Silicon induces ROS scavengers, hormone signalling, antifungal metabolites, and silicon deposition against brown stripe disease in sugarcane.

Bipolaris setariae is known to cause brown stripe disease in sugarcane, resulting in significant yield losses. Silicon (Si) has the potential to enhance plant growth and biotic resistance. In this study, the impact of Si on brown stripe disease was investigated across susceptible and resistant sugarcane varieties, utilizing four Si concentrations (0, 15, 30, and 45 g per barrel of Na2SiO3·5H2O). Si significantly reduced the incidence of brown stripe disease (7.41-59.23%) and alleviated damage to sugarcane growth parameters, photosynthetic parameters, and photosynthetic pigments. Submicroscopic observations revealed that Si induced the accumulation of silicified cells in leaves, reduced spore accumulation, decreased stomatal size, and protected organelles from B. setariae damage. In addition, Si increased the activity of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase), reduced reactive oxygen species production (malondialdehyde and hydrogen peroxide) and modulated the expression of genes associated with hormone signalling (PR1, TGA, AOS, AOC, LOX, PYL8, and SnRK2), leading to the accumulation of abscisic acid and jasmonic acid and inhibiting SA synthesis. Si also activated the activity of metabolism-related enzymes (polyphenol oxidase and phenylalanine ammonia lyase) and the gene expression of PAL-dependent genes (PAL, C4H, and 4CL), regulating the accumulation of metabolites, such as chlorogenic acid and lignin. The antifungal test showed that chlorogenic acid (15ug µL-1) had a significant inhibitory effect on the growth of B. setariae. This study is the first to demonstrate the inhibitory effect of Si on B. setariae in sugarcane, highlighting Si as a promising and environmentally friendly strategy for managing brown stripe disease.

Engineering cytokines for cancer immunotherapy: a systematic review.

Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production and function of these cytokines are usually dysregulated during malignant tumor progression. Considering their clinical potential and the early successful use of cytokines in cancer immunotherapy, such as interferon alpha-2b (IFNα-2b; IntronA®) and IL-2 (Proleukin®), cytokine-based therapeutics have been extensively evaluated in many follow-up clinical trials. Following these initial breakthroughs, however, clinical translation of these natural messenger molecules has been greatly limited owing to their high-degree pleiotropic features and complex biological properties in many cell types. These characteristics, coupled with poor pharmacokinetics (a short half-life), have hampered the delivery of cytokines via systemic administration, particularly because of severe dose-limiting toxicities. New engineering approaches have been developed to widen the therapeutic window, prolong pharmacokinetic effects, enhance tumor targeting and reduce adverse effects, thereby improving therapeutic efficacy. In this review, we focus on the recent progress and competitive landscape in cytokine engineering strategies and preclinical/clinical therapeutics for cancer. In addition, aiming to promote engineered cytokine-based cancer immunotherapy, we present a profound discussion about the feasibility of recently developed methods in clinical medicine translation.

[Scientific basis of acupuncture on mesenchymal stem cells for treating ischemic stroke].

The scientific basis of acupuncture on mesenchymal stem cells (MSCs) for treating ischemic stroke (IS) is discussed. MSCs transplantation has great potential for the treatment of tissue damage caused by early stage inflammatory cascade reactions of IS, but its actual transformation is limited by various factors. How to improve the homing efficiency of MSCs is the primary issue to enhance its efficacy. As such, the possible mechanisms of acupuncture and MSCs transplantation in inhibiting inflammatory cascade reactions induced by IS are explored by reviewing literature, and a hypothesis that acupuncture could promote the secretion of stromal cell-derived factor-1α (SDF-1α) from ischemic foci to regulate SDF-1α/CXC chemokine receptor 4 (CXCR4) axis, thereby improving the homing efficiency of MSCs transplantation, exerting its neuroprotective function, and improving the bed transformation ability, is proposed.

[Species, Habitat Characteristics, and Screening Suggestions of Cadmium Hyperaccumulators in China].

Phytoremediation, as a green and effective in-situ remediation technology for heavy metal-contaminated soil, has attracted the attention of Chinese scholars and has resulted in a series of achievements over the past 20 years. In this study, the species characteristics, distribution of field discovery sites in various vegetation zones, habitat characteristics, habitat geological characteristics, and geochemistry of cadmium (Cd) of the Cd hyperaccumulators in China reported in the relevant literature from the past 20 years (from 2002 to 2021) were summarized by searching for related keywords. Finally, suggestions were proposed for the screening of new Cd hyperaccumulators. The results showed that a total of 45 species of Cd hyperaccumulators in China have been reported so far. In terms of plant species, they belonged to 22 families and 36 genera, among which Compositae with 14 species was the most abundant. There were 25 species discovered through the field investigation, which were mainly distributed in the subtropical broadleaf evergreen forest region of southern China. Additionally, the Cd hyperaccumulators discovered by field surveys were mainly found in high Cd-concentrated soils surrounding lead-zinc mines. In conclusion, abundant plant resources, high concentrations of heavy metal soils, and long-term domestication jointly promoted the formation of hyperaccumulators. Therefore, the region with these three points could be considered a high probability region for the presence of hyperaccumulators, and the screening of hyperaccumulators could be carried out around this. We proposed that the screening of new hyperaccumulators can be carried out through the following six steps:the identification and investigation of high probability areas, the enrichment capability test, the enrichment capability test in low concentration levels, the enrichment capability test between different ecotypes, the succession of enrichment capability, and the test of remediation proficiency.

Characterization of Elimination Pathways and the Feasibility of Endogenous Metabolites as Biomarkers of Organic Anion Transporter 1/3 Inhibition in Cynomolgus Monkeys.

Organic anion transporters 1 and 3 (OAT1/3) occupy a key role in mediating renal elimination. Kynurenic acid (KYNA) was previously discovered as an effective endogenous biomarker to assess drug-drug interaction (DDI) for OAT inhibitors. Here, further in vitro and in vivo investigation was performed to characterize the elimination routes and feasibility of KYNA, along with other reported endogenous metabolites, as biomarkers of Oat1/3 inhibition in bile duct-cannulated (BDC) cynomolgus monkeys. Our results suggested that KYNA is a substrate of OAT1/3 and OAT2, but not OCT2, MATE1/2K, or NTCP, and that it shares comparable affinities between OAT1 and OAT3. Renal and biliary excretions and plasma concentration-time profiles of KYNA, pyridoxic acid (PDA), homovanillic acid (HVA), and coproporphyrin I (CP-I) were assessed in BDC monkeys dosed with either probenecid (PROB) at 100 mg/kg or the control vehicle. Renal excretion of KYNA, PDA, and HVA was determined to be the major elimination route. The maximum concentration and the area under the plasma concentration-time curve (Cmax and AUC0-24h) of KYNA were about 11.6- and 3.7-fold higher in the PROB group than in the vehicle group. Renal clearance of KYNA decreased by 3.2-fold, but biliary clearance (CLbile) was not altered after PROB administration. A similar trend was observed for PDA and HVA. Interestingly, an elevation of plasma concentration and reduction of CP-I CLbile were observed after PROB treatment, which suggested inhibition of the CP-I Oatp-Mrp2 transport axis by PROB. Overall, our results indicated that KYNA could potentially facilitate early and reliable assessment of DDI liabilities of Oat inhibition in monkeys. SIGNIFICANCE STATEMENT: This work reported renal excretion as the major elimination pathway for kynurenic acid, pyridoxic acid, and homovanillic acid. Administration of probenecid reduced renal clearance and increased plasma exposure of these biomarkers in monkeys, consistent with the observation in humans. These endogenous biomarkers discovered in monkeys could be potentially used to evaluate the clinical drug-drug interactions in the early phase of drug development.

Management of pain in patients with bone metastases.

Cancer-induced bone pain (CIBP) has a considerable impact on patients' quality of life as well as physical and mental health. At present, patients with CIBP are managed according to the three-step analgesic therapy algorithm proposed by the World Health Organization. Opioids are commonly used as the first-line treatment for moderate-to-severe cancer pain but are limited due to addiction, nausea, vomiting and other gastrointestinal side effects. Moreover, opioids have a limited analgesic effect in some patients. In order to optimize the management of CIBP, we must first identify the underlying mechanisms. In some patients, surgery, or surgery combined with radiotherapy or radiofrequency ablation is the first step in the management of CIBP. Various clinical studies have shown that anti-nerve growth factor (NGF) antibodies, bisphosphonates, or RANKL inhibitors can reduce the incidence and improve the management of cancer pain. Herein, we review the mechanisms of cancer pain and potential therapeutic strategies to provide insights for optimizing the management of CIBP.

Lumbar Intradural Disc Herniation Caused by Injury: A Case Report and Literature Review.

BACKGROUND: Intradural disc herniation(IDH) caused by trauma is a rare type of disease，which is difficult to diagnose clinically and is easily misdiagnosed. We received a patient with the disease, reported the case to share the process of diagnosis and treatment and put forward our own opinions, so as to increase the probability of correct diagnosis. CASE PRESENTATION: We report the case of a 48-year-old male who fell from a scaffold at a height of 2 m. Later, he developed low back pain, restricted movement, numbness and hyperalgesia of the lower left limb, and decreased left muscle strength. He was diagnosed with IDH. Treatment with posterior decompression and intramedullary decompression with pedicle screw internal fixation was performed. His postoperative course was uneventful, and he underwent regular follow up for 1 year. Good neurologic symptom improvement was achieved. CONCLUSIONS: IDH is rare, and comprehensive consideration and film reading can improve the correct diagnosis rate. Accurate diagnosis and early decompression of laminae and intramedullary decompression can lead to good recovery after neurologic impingement.

Comparison of low-cost phantoms for ultrasound-guided fine-needle aspiration biopsy training.

INTRODUCTION: Phantoms and simulators are widely accepted methods to gain valuable experience and confidence for inexperienced trainees prior to seeing their patient and for refining their skills. A phantom model that is durable, simple, and inexpensive to produce and use would be ideal to train practitioners in ultrasound-guided fine-needle aspiration biopsy (USFNA) technique. MATERIALS AND METHODS: In this study, we systematically compared several low-cost phantom models including gelatin, extra firm tofu, canned cooked pork, ballistics gel, and chicken breast for their haptic properties, echogenicity, teaching utility, and overall performance based on a Likert scale (1-5; 5 = best). Nine cytopathologists and cytopathology fellows who perform FNA regularly evaluated these models and completed the survey. RESULTS: The gelatin phantom, with a gelatin to water ratio of 1:8 by weight, was found to be the best for USFNA practice and overall performance, followed by the 1:10 gelatin phantom. Tofu and chicken breast phantoms were also good low-cost alternatives that needed only a few minutes of total preparation time. CONCLUSIONS: Low-cost, homemade phantoms can serve as excellent alternatives to commercial phantoms for practicing and teaching USFNA.

Clinical Efficacy Analysis of the New PRUNUS Spine Plate System for Anterior Cervical Spine Surgery.

OBJECTIVE: Although the role of anterior cervical titanium plate system in stabilizing the spine sequence and promoting bone graft fusion has been widely recognized, more and more attention has been paid to the design of the plate itself and the complications caused by it. In order to solve the problems of poor stability of internal fixation, plate displacement and screw looseness, we designed the new PRUNUS spine plate system. Hence, the present study was conducted to describe observe and evaluate the clinical efficacy of a new type of three-leaf reinforced cervical anterior screw plate system (PRUNUS nailing system) developed for anterior cervical surgery. METHODS: A retrospective analysis of 56 patients from June 2018 to October 2019 was used. Twenty-seven patients with cervical spine disease treated with new PRUNUS nail plate internal fixation were selected as the observation group, and 29 patients with cervical spine disease treated with conventional cervical anterior screw fixation were selected as the control group. Postoperative follow-up was performed. Cervical stability, internal fixation position and bone graft fusion were evaluated according to imaging data. The operative time, intraoperative blood loss, cervical Cobb angle, pain visual analogue scale (VAS), and Japanese orthopaedic association (JOA) were compared between the two groups. Spinal function scores and neurological improvement rates were used to evaluate the clinical efficacy of the new PRUNUS spine plate. RESULTS: The patients were followed up for 5-18 months, with an average of 7.33 months. The average operative time of the observation group was 98.4 ± 9.2 min, and the mean intraoperative blood loss was 65.3 ± 10.6 ml, which were significant different from the control group's 109.7 ± 9.4 minutes (P < 0.05), 72.9 ± 15.6 ml (P < 0.05). Comparison between the two groups in postoperative and final follow-up of cervical Cobb angle, JOA score and improvement rate, VAS score and preoperative comparison showed no significant differences (P > 0.05). CONCLUSION: The new PRUNUS spine plate system can be applied to the anterior cervical spine surgery, and its clinical efficacy was similar to the traditional cervical anterior plate. But PRUNUS simplified the operation process, especially suitable for the surgical treatment of anterior cervical revision and osteoporosis patients.

Effects of photodynamic therapy in the treatment of high-grade vaginal intraepithelial lesions following hysterectomy and HPV infection.

BACKGROUND: Non-invasive treatment therapy, such as 5-Aminolevulinic acid photodynamic therapy (ALA-PDT), has gained attention for its effect on select cervical and vaginal lesions. To investigate the effect of ALA-PDT on high-grade vaginal intraepithelial lesions (HG VAIN) after hysterectomy and high-risk human papillomavirus (HR-HPV) infection, in this study, we evaluated the clinical efficacy and safety of ALA-PDT in 23 patients with HG VAIN following hysterectomy and HPV. METHODS: 23 patients with HG VAIN after hysterectomy were selected for photodynamic therapy, and the therapeutic effect, adverse reactions, recurrence rate and HPV clearance rate were analyzed respectively. The patients were followed up at 3, 6, 9, and 12 months after ALA-PDT. HPV, thinprep cytologic test (TCT) and reid colposcopic index (RCI) score should be performed 3 months after treatment. When the RCI score is higher than or equal to 3, a colposcopy biopsy should be conducted, the additional ALA-PDT should be continued if residual lesions were detected. When the RCI score is lower than or equal to 2, HPV and TCT should be reviewed every 3 months. RESULTS: After 3 months of photodynamic therapy, 21 patients were cured, with the cure rate of 91.3% (21/23). Two patients (8.7%) had residual lesions, which had degraded compared with the previous. After treatment, the overall HR-HPV clearance rate was 56.5% at 3 months, 65.2% at 6 months, 69.5% at 9 months, and 74% at 12 months. No obvious adverse reactions were found during and after treatment. Moreover, no recurrence occurred during the whole follow-up period. CONCLUSIONS: Compared with other therapies, ALA-PDT is a novel therapy with non-invasive procedure in HG VAIN after hysterectomy. ALA-PDT can be used for the treatment of HG VAIN after hysterectomy, moreover, it can not only effectively clear HR-HPV, but also can prevent the recurrence and progression of vaginal lesions caused by persistent HR-HPV infection.

Primary Alveolar Soft-Part Sarcoma (ASPS) of the Prostate: Report of a Deceptive Case.

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor that primarily involves the extremities. We report a case of a 30-year-old never-smoker man who presented with hematuria, dysuria, and constipation at an outside hospital. He was diagnosed with and treated for multiple episodes of urinary tract infection. However, he continued to have voiding symptoms for which a cystoscopy was performed and revealed a bladder neck mass. He underwent transurethral resection of a bladder tumor and was diagnosed with muscle-invasive urothelial carcinoma, nested variant, at an outside hospital. Subsequent to this diagnosis he transferred his care to our center. In-house imaging revealed a large vascular mass involving the prostate and pushing against the bladder base. Prostate needle biopsies were performed and revealed an epithelioid neoplasm with a nested growth pattern composed of cells with a moderate amount of eosinophilic cytoplasm, mildly pleomorphic nuclei, and occasional prominent nucleoli. Since the findings were not classic for urothelial carcinoma or for prostate cancer, we included a wider differential of poorly differentiated carcinoma, sarcoma, and paraganglioma. A wide panel of keratin stains was negative, ETS (erythroblast transformation-specific)-related gene highlighted an extensive vascular network and neuroendocrine stains were all negative. A transcription factor E3 fluorescent in-situ hybridization was positive and subsequently, an ASPSCR1 gene rearrangement was demonstrated. The outside hospital transurethral resection of bladder tumor was obtained for review and the tumor was morphologically similar to that seen on the in-house prostate needle biopsies. Based on the above findings a final diagnosis of primary ASPS of the prostate with involvement of the bladder was made. The patient was later diagnosed with bilateral lung metastases. He was treated with pazopanib, radiation therapy, and cystoprostatectomy and is symptom-free on a 15-month follow-up.

Bilateral medial sacrospinous ligament suture for apical suspension through natural spaces: A single-center study with low perioperative complications.

Sacrospinous ligament fixation (SSLF) is one of the most used native tissue approaches for apical suspension with a high rate of perioperative complications. This study aimed to review cases undergoing a modified SSLF and assess its perioperative adverse events. It was a retrospective study of 168 consecutive patients undergoing modified transvaginal SSLF at a single tertiary center from 2017 to 2021. The sutures were placed on the sacrospinous ligament (SSL) approaching the sacrum through natural spaces under direct vision. Moreover, it was performed bilaterally. Patient demographics and perioperative complications were reviewed. The median age was 65 years, and 85.7% (144/168) had stage III-IV prolapse. Among the 168 patients undergoing this modified SSLF, 161 were for uterovaginal prolapse, and seven were for posthysterectomy vaginal vault prolapse. 83.9% (135/161) patients were concomitant with hysterectomy, and 70.2% (118/168) were with anteroposterior colporrhaphy. The median operation time was 82 min (interquartile range [IQR], 61-100 min), and the median intraoperative blood loss was 50 ml (IQR, 30-50 ml). Two cases had pelvic hematoma, and both were cured after expectant treatment. No patient required a homologous blood transfusion, and none complained about buttock or lower limb pain 2 weeks postoperatively. Nor did injury of the ureters, bladder, or rectum occur intraoperatively. This modified transvaginal SSLF procedure was safe and had no severe perioperative complications.

Effectiveness and feasibility of self-sampling for human papillomavirus testing for internet-based cervical cancer screening.

Objectives: Worldwide, around 18.2% of cervical cancer occurred in China, mainly because of lower screening coverage and screening quality in regional disparities. To assess self-sampling for human papillomavirus (HPV) testing, combined with the internet, as a primary cervical cancer screening (CCS) method in low-resource settings, and to establish an internet-based self-sampling CCS-management model. Methods: The women who participated registered on a CCS website. We recruited 20,136 women, aged 30-59 years, from 13 provinces in China, to perform vaginal self-sampling for HPV testing as a primary CCS, based on the internet. A questionnaire was subsequently used to investigate the acceptability of self-sampling. Results: Of the 20,103 women with qualified samples, 35.80% lived in remote areas, 37.69% had never undergone CCS, 59.96% were under-screened, and the overall prevalence of a high-risk of HPV was 13.86%. Of 8,136 respondents, 95.97% of women felt that self-sampling was easy to perform, 84.61% had no discomfort when using a self-sampling brush, 62.37% women were more likely to choose self-sampling for CCS in future, and 92.53% were willing to introduce the concept to others around them. The reliability and ease of self-sampling were independent factors influencing selection of self-sampling (p < 0.05). Conclusions: The Internet-facilitated self-sampling for HPV testing and management model for cervical cancer prevention is feasible and effective. It can be used as a supplement to the conventional screening, particularly in outlying areas with few medical resources, to improve the coverage of CCS. Clinical trial registration: https://www.chictr.org.cn, identifier: ChiCTR2000032331.

Retrorectal mucinous adenocarcinoma arising from a tailgut cyst: A case report and review of literature.

BACKGROUND: Tailgut cysts are defined as congenital cysts that develop in the rectosacral space from the residue of the primitive tail. As a congenital disease, caudal cysts are very rare, and their canceration is even rarer, which makes the disease prone to misdiagnosis and delayed treatment. We describe a case of caudal cyst with adenocarcinogenesis and summarize in detail the characteristics of cases with analytical value reported since 1990. CASE SUMMARY: A 35-year-old woman found a mass in her lower abdomen 2 mo ago. She was asymptomatic at that time and was not treated because of the coronavirus disease 2019 pandemic. Two weeks ago, the patient developed abdominal distension and right waist discomfort and came to our hospital. Except for the high level of serum carcinoembryonic antigen, the medical history and laboratory tests were not remarkable. Magnetic resonance imaging showed a well-defined, slightly lobulated cystic-solid mass with a straight diameter of approximately 10 cm × 9 cm in the presacral space, slightly high signal intensity on T2-weighted imaging, and moderate signal intensity on T1-weighted imaging. The mass was completely removed by laparoscopic surgery. Histopathological examination showed that the lesion was an intestinal mucinous adenocarcinoma, and the multidisciplinary team decided to implement postoperative chemotherapy. The patient recovered well, the tumor marker levels returned to normal, and tumor-free survival has been achieved thus far. CONCLUSION: The case and literature summary can help clinicians and researchers develop appropriate examination and therapeutic methods for diagnosis and treatment of this rare disease.

Knowledge Mapping of the Phytoremediation of Cadmium-Contaminated Soil: A Bibliometric Analysis from 1994 to 2021.

Cadmium pollution of soil threatens the environmental quality and human health. Phytoremediation of cadmium-contaminated soil has attracted global attention in recent decades. This study aimed to conduct a comprehensive and systematic review of the literature on phytoremediation of cadmium-contaminated soil based on bibliometric analysis. A total of 5494 articles published between 1994 and 2021 were retrieved from the Web of Science Core Collection. Our knowledge mapping presented the authors, journals, countries, institutions, and other basic information to understand the development status of phytoremediation of cadmium-contaminated soil. Based on a keyword cluster analysis, the identified major research domains were "biochar", "Thlaspi caerulescens", "endophytic bacteria", "oxidative stress", "EDTA", and "bioconcentration factor". Overall, this study provided a detailed summary of research trends and hotspots. Based on the keyword co-occurrence and burst analysis, the core concepts and basic theories of this field were completed in 2011. However, the pace of theoretical development has been relatively slow. Finally, future research trends/frontiers were proposed, such as biochar addition, rhizosphere bacterial community manipulation, cadmium subcellular distribution, and health risk assessment.

Anatomic identification of laparoscopic uterosacral ligament suspension: A step-by-step procedure.

INTRODUCTION AND HYPOSTHESIS: The uterosacral ligament (USL) is the main structure of physiological apical support, and USL suspension is one of the most commonly used methods for native tissue apical suspension. Structures surrounding the USL are complex, and the USL itself is difficult to identify, especially the sacral portion of the USL. Laparoscopy improves visualization, but exposure of the USL is still unsatisfactory. METHODS: In this study, we report a simple method for exposing and suturing the USL laparoscopically, with step-by-step instructions, well-presented figures and videos. The key techniques are shown as follows: keeping tension on the USL with a uterine manipulator, dissecting the space medial to the USL, exposing the portion of the USL near the sacrum through the natural space, and then suturing it medially and connecting it directly to the posterior cervix. RESULTS: 95 consecutive patients have undergone this modified USLS and none had serious perioperative complication. CONCLUSION: In this way, the USL anatomy is exposed well, which may make placement of sutures in USL suspension safe and effective.

EGF signaling promotes the lineage conversion of astrocytes into oligodendrocytes.

BACKGROUND: The conversion of astrocytes activated by nerve injuries to oligodendrocytes is not only beneficial to axonal remyelination, but also helpful for reversal of glial scar. Recent studies have shown that pathological niche promoted the Sox10-mediated astrocytic transdifferentiation to oligodendrocytes. The extracellular factors underlying the cell fate switching are not known. METHODS: Astrocytes were obtained from mouse spinal cord dissociation culture and purified by differential adherent properties. The lineage conversion of astrocytes into oligodendrocyte lineage cells was carried out by Sox10-expressing virus infection both in vitro and in vivo, meanwhile, epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibitor Gefitinib were adopted to investigate the function of EGF signaling in this fate transition process. Pharmacological inhibition analyses were performed to examine the pathway connecting the EGF with the expression of oligodendrogenic genes and cell fate transdifferentiation. RESULTS: EGF treatment facilitated the Sox10-induced transformation of astrocytes to O4+ induced oligodendrocyte precursor cells (iOPCs) in vitro. The transdifferentiation of astrocytes to iOPCs went through two distinct but interconnected processes: (1) dedifferentiation of astrocytes to astrocyte precursor cells (APCs); (2) transformation of APCs to iOPCs, EGF signaling was involved in both processes. And EGF triggered astrocytes to express oligodendrogenic genes Olig1 and Olig2 by activating extracellular signal-regulated kinase 1 and 2 (Erk1/2) pathway. In addition, we discovered that EGF can enhance astrocyte transdifferentiation in injured spinal cord tissues. CONCLUSIONS: These findings provide strong evidence that EGF facilitates the transdifferentiation of astrocytes to oligodendrocytes, and suggest that targeting the EGF-EGFR-Erk1/2 signaling axis may represent a novel therapeutic strategy for myelin repair in injured central nervous system (CNS) tissues.

Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.

TNF-α (G-308A) Polymorphism, Circulating Levels of TNF-α and IGF-1: Risk Factors for Ischemic Stroke-An Updated Meta-Analysis.

Objective: Accumulated studies have explored gene polymorphisms and circulating levels of tumor necrosis factor (TNF)-α and insulin-like growth factor (IGF)-1 in the etiology of ischemic stroke (IS). Of the numerous etiopathological factors for IS, a single-nucleotide polymorphism (SNP) rs1800629 located in the TNF-α gene promoter region and increased levels of TNF-α were found to be associated with IS in different ethnic backgrounds. However, the published results are inconsistent and inconclusive. The primary objective of this meta-analysis was to investigate the concordance between rs1800629 polymorphism and IS. A secondary aim was to explore circulating levels of TNF-α and IGF-1 with IS in different ethnic backgrounds and different sourced specimens. Methods: In this study, we examined whether rs1800629 genetic variant and levels of TNF-α and IGF-1 were related to the etiology of IS by performing a meta-analysis. Relevant case-control studies were retrieved by database searching and systematically selected according to established inclusion criteria. Results: A total of 47 articles were identified that explored the relationship between the rs1800629 polymorphism and levels of TNF-α and IGF-1 with IS risk susceptibility. Statistical analyses revealed a significant association between the rs1800629 polymorphism and levels of TNF-α and IGF-1 with IS pathogenesis. Conclusion: Our findings demonstrated that the TNF-α rs1800629 polymorphism, the increased levels of TNF-α, and decreased levels of IGF-1 were involved in the etiology of IS.