E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma.

Ribonucleotide reductase (RR) is a rate-limiting enzyme that facilitates DNA replication and repair by reducing nucleotide diphosphates (NDPs) to deoxyribonucleotide diphosphates (dNDPs) and is thereby crucial for cell proliferation and cancer development. The E2F family of transcription factors includes key regulators of gene expression involved in cell cycle control. In this study, E2F8 expression was significantly increased in most cancer tissues of lung adenocarcinoma (LUAD) patients and was correlated with the expression of RRM2 through database and clinical samples analysis. The protein expression of E2F8 and RRM2 were positively correlated with tumor-node-metastasis (TNM) pathological stage, and high expression of E2F8 and RRM2 predicted a low 5-year overall survival rate in LUAD patients. Overexpression and knockdown experiments showed that E2F8 was essential for LUAD cell proliferation, DNA synthesis, and cell cycle progression, which were RRM2-dependent. Reporter gene, ChIP-qPCR, and DNA pulldown-Western blot assays indicated that E2F8 activated the transcription of the RRM2 gene by directly binding with the RRM2 promoter in LUAD cells. Previous studies indicated that inhibition of WEE1 kinase can suppress the phosphorylation of CDK1/2 and promote the degradation of RRM2. We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.

Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model.

Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 µM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6-18 µM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future.

Effects of silver foam combined with Dermlin wound healing dressing on inflammation and quality of life in patients with diabetic lower limb ulcers.

OBJECTIVE: To investigate the effects of silver foam combined with Dermlin wound healing dressing on concentrations of inflammatory factors of wound surface and quality of life of the patients with diabetic lower limb ulcers. METHODS: A total of 60 patients with diabetic lower limb ulcers admitted to the First Affiliated Hospital of Anhui Medical University during January 2020 and December 2020 were retrospectively enrolled in this study. According to the different treatments, they were divided into a control group (30 cases treated with Dermlin wound healing dressing only), and a research group (30 cases treated with silver foam combined with Dermlin dressing). The clinical efficacy, wound healing status, pain intensity (visual analog scale (VAS) scores), concentrations of inflammatory factor (high-sensitivity C-reactive protein (hsCRP), leukocyte interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT)), angiogenesis factors levels (basic fibroblast growth factor (BFGF), vascular endothelial growth factor (VEGF)), oxidative stress reaction indexes (advanced protein oxidation products (AOPP), malondialdehyde (MDA) and superoxide dismutase (SOD)) and quality of life (SF-36 scale) were compared between two groups. The bacterial removal rate was calculated based on the results of bacterial culture before and after treatment. The central granulated tissue was collected after the granulation tissue coverage rate was calculated. RESULTS: The research group had significantly higher overall response rate (96.67% vs 73.33%), shorter wound healing time and higher wound healing rate than the control group (all P<0.05). The VAS scores were decreased in both Groups 1, 3 and 7 d after treatment as compared with those before treatment, and the VAS scores were significantly lower in the research group than in the control group during the same period (all P<0.05). After treatment, the concentrations of hsCRP, IL-6, TNF-α, PCT, AOPP and MDA were decreased in both groups, while the levels of bFGF, VEGF, l TGF-ß1, SOD and SF-36 scores were increased significantly (all P<0.05). The above-mentioned indicators of the research group improved significantly compared with those of the control group (all P<0.05). The bacterial removal rate and granulation tissue coverage rate of the research group were significantly higher than those of the control group (both P<0.05). CONCLUSION: The treatment of diabetic lower limb ulcers with silver foam combined with Dermlin dressing can effectively promote wound healing, reduce pain intensity, and improve quality of life in patients with diabetic lower limb ulcers. Such effects may be attributed to lower levels of inflammatory factor levels, regulation of oxidative stress, and improvement of angiogenesis.

Preoperative Status of Gut Microbiota Predicts Postoperative Delirium in Patients With Gastric Cancer.

Introduction: Post-operative delirium (POD) is a serious complication which occurs after surgery, especially in the elderly undergoing abdominal surgery. Increasing evidence has revealed an association between the gut microbiota and psychological disorders involving the "brain-gut" axis. However, the association between the pathogenesis of POD after abdominal surgery in aging and composition of the gut microbiota remains unclear. Methods: Forty patients (≥65 years old) who underwent abdominal surgery were included in the study. Twenty patients had POD, whereas 20 patients did not. POD was diagnosed and assessed using the confusion assessment method (CAM) during the postoperative period. Total DNA fractions were extracted from all fecal samples of patients. 16S rRNA sequencing was performed to determine the composition of the gut microbiota. The quality of the samples was determined by calculating the α- and ß-diversities. Results: The α- and ß-diversities indicated that the samples were eligible for detection and comparison. We observed multiple differentially abundant bacteria in patients with and without POD. Generally, Proteobacteria, Enterbacteriaceae, Escherichia shigella, Klebsiella, Ruminococcus, Roseburia, Blautia, Holdemanella, Anaerostipes, Burkholderiaceae, Peptococcus, Lactobacillus, and Dorea were abundant in the POD cohort, whereas Streptococcus equinus and Blautia hominis were abundant in the control cohort. The results of receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of Escherichia shigella was 0.75. Phenotype prediction showed that the gut microbiota may influence POD by altering the tolerance to oxidative stress. Conclusion: There were significant associations between the pathogenesis of POD and composition of the gut microbiota. Escherichia shigella are promising diagnostic bacterial species for predicting POD onset after abdominal surgery in elderly people. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx, Chinese Clinical Trial Registry ChiCTR200030131.

The influence of anesthesia and surgery on fear extinction.

Accumulating evidence has demonstrated significant clinical post-traumatic stress disorder (PTSD) symptoms after anesthesia or surgery. Fear extinction dysfunction is a notable feature of PTSD. Although anesthetics and surgery profoundly affect memory processes, their designated effects on fear extinction have not been dissertated. Previous studies have suggested that innate immune system activation disrupts fear extinction, and surgery has been shown to increase the inflammatory response. Thus, in the current study, we examined the effects of propofol, sevoflurane, dexmedetomidine and surgery on fear extinction in adolescent mice, and further tested whether dexmedetomidine could reverse the injury effect of surgery on fear extinction through its anti-inflammatory effects. Our results showed that propofol (200 mg/kg) impaired the acquisition and recall of cued fear extinction, and surgery disrupted cued fear extinction acquisition/recall and consolidation. In contrast to cued fear extinction, contextual fear extinction was not affected by propofol or surgery. Moreover, dexmedetomidine prevented surgery-induced impairment of cued extinction acquisition and recall but not consolidation. Finally, TNF-α and IL-6 levels in the ventromedial prefrontal cortex were not necessary for the dexmedetomidine treatment effect of surgery-induced fear extinction dysfunction. The study results showed that propofol and surgery selective impaired the cued fear extinction stage in adolescent mice, and dexmedetomidine may unleash a protective effect in preventing postoperative PTSD.

Vaccines and the risk of Guillain-Barré syndrome.

The role of vaccination in the development of Guillain-Barré syndrome (GBS) is controversial, although cases of GBS have been reported following a wide range of vaccines. A nested case-control study was conducted between January 2011 and December 2015 in three Chinese cities. Four controls were matched to a case by gender, age, address and index date. An independent expert committee validated the diagnoses of cases and controls according to the Brighton Collaboration GBS case definition. Data on vaccinations were obtained from computerized vaccination records. Causal relations were assessed by conditional logistic regression. 1056 cases of GBS and 4312 controls were included in the analyses. Among paediatric and adult population, adjusted ORs for GBS occurrence within 180 days following vaccination were 0.94 (95% CI 0.54-1.62) and 1.09 (95% CI 0.88-1.32), respectively. No increased risk of GBS was detected for vaccination against hepatitis B, influenza, hepatitis A, varicella, rabies, polio(live), diphtheria, pertuss(acellular), tetanusis, measles, mumps, rubella, Japanese Encephalitis, and meningitis vaccines. Adjusted ORs for the recurrence of GBS after vaccination among paediatric and adult population were 0.85 (95% CI 0.07-9.50) and 1.18 (95% CI 0.49-2.65), respectively. In this large retrospective study, we did not find evidence of an increased risk of GBS and its recurrence among either paediatric (≤ 18 years) or adult (> 18 years) individuals within the 180 days following vaccinations of any kind, including influenza vaccination.

Vaccines and the risk of acute disseminated encephalomyelitis.

BACKGROUND: It is important to examine the risk of Acute disseminated encephalomyelitis (ADEM) after vaccination. METHODS: We conducted a nested case-control study between January 2011 and December 2015. Four controls per case were matched for age, gender, address. An independent expert committee validated the diagnoses of cases and controls. Data on vaccinations were obtained from computerized vaccination records. The analyses were conducted with the use of conditional logistic regression. RESULTS: The analyses include 272 cases of ADEM and 1096 controls. No increase in the risk of ADEM was observed for vaccination against hepatitis B, influenza, polio(live), diphtheria, pertuss(acellular), tetanusis, measles, mumps, rubella, Japanese Encephalitis, meningitis, hepatitis A, varicella and rabies vaccines. Vaccine was associated with a statistically significant increase in risk in the 31-60-day exposure interval (OR, 4.04 [95% CI, 1.07-12.69]), but not the 0-30 and 61-180-day interval. There was no association between vaccine received and the recurrence of ADEM. CONCLUSIONS: Findings from the present study do not demonstrate an association of vaccines with an increased risk of ADEM and its recurrence among either paediatric (≤18 years) or adult (>18 years) individuals within the 180 days after vaccinations. The finding in children in the 31-60 day risk interval is likely coincidental and was not confirmed in separate self-control analyses.

Progressive and painful wound as a feature of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): report of a case and review of literature.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon extranodal non-Hodgkin lymphoma, with an aggressive course with no well-defined treatment. This article describes a 56-year-old man, treated surgically 7 months earlier for a subcutaneous nodosity near the left axilla, presenting with a progressive inflamed wound, pain, and high fever (39 °C). Treatment with systemic antibiotics and topical anti-inflammatory dressings failed. After 7 months, the patient was diagnosed with SPTCL based on biopsy results and a multidisciplinary consultation. While undergoing systemic chemotherapy with corticosteroid therapy, his wound become more painful, larger, and covered with necrotic tissue. Fifty days after chemotherapy with corticosteroid therapy, his wound became seriously painful and increasingly necrotic. He developed a serious stomachache and abdominal distension, rapidly became comatose, and died. The aim of this case report is to present our experience of the different clinical signs of SPTCL to expedite its early diagnosis in future. We summarize the main clinical characteristics of SPTCL as a rapidly progressing and increasingly painful wound with necrotic tissue, involving a multisystem disorder, which is easily misdiagnosed, responds poorly to corticosteroid and chemotherapy treatments, and has a high mortality rate. The pathological characteristics are early inflammation, advancing to profuse infiltration of the subcutaneous adipose tissues by CD3(+) and/or CD8(+) T-cell lymphoma cells. Clinicians must cooperate with pathologists and oncologists to diagnose this disease as soon as possible and to avoid a misdiagnosis. The use of antibiotic and painkillers should minimize the patient's discomfort and control rapid wound development. Future studies are required to investigate the optimal wound treatment and whether the necrotic tissue should be removed.

Incidence of acute disseminated encephalomyelitis in the Jiangsu province of China, 2008-2011.

BACKGROUND: It is important to have an estimate of the incidence of acute disseminated encephalomyelitis (ADEM) because the incidence of ADEM is unknown and the outcomes undefined in China. OBJECTIVES: This study attempts to describe ADEM incidence in large Chinese populations located in four geographically different and moderately distant areas of the same province. METHODS: A retrospective investigation was conducted with ADEM patients in Nanjing, Nantong, Yancheng and Xuzhou. The survey was carried out in regions that might have received patients meeting the case definition of ADEM provided by the International Pediatric MS Study Group from 2008 to 2011. A total of 125 hospitals were included and 412 patients were identified through the hospital information systems (HIS). RESULTS: The incidence of ADEM was 0.32/100,000/year. There are two peaks on the age-specific ADEM rates curve. One is 0.77/100,000/year among 0- to 9-year-olds, the other is 0.45/100,000/year in those aged 50-59 years. The incidence rate found for ADEM in males was 0.34/100,000/year, and in females was 0.29/100,000/year. The highest incidence rate was in Nanjing (0.40/100,000/year). CONCLUSIONS: The average annual incidence of ADEM was 0.32/100,000/year. The peak age of onset was 50-59 years old and 0-9 years old. The incidence among males was insignificantly higher than that among females. There was no significant difference in incidence by seasonal variation.