinical presentation compatible with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), but no pathological expansions in the RFC1 gene. In conclusion, patients with PNPLA6 variants present a variable age of onset spanning from infancy to adulthood, and each clinical symptom has an age-dependent manifestation thus requiring a multi-systemic diagnostic approach. The description of patients presenting very late-onset cerebellar ataxia suggests that PNPLA6 genetic screening should also be considered in the diagnostic workout of adult cerebellar ataxia.
Worse Physical Disability Is Associated With the Expression of PD-1 on Inflammatory T-Cells in Multiple Sclerosis Patients With Older Appearing Brains
Authors: Jacobs Sophie A. H. , Muraro Paolo A. , Cencioni Maria T. , Knowles Sarah , Cole James H. , Nicholas Richard
Published: January 2022

Background: Magnetic Resonance Imaging (MRI) analysis method “brain-age” paradigm could offer an intuitive prognostic metric (brain-predicted age difference: brain-PAD) for disability in Multiple Sclerosis (MS), reflecting structural brain health adjusted for aging. Equally, cellular senescence has been reported in MS using T-cell biomarker CD8+CD57+.

Objective: Here we explored links between MRI-derived brain-age and blood-derived cellular senescence. We examined the value of combining brain-PAD with CD8+CD57+(ILT2+PD-1+) T-cells when predicting disability score in MS and considered whether age-related biological mechanisms drive disability.

Methods: Brain-age analysis was applied to T1-weighted MRI images. Disability was assessed and peripheral blood was examined for CD8+CD57+ T-cell phenotypes. Linear regression models were used, adjusted for sex, age and normalized brain volume.

Results: We included 179 mainly relapsing-remitting MS patients. A high brain-PAD was associated with high physical disability (mean brain-PAD = +6.54 [5.12–7.95]). CD8+CD57+(ILT2+PD-1+) T-cell frequency was neither associated with disability nor with brain-PAD. Physical disability was predicted by the interaction between brain-PAD and CD8+CD57+ILT2+PD-1+ T-cell frequency (AR2 = 0.196), yet without improvement compared to brain-PAD alone (AR2 = 0.206; AICc = 1.8).

Conclusion: Higher frequency of CD8+CD57+ILT2+PD-1+ T-cells in the peripheral blood in patients with an older appearing brain was associated with worse disability scores, suggesting a role of these cells in the development of disability in MS patients with poorer brain health.
Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence
Authors: Manini Arianna , Abati Elena , Nuredini Andi , Corti Stefania , Comi Giacomo Pietro
Published: January 2022

Duchenne muscular dystrophy (DMD) is an X-linked recessive, infancy-onset neuromuscular disorder characterized by progressive muscle weakness and atrophy, leading to delay of motor milestones, loss of autonomous ambulation, respiratory failure, cardiomyopathy, and premature death. DMD originates from mutations in the DMD gene that result in a complete absence of dystrophin. Dystrophin is a cytoskeletal protein which belongs to the dystrophin-associated protein complex, involved in cellular signaling and myofiber membrane stabilization. To date, the few available therapeutic options are aimed at lessening disease progression, but persistent loss of muscle tissue and function and premature death are unavoidable. In this scenario, one of the most promising therapeutic strategies for DMD is represented by adeno-associated virus (AAV)-mediated gene therapy. DMD gene therapy relies on the administration of exogenous micro-dystrophin, a miniature version of the dystrophin gene lacking unnecessary domains and encoding a truncated, but functional, dystrophin protein. Limited transgene persistence represents one of the most significant issues that jeopardize the translatability of DMD gene replacement strategies from the bench to the bedside. Here, we critically review preclinical and clinical studies of AAV-mediated gene therapy in DMD, focusing on long-term transgene persistence in transduced tissues, which can deeply affect effectiveness and sustainability of gene replacement in DMD. We also discuss the role played by the overactivation of the immune host system in limiting long-term expression of genetic material. In this perspective, further studies aimed at better elucidating the need for immune suppression in AAV-treated subjects are warranted in order to allow for life-long therapy in DMD patients.
Greater Social Competence Is Associated With Higher Interpersonal Neural Synchrony in Adolescents With Autism
Authors: Key Alexandra P. , Yan Yan , Metelko Mary , Chang Catie , Kang Hakmook , Pilkington Jennifer , Corbett Blythe A.
Published: January 2022

Difficulty engaging in reciprocal social interactions is a core characteristic of autism spectrum disorder. The mechanisms supporting effective dynamic real-time social exchanges are not yet well understood. This proof-of-concept hyperscanning electroencephalography study examined neural synchrony as the mechanism supporting interpersonal social interaction in 34 adolescents with autism spectrum disorder (50% female), age 10–16 years, paired with neurotypical confederates of similar age. The degree of brain-to-brain neural synchrony was quantified at temporo-parietal scalp locations as the circular correlation of oscillatory amplitudes in theta, alpha, and beta frequency bands while the participants engaged in a friendly conversation. In line with the hypotheses, interpersonal neural synchrony was significantly greater during the social interaction compared to the baseline. Lower levels of synchrony were associated with increased behavioral symptoms of social difficulties. With regard to sex differences, we found evidence for stronger interpersonal neural synchrony during conversation than baseline in females with autism, but not in male participants, for whom such condition differences did not reach statistical significance. This study established the feasibility of hyperscanning during real-time social interactions as an informative approach to examine social competence in autism, demonstrated that neural coordination of activity between the interacting brains may contribute to social behavior, and offered new insights into sex-related variability in social functioning in individuals with autism spectrum disorders.
Like/Dislike Prediction for Sport Shoes With Electroencephalography: An Application of Neuromarketing
Authors: Zeng Li , Lin Mengsi , Xiao Keyang , Wang Jigan , Zhou Hui
Published: January 2022

Neuromarketing is an emerging research field for prospective businesses on consumer’s preference. Consumer’s preference prediction based on electroencephalography (EEG) can reliably predict likes or dislikes of a product. However, the current EEG prediction and classification accuracy have yet to reach ideal level. In addition, it is still unclear how different brain region information and different features such as power spectral density, brain asymmetry, differential entropy, and Hjorth parameters affect the prediction accuracy. Our study shows that by taking footwear products as an example, the recognition accuracy of product likes or dislikes reaches 94.22%. Compared with other brain regions, the features of the frontal and occipital brain region obtained a higher prediction accuracy, but the fusion of the features of the whole brain region could improve the prediction accuracy of likes or dislikes even further. Future work would be done to correlate the EEG-based like or dislike prediction results with product sales and self-reports.
Trans ε-Viniferin Decreases Amyloid Deposits With Greater Efficiency Than Resveratrol in an Alzheimer’s Mouse Model
Authors: Freyssin Aline , Rioux Bilan Agnès , Fauconneau Bernard , Galineau Laurent , Serrière Sophie , Tauber Clovis , Perrin Flavie , Guillard Jérôme , Chalon Sylvie , Page Guylène
Published: January 2022

In a previous study, we showed that viniferin decreased amyloid deposits and reduced neuroinflammation in APPswePS1dE9 transgenic mice between 3 and 6 months of age. In the present study, wild type and APPswePS1dE9 transgenic mice were treated from 7 to 11 or from 3 to 12 months by a weekly intraperitoneal injection of either 20 mg/kg viniferin or resveratrol or their vehicle, the polyethylene glycol 200 (PEG 200). The cognitive status of the mice was evaluated by the Morris water maze test. Then, amyloid burden and neuroinflammation were quantified by western-blot, Enzyme-Linked ImmunoSorbent Assay (ELISA), immunofluorescence, and in vivo micro-Positon Emission Tomography (PET) imaging. Viniferin decreased hippocampal amyloid load and deposits with greater efficiency than resveratrol, and both treatments partially prevented the cognitive decline. Furthermore, a significant decrease in brain uptake of the TSPO PET tracer [18F]DPA-714 was observed with viniferin compared to resveratrol. Expression of GFAP, IBA1, and IL-1β were decreased by viniferin but PEG 200, which was very recently shown to be a neuroinflammatory inducer, masked the neuroprotective power of viniferin.
A Versatile Clustered Regularly Interspaced Palindromic Repeats Toolbox to Study Neurological CaV3.2 Channelopathies by Promoter-Mediated Transcription Control
Authors: Tsortouktzidis Despina , Tröscher Anna R. , Schulz Herbert , Opitz Thoralf , Schoch Susanne , Becker Albert J. , van Loo Karen M. J.
Published: January 2022

Precise genome editing in combination with viral delivery systems provides a valuable tool for neuroscience research. Traditionally, the role of genes in neuronal circuits has been addressed by overexpression or knock-out/knock-down systems. However, those techniques do not manipulate the endogenous loci and therefore have limitations. Those constraints include that many genes exhibit extensive alternative splicing, which can be regulated by neuronal activity. This complexity cannot be easily reproduced by overexpression of one protein variant. The CRISPR activation and interference/inhibition systems (CRISPRa/i) directed to promoter sequences can modulate the expression of selected target genes in a highly specific manner. This strategy could be particularly useful for the overexpression of large proteins and for alternatively spliced genes, e.g., for studying large ion channels known to be affected in ion channelopathies in a variety of neurological diseases. Here, we demonstrate the feasibility of a newly developed CRISPRa/i toolbox to manipulate the promoter activity of the Cacna1h gene. Impaired, function of the low-voltage-activated T-Type calcium channel CaV3.2 is involved in genetic/mutational as well as acquired/transcriptional channelopathies that emerge with epileptic seizures. We show CRISPR-induced activation and inhibition of the Cacna1h locus in NS20Y cells and primary cortical neurons, as well as activation in mouse organotypic slice cultures. In future applications, the system offers the intriguing perspective to study functional effects of gain-of-function or loss-of-function variations in the Cacna1h gene in more detail. A better understanding of CaV3.2 channelopathies might result in a major advancement in the pharmacotherapy of CaV3.2 channelopathy diseases.
Qualitative and Quantitative Analysis of Phenolic Compounds in Spray-Dried Olive Mill Wastewater
Authors: Benincasa Cinzia , Pellegrino Massimiliano , Romano Elvira , Claps Salvatore , Fallara Carmelo , Perri Enzo
Published: January 2022

The processing of olives for oil production generates the most abundant agro-industrial by-products in the Mediterranean area. The three-phase olive oil extraction process requires the addition of a large amount of water to the system, which is difficult to dispose of for its load of toxic pollutants. On the other hand, olive mill wastewater is a rich source of bioactive substances with various biological properties that can be used as ingredients in the food industry for obtaining functional and nutraceutical foods as well as in the pharmaceutical industry. In this study, we present the results relative to the phenolic compounds detected in dried olive mill wastewaters obtained using a spray dryer. Qualitative and quantitative analyses were obtained by high-pressure liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). In particular, the compounds here discussed are: apigenin (9.55 mg/kg dry weight), caffeic acid (2.89 mg/kg dry weight), catecol (6.12 mg/kg dry weight), p-cumaric acid (5.01 mg/kg dry weight), diosmetin (3.58 mg/kg dry weight), hydroxytyrosol (1.481 mg/kg dry weight), hydroxytyrosyl oleate (564 mg/kg dry weight), luteolin (62.38 mg/kg dry weight), luteolin-7-O-glucoside (88.55 mg/kg dry weight), luteolin-4-O-glucoside (11.48 mg/kg dry weight), oleuropein (103 mg/kg dry weight), rutin (48.52 mg/kg dry weight), tyrosol (2043 mg/kg dry weight), vanillin (27.70 mg/kg dry weight), and verbascoside (700 mg/kg dry weight). The results obtained highlighted that the use of dehumidified air as a drying medium, with the addition of maltodextrin, appears to be an effective way to produce a phenol-rich powder to be included in food formulations as well as in pharmaceutical preparations having different biological properties.
Advances in Drugs Targeting Lymphangiogenesis for Preventing Tumor Progression and Metastasis
Authors: Wang Chuqi , Chu Ming
Published: January 2022

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.
Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy
Authors: Ding Xiaoling , Sun Xinchen , Cai Huihui , Wu Lei , Liu Ying , Zhao Yu , Zhou Dingjingyu , Yu Guiping , Zhou Xiaorong
Published: January 2022

Macrophages play critical roles in tumor progression. In the tumor microenvironment, macrophages display highly diverse phenotypes and may perform antitumorigenic or protumorigenic functions in a context-dependent manner. Recent studies have shown that macrophages can be engineered to transport drug nanoparticles (NPs) to tumor sites in a targeted manner, thereby exerting significant anticancer effects. In addition, macrophages engineered to express chimeric antigen receptors (CARs) were shown to actively migrate to tumor sites and eliminate tumor cells through phagocytosis. Importantly, after reaching tumor sites, these engineered macrophages can significantly change the otherwise immune-suppressive tumor microenvironment and thereby enhance T cell-mediated anticancer immune responses. In this review, we first introduce the multifaceted activities of macrophages and the principles of nanotechnology in cancer therapy and then elaborate on macrophage engineering via nanotechnology or genetic approaches and discuss the effects, mechanisms, and limitations of such engineered macrophages, with a focus on using live macrophages as carriers to actively deliver NP drugs to tumor sites. Several new directions in macrophage engineering are reviewed, such as transporting NP drugs through macrophage cell membranes or extracellular vesicles, reprogramming tumor-associated macrophages (TAMs) by nanotechnology, and engineering macrophages with CARs. Finally, we discuss the possibility of combining engineered macrophages and other treatments to improve outcomes in cancer therapy.
The Role of Circular RNAs in the Drug Resistance of Cancers
Authors: Liu Xin-Yuan , Zhang Qi , Guo Jing , Zhang Peng , Liu Hua , Tian Zi-Bin , Zhang Cui-Ping , Li Xiao-Yu
Published: January 2022

Cancer is a major threat to human health and longevity. Chemotherapy is an effective approach to inhibit cancer cell proliferation, but a growing number of cancer patients are prone to develop resistance to various chemotherapeutics, including platinum, paclitaxel, adriamycin, and 5-fluorouracil, among others. Significant progress has been made in the research and development of chemotherapeutic drugs over the last few decades, including targeted therapy drugs and immune checkpoint inhibitors; however, drug resistance still severely limits the application and efficacy of these drugs in cancer treatment. Recently, emerging studies have emphasized the role of circular RNAs (circRNAs) in the proliferation, migration, invasion, and especially chemoresistance of cancer cells by regulating the expression of related miRNAs and targeted genes. In this review, we comprehensively summarized the potential roles and mechanisms of circRNAs in cancer drug resistance including the efflux of drugs, apoptosis, intervention with the TME (tumor microenvironment), autophagy, and dysfunction of DNA damage repair, among others. Furthermore, we highlighted the potential value of circRNAs as new therapeutic targets and prognostic biomarkers for cancer.
Induction Therapy Followed by Surgery for Unresectable Thymic Epithelial Tumours
Authors: Wang Shuai , Jiang Jiahao , Gao Jian , Chen Gang , Fan Yue , Xu Bei , Dong Jihong , Du Shisuo , Liu Junzhen , Ding Jianyong
Published: January 2022

Background and Objectives

The treatment of unresectable thymic epithelial tumours (TETs) remains controversial. Here, we present the efficacy and safety of induction therapy followed by surgery for unresectable TET.

Methods

Eighty-one patients with unresectable TETs treated with induction therapy followed by surgery were selected from a retrospective review of consecutive TETs from January 2005 to January 2021. Clinicopathological data were analyzed to assess tumour responses, resectability, adverse events, progression-free survival (PFS) and overall survival (OS).

Results

Induction therapy produced a major tumour response rate of 69.1%, a tumour response grade (TRG) 1-3 rate of 84.0% and an R0 resection rate of 74.1%. The most common toxic effects were all-grade neutropenia (35.8%) and anaemia (34.6%). The 10-year OS and PFS rates were 45.7% and 35.2%. Multivariate analysis showed that ypTNM stage, ypMasaoka stage, complete resection, and TRG were significant independent prognostic factors. Exploratory research revealed that different induction modalities and downstaging of T, N, M, TNM, or Masaoka classifications did not significantly alter the pooled hazard ratio for survival.

Conclusions

Induction therapy followed by surgery is well tolerated in patients with unresectable TETs, with encouraging R0 resection rates. Multimodality management provides good control of tumors for unresectable TET patients.
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments
Authors: de Bakker Tycho , Journe Fabrice , Descamps Géraldine , Saussez Sven , Dragan Tatiana , Ghanem Ghanem , Krayem Mohammad , Van Gestel Dirk
Published: January 2022

TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV+ cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.
Perioperative Mortality Risk in Patients Undergoing Transoral Robotic Surgery for T1-T2 Oropharyngeal Squamous Cell Carcinoma: A National Cancer Database Study
Authors: Davies Joel C. , Husain Zain , Day Terry A. , Graboyes Evan M. , Eskander Antoine
Published: January 2022

The National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methods used or for the conclusions drawn from these data by the investigators.

Introduction

Transoral robotic surgery (TORS) is well established as initial definitive treatment for early-stage oropharyngeal squamous cell carcinoma (OPSCC) as an alternative to radiation therapy with similar survival rates. While proponents of TORS focus on the reduced morbidity of treatment compared to open procedures, shortened hospital admissions and equivalent survival outcomes to non-surgical treatment, there remain concerns over the risk of mortality within the acute perioperative period. Therefore, we sought to determine the 30-day and 90-day perioperative mortality risk using the National Cancer Database.

Methods

A retrospective cohort analysis was performed for patients diagnosed with pathologic T1/2 OPSCC between January 1, 2010, and December 31, 2016 that underwent primary surgical treatment with TORS and was not restricted by HPV status. The primary outcome was 30-day perioperative mortality. The secondary outcome was 90-day perioperative mortality. Univariable analysis was used to identify variables associated with 30-day perioperative mortality.

Results

In total, 4,127 patients (mean [SD; range] age, 59 [9.5; 22-90] years; 3,476 [84%] men and 651 [16%] women) met inclusion criteria. The number of patients with pT1-2 OPSCC undergoing TORS increased three-fold between 2010 (279/4,127; 7%) to 2016 (852/4,127; 21%). The overall 30-day and 90-day perioperative mortality rate for TORS during the study period was 0.6% (23/4,127) and 0.9% (38/4,127), respectively. On univariable analysis (UVA), age≥65 was the only predictor of 30-day perioperative mortality (OR 3.41; 95% CI 1.49-7.81).

Conclusion

The overall risk of all cause mortality following TORS for early-stage OPSCC remains low. The risk of mortality is higher in elderly patients and should be considered, in addition to previously established risk factors, during patient selection and counselling.
Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis
Authors: Yu Weina , Liu Fengsen , Lei Qingyang , Wu Peng , Yang Li , Zhang Yi
Published: January 2022

Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.
Factors Associated With Clinical Responses to Spinal Manipulation in Patients With Non-specific Thoracic Back Pain: A Prospective Cohort Study
Authors: Pasquier Mégane , Young James J. , Lardon Arnaud , Descarreaux Martin
Published: January 2022

Introduction: The management of musculoskeletal disorders is complex and requires a multidisciplinary approach. Manual therapies, such as spinal manipulative therapy (SMT), are often recommended as an adjunct treatment and appear to have demonstrable effects on pain and short-term disability in several spinal conditions. However, no definitive mechanism that can explain these effects has been identified. Identifying relevant prognostic factors is therefore recommended for people with back pain.

Objective: The main purpose of this study was to identify short-term candidate prognostic factors for clinically significant responses in pain, disability and global perceived change (GPC) following a spinal manipulation treatment in patients with non-specific thoracic back pain.

Methods: Patients seeking care for thoracic spine pain were invited to participate in the study. Pain levels were recorded at baseline, post-intervention, and 1 week after a single session of SMT. Disability levels were collected at baseline and at 1-week follow-up. GPC was collected post-intervention and at 1-week follow-up. Biomechanical parameters of SMT, expectations for improvement in pain and disability, kinesiophobia, anxiety levels as well as perceived comfort of spinal manipulative therapy were assessed.

Analysis: Differences in baseline characteristics were compared between patients categorized as responders or non-responders based on their pain level, disability level, and GPC at each measurement time point. Binary logistic regression was calculated if the statistical significance level of group comparisons (responder vs. non-responders) was equal to, or <0.2 for candidate prognostic factors.

Results: 107 patients (62 females and 45 males) were recruited. Mean peak force averaged 450.8 N with a mean thrust duration of 134.9 ms. Post-intervention, comfort was associated with pain responder status (p < 0.05) and GPC responder status (p < 0.05), while expectation of disability improvement was associated with GPC responder status (p < 0.05). At follow-up, comfort and expectation of pain improvement were associated with responder GPC status (p < 0.05). No association was found between responder pain, disability or GPC status and biomechanical parameters of SMT at any time point.

Discussion: No specific dosage of SMT was associated with short-term clinical responses to treatment. However, expectations of improvement and patient comfort during SMT were associated with a positive response to treatment.
The Effect of Artemisinin-Based Drugs vs Non-artemisinin-based Drugs on Gametophyte Carrying in the Body After the Treatment of Uncomplicated Falciparum Malaria: A Systematic Review and Meta-analysis
Authors: Zou Yuanyuan , Julie Nadia , Guo Shiyuan , Tang Yexiao , Zhang Hongying , Xu Zhiyong , Wu Wanting , Yuan Yueming , Wu Zhibin , Guo Wenfeng , Li Changqing , Huang Xinan , Xu Qin , Deng Changsheng , Song Jianping , Wang Qi
Published: January 2022

The WHO recommends Artemisinin-based combination therapy (ACTs) as the first-line treatment for malaria. This meta-analysis aims to analyze the effects of artemisinin and its derivatives as well as non-artemisinin drugs on the gametophytes in the host during the treatment of falciparum malaria. Fourteen studies were included in this analysis, and the artemisinin combination drugs involved were: artemether-lumefantrine (AL), artemisinin (AST), artemether-benflumetol (AB), dihydroartemisinin-piperaquine + trimethoprim + primaquine (CV8), amodiaquine + sulfadoxine-pyrimethamine (ASP), pyronaridine-phosphate + dihydroartemisinin (PP-DHA), dihydroartemisinin (DHA), and mefloquine + artesunate (MA), with 1702 patients. The control intervention measures involved the following: sulfadoxine-pyrimethamine (SP), mefloquine (MQ), atovaquone-proguanil (AT-PG), chloroquine + sulfadoxine-pyrimethamine (C-SP), quinine (Q), pyronaridine-phosphate (PP), pyronaridine (PN), and mefloquine + primaquine (MP), with 833 patients. The effect of ACTs was more obvious (OR = 0.37, 95%CI: 0.22–0.62, p < 0.05). In the control group of second malaria attacks, the difference between the two groups was not statistically significant (RD = 1.16, 95%CI: 0.81–1.66, p < 0.05); there was no significant difference in treatment failure during follow-up (RD = -0.01, 95%CI: 0.04–0.03, p < 0.05). There were also very few serious adverse events in both groups. ACTs showed good therapeutic effects in preventing gametocythemia but did not control the recrudescence rate and overall cure, which indicated the effectiveness of the combination of antimalarial drugs. Further research is required to explore which compatibility method is most conducive to the development of clinical malaria control.
Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics
Authors: Pauli Ivani , Rezende Jr. Celso de O. , Slafer Brian W. , Dessoy Marco A. , de Souza Mariana L. , Ferreira Leonardo L. G. , Adjanohun Abraham L. M. , Ferreira Rafaela S. , Magalhães Luma G. , Krogh Renata , Michelan-Duarte Simone , Del Pintor Ricardo Vaz , da Silva Fernando B. R. , Cruz Fabio C. , Dias Luiz C. , Andricopulo Adriano D.
Published: January 2022

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.
Protectin DX Attenuates Lumbar Radicular Pain of Non-compressive Disc Herniation by Autophagy Flux Stimulation via Adenosine Monophosphate-Activated Protein Kinase Signaling
Authors: Zhao Qing-xiang , Wang Yi-hao , Wang Si-cong , Xue Song , Cao Zhen-xin , Sun Tao
Published: January 2022

Background: Neuroinflammation plays a crucial role in initiating and sustaining lumbar radicular pain (LRP). Protectin DX (PDX) has been experimentally verified to possess pro-resolving properties and anti-inflammatory effects. This study aimed to observe the analgesic effects of PDX and its potential mechanisms in LRP rats with non-compressive lumbar disc herniation (NCLDH).

Method: Only male rats were selected to avoid gender-related interferences. Rat models of NCLDH were established, and rats were randomly divided into four groups: the sham group, the vehicle group, the PDX (10 ng PDX) group, and the PDX (100 ng PDX) group. Changes in the mechanical withdrawal threshold and thermal withdrawal latency were observed for 7 days. The mRNAs of pro-inflammatory and anti-inflammatory mediators were evaluated via real-time polymerase chain reaction, whereas western blot and immunohistochemistry were separately conducted to assess the expression levels of autophagy-related proteins and adenosine monophosphate-activated protein kinase (AMPK) signaling.

Results: Intrathecal delivery of PDX reduced interleukin (IL)-6 and IL-1β mRNA levels and facilitated mRNA transcription of transforming growth factor-β1, with attenuation of mechanical and thermal hyperalgesia in LRP rat models. With the application of nucleus pulposus to the dorsal root ganglion, autophagy flux and AMPK signaling were severely disrupted in the spinal dorsal horns, and intrathecal treatment with PDX could dose-dependently restore the dysfunction of autophagy flux and AMPK signaling.

Conclusion: These data suggest that PDX possesses pro-resolving properties and exerts potent analgesic effects in LRP by affecting autophagy flux via AMPK signaling.
Image-Based Computational Hemodynamics Analysis of Systolic Obstruction in Hypertrophic Cardiomyopathy
Authors: Fumagalli Ivan , Vitullo Piermario , Vergara Christian , Fedele Marco , Corno Antonio F. , Ippolito Sonia , Scrofani Roberto , Quarteroni Alfio
Published: January 2022

Hypertrophic Cardiomyopathy (HCM) is a pathological condition characterized by an abnormal thickening of the myocardium. When affecting the medio-basal portion of the septum, it is named Hypertrophic Obstructive Cardiomyopathy (HOCM) because it induces a flow obstruction in the left ventricular outflow tract. In any type of HCM, the myocardial function can become compromised, possibly resulting in cardiac death. In this study, we investigated with computational analysis the hemodynamics of patients with different types of HCM. The aim was quantifying the effects of this pathology on the intraventricular blood flow and pressure gradients, and providing information potentially useful to guide the indication and the modality of the surgical treatment (septal myectomy). We employed an image-based computational approach, integrating fluid dynamics simulations with geometric and functional data, reconstructed from standard cardiac cine-MRI acquisitions. We showed that with our approach we can better understand the patho-physiological behavior of intraventricular blood flow dynamics due to the abnormal morphological and functional aspect of the left ventricle. The main results of our investigation are: (a) a detailed patient-specific analysis of the blood velocity, pressure and stress distribution associated to HCM; (b) a computation-based classification of patients affected by HCM that can complement the current clinical guidelines for the diagnosis and treatment of HOCM.
Coordinated Translocation of Presequence-Containing Precursor Proteins Across Two Mitochondrial Membranes: Knowns and Unknowns of How TOM and TIM23 Complexes Cooperate With Each Other
Authors: Genge Marcel G. , Mokranjac Dejana
Published: January 2022

The vast majority of mitochondrial proteins are encoded in the nuclear genome and synthesized on cytosolic ribosomes as precursor proteins with specific mitochondrial targeting signals. Mitochondrial targeting signals are very diverse, however, about 70% of mitochondrial proteins carry cleavable, N-terminal extensions called presequences. These amphipathic helices with one positively charged and one hydrophobic surface target proteins to the mitochondrial matrix with the help of the TOM and TIM23 complexes in the outer and inner membranes, respectively. Translocation of proteins across the two mitochondrial membranes does not take place independently of each other. Rather, in the intermembrane space, where the two complexes meet, components of the TOM and TIM23 complexes form an intricate network of protein–protein interactions that mediates initially transfer of presequences and then of the entire precursor proteins from the outer to the inner mitochondrial membrane. In this Mini Review, we summarize our current understanding of how the TOM and TIM23 complexes cooperate with each other and highlight some of the future challenges and unresolved questions in the field.
Differential Expression of lncRNAs and miRNAs Between Self-Rooting Juvenile and Donor Clones Unveils Novel Insight Into the Molecular Regulation of Rubber Biosynthesis in Hevea brasiliensis
Authors: Li Hui-Liang , Wang Ying , Guo Dong , Zhu Jia-Hong , Peng Shi-Qing
Published: January 2022

The rubber tree (Hevea brasiliensisMuell. Arg.) is a tropical tree species that produce natural rubber. Self-rooted juvenile clones (SRJCs) are novel rubber tree planting materials developed through primary somatic embryogenesis. SRJCs have a higher rubber yield compared with donor clones (DCs). The molecular basis underlying increased rubber yield in SRJCs remains largely unknown. Here, the latex from SRJCs and DCs were collected for strand-specific and small RNA-seq methods. A total of 196 differentially expressed long noncoding RNAs (DELs), and 11 differentially expressed microRNAs were identified in latex between SRJCs and DCs. Targeted genes of DELs were markedly enriched for various biological pathways related to plant hormone signal transduction, photosynthesis, glutathione metabolism, and amino acids biosynthesis. DELs probably acted as cis-acting regulation was calculated, and these DELs relevant to potentially regulate rubber biosynthesis, reactive oxygen species metabolism, and epigenetic modification. Furthermore, the DELs acting as microRNA targets were studied. The interaction of microRNA and DELs might involve in the regulation of natural rubber biosynthesis.
Metabolic Disturbance Induced by the Embryo Contributes to the Formation of Chalky Endosperm of a Notched-Belly Rice Mutant
Authors: Tao Yang , Mohi Ud Din Atta , An Lu , Chen Hao , Li Ganghua , Ding Yanfeng , Liu Zhenghui
Published: January 2022

Grain chalkiness is a key quality trait of the rice grain, whereas its underlying mechanism is still not thoroughly understood because of the complex genetic and environmental interactions. We identified a notched-belly (NB) mutant that has a notched-line on the belly of grains. The line dissects the endosperm into two distinct parts, the upper translucent part, and the bottom chalky part in the vicinity of the embryo. Using this mutant, our previous studies clued the negative influence of embryo on the biochemical makeup of the endosperm, suggesting the need for the in-depth study of the embryo effect on the metabolome of developing endosperm. This study continued to use the NB mutant to evolve a novel comparison method to clarify the role of embryo in the formation of a chalky endosperm. Grain samples of the wild-type (WT) and NB were harvested at 10, 20, and 30 days after fertilization (DAF), and then divided into subsamples of the embryo, the upper endosperm, and the bottom endosperm. Using non-targeted metabolomics and whole-genome RNA sequencing (RNA-seq), a nearly complete catalog of expressed metabolites and genes was generated. Results showed that the embryo impaired the storage of sucrose, amino acid, starch, and storage proteins in the bottom endosperm of NB by enhancing the expression of sugar, amino acids, and peptide transporters, and declining the expression of starch, prolamin, and glutelin synthesis-related genes. Importantly, the competitive advantage of the developing embryo in extracting the nutrients from the endosperm, transformed the bottom endosperm into an “exhaustive source” by diverting the carbon (C) and nitrogen (N) metabolism from synthetic storage to secondary pathways, resulting in impaired filling of the bottom endosperm and subsequently the formation of chalky tissue. In summary, this study reveals that embryo-induced metabolic shift in the endosperm is associated with the occurrence of grain chalkiness, which is of relevance to the development of high-quality rice by balancing the embryo–endosperm interaction.
Genome-Wide Association Studies of Salt Tolerance at Seed Germination and Seedling Stages in Brassica napus
Authors: Zhang Guofang , Zhou Jinzhi , Peng Yan , Tan Zengdong , Li Long , Yu Liangqian , Jin Cheng , Fang Shuai , Lu Shaoping , Guo Liang , Yao Xuan
Published: January 2022

Most crops are sensitive to salt stress, but their degree of susceptibility varies among species and cultivars. In order to understand the salt stress adaptability of Brassica napus to salt stress, we collected the phenotypic data of 505 B. napus accessions at the germination stage under 150 or 215 mM sodium chloride (NaCl) and at the seedling stage under 215 mM NaCl. Genome-wide association studies (GWAS) of 16 salt tolerance coefficients (STCs) were applied to investigate the genetic basis of salt stress tolerance of B. napus. In this study, we mapped 31 salts stress-related QTLs and identified 177 and 228 candidate genes related to salt stress tolerance were detected at germination and seedling stages, respectively. Overexpression of two candidate genes, BnCKX5 and BnERF3 overexpression, were found to increase the sensitivity to salt and mannitol stresses at the germination stage. This study demonstrated that it is a feasible method to dissect the genetic basis of salt stress tolerance at germination and seedling stages in B. napus by GWAS, which provides valuable loci for improving the salt stress tolerance of B. napus. Moreover, these candidate genes are rich genetic resources for the following exploration of molecular mechanisms in adaptation to salt stress in B. napus.