bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proton-induced DNA damage promotes integration of foreign plasmid DNA into human genome
Authors: Katerji Meghri , Bertucci Antonella , Filippov Valery , Vazquez Marcelo , Chen Xin , Duerksen-Hughes Penelope J. 
Published: September 2022

High-risk human papillomaviruses (HPVs) cause virtually all cervical cancer cases and are also associated with other types of anogenital and oropharyngeal cancers. Normally, HPV exists as a circular episomal DNA in the infected cell. However, in some instances, it integrates into the human genome in such a way as to enable increased expression of viral oncogenes, thereby leading to carcinogenesis. Since viral integration requires breaks in both viral and human genomes, DNA damage likely plays a key role in this critical process. One potentially significant source of DNA damage is exposure to elevated doses of ionizing radiation. Natural background radiation is ubiquitous; however, some populations, including radiological workers, radiotherapy patients, and astronauts, are exposed to significantly higher radiation doses, as well as to different types of radiation such as particle radiation. We hypothesize that ionizing radiation-induced DNA damage facilitates the integration of HPV into the human genome, increasing the risk of developing HPV-related cancers in the exposed population. To test this, we first determined the kinetics of DNA damage in keratinocytes exposed to ionizing radiation (protons) by assessing γ-H2AX foci formation using immunofluorescence (direct damage), and also measured ROS and 8-oxoG levels via DCFDA and Avidin-FITC (indirect damage).As anticipated, direct DNA damage was observed promptly, within 30 min, whereas indirect DNA damage was delayed due to the time required for ROS to accumulate and cause oxidative damage. Although radiation was lethal at high doses, we were able to establish an experimental system where radiation exposure (protons and X-rays) induced DNA damage dose-dependently without causing major cytotoxic effects as assessed by several cytotoxicity assays. Most importantly, we explored the impact of radiation exposure on integration frequency using a clonogenic assay and demonstrated that as predicted, proton-induced DNA damage promotes the integration of HPV-like foreign DNA in oral keratinocytes. Overall, the insights gained from this work enable us to better understand the contribution of radiation exposure and DNA damage to HPV-mediated carcinogenesis and direct us toward strategies aimed at preventing malignancies in HPV-infected individuals.
The expression and biological effect of NR2F6 in non-small cell lung cancer
Authors: Yang Shu lin , Guan Huan qin , Yang Hong bao , Chen Yao , Huang Xiao ying , Chen Lei , Shen Zhi fa , Wang Liang xing 
Published: September 2022

ObjectiveThis study aimed to explore the expression and effect of the nuclear receptor subfamily 2 group F member 6 (NR2F6) gene in non-small cell lung cancer (NSCLC) and provide an experimental basis for the targeted therapy of NSCLC.MethodFirst, the expression of NR2F6 in lung cancer tissues was analyzed using the Gene Expression Omnibus and the Cancer Genome Atlas (TCGA) databases, and the expression of NR2F6 in lung cancer tissues and cells was verified by Western blotting and quantitative polymerase chain reaction. Next, the relationship between NR2F6 expression and the clinicopathological features of lung cancer was analyzed via immunohistochemistry, and the relationship between NR2F6 expression and prognosis was analyzed using the Kaplan–Meier Plotter. The influence of NR2F6 knockdown on the proliferation capacity of lung cancer cells was then verified at cell level. Finally, the expression of heterogeneous nuclear ribonucleoprotein D (HNRNPD) in lung cancer tissue was analyzed using the TCGA database and immunohistochemistry. The impact of HNRNPD knockdown on the proliferation capacity of lung cancer cells was verified at cell level, and the relationship between NR2F6 and HNRNPD was verified by co-immunoprecipitation.ResultsNR2F6 was highly expressed in lung cancer tissues and cells, and its expression was positively correlated with the depth of invasion, lymphatic metastasis, and clinical stage of lung cancer. High expression of NR2F6 in lung cancer was also significantly associated with poor prognosis. At cell level, NR2F6 knockdown was found to inhibit the proliferation of H460 and H358 in lung cancer cells. Furthermore, the TCGA database and immunohistochemical results showed that HNRNPD was highly expressed in lung cancer tissues and was highly consistent with NR2F6 expression in these tissues. Knockdown of HNRNPD also inhibited the proliferation of lung cancer cells. The co-immunoprecipitation experiment verified that NR2F6 interacted with HNRNPD.ConclusionNR2F6 may interact with HNRNPD to jointly regulate the progression of lung cancer, and this conclusion provides a new experimental basis for the study of the molecular targeted therapy of NSCLC.
A case report of the sustained and rapid response of bevacizumab in a TP53-positive breast cancer and liver metastatic patient through personalized medicine
Authors: Eskandarion Mohammad Reza , Tizmaghz Zahra , Andalib Bahram , Parsa Nasser , Emami Seyed Amir Hossein , Shahsiah Reza , Oghabian Mohammad Ali , Shirkoohi Reza 
Published: September 2022

HER2-positive metastatic breast cancer is much less frequent than other subgroups of breast cancer. Treatment options for this cancer are mostly limited to systemic chemotherapy, which leads to moderate improvements. Targeted therapy against malignant breast cancer requires the identification of reliable biomarkers for personalized medicine to obtain the maximum benefit of this therapy. Any mutations in the TP53 signaling pathway can be considered as a significant causative factor of breast cancer, for which the identification of target genes plays an important role in selecting the appropriate treatment. The use of personalized gene expression profiling could be valuable to find the direct target of the treatment in this case. The present study assessed the genetic profile of an HER2-positive metastatic breast cancer patient (with a liver metastasis) and figured out a complete and sustained response to bevacizumab. According to the results of next-generation sequencing (NGS) analysis, the patient’s genetic profile showed an increased expression of p4EBP1 and PTEN and the activation of the mTOR signaling pathway with a mutation in the TP53 gene. Based on the common treatment of similar profiling, we administrated bevacizumab/Taxol/Gemzar chemotherapy up to six courses. Accordingly, as the response to treatment was revealed by reducing the volume of the liver metastasis from 4 to 1.4 cm, metastasectomy was performed as a complementary treatment. Hence, personalized gene expression profiling not only is useful for targeted therapy but also could be recommended to avoid prescription of non-responsive drugs.
Low-dose PD-1 inhibitor combined with lenvatinib for preemptive treatment of recurrence after liver transplantation for hepatocellular carcinoma: Case report and literature review
Authors: Jin Xin , Zhang Kangjun , Fang Taishi , Zeng Xinchen , Yan Xu , Tang Jianxin , Liang Ziming , Xie Linjie , Zhao Dong 
Published: September 2022

Orthotopic liver transplantation (OLT), as one of the curative methods for the treatment of hepatocellular carcinoma (HCC), has brought hope to patients with HCC. However, treatment options for HCC recurrence and metastasis after liver transplantation are limited. Immune checkpoint inhibitor (ICI), such as programmed cell death protein 1 (PD-1) inhibitor, have been successfully used in advanced or metastatic HCC, but the data on the safety of PD-1 inhibitor after liver transplantation is limited. In this article, we report a 47-year-old patient with acute-on-chronic liver failure and multiple HCC who was successfully treated with liver transplantation. On the 45th day after OLT, the patient’s alpha fetoprotein (AFP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) were increased, and imaging examination showed no residual tumor. The patient had high risk factors for tumor recurrence before operation, so the possibility of tumor recurrence was considered. When the tumor markers showed an upward trend, we immediately treated the patient with lenvatinib 8 mg, after half a month, the AFP and AFP-L3 continued to increase compared with before. Then we used low-dose nivolumab 40mg, the patient’s AFP and AFP-L3 gradually decreased. One month later, a second low-dose nivolumab 40mg was given, and the patient’s tumor markers gradually decreased to normal. No acute rejection and other complications occurred during the treatment. So far, we have followed up this patient for 2 years, and no tumor recurrence was observed. To our knowledge, this is the first reported case using a low dose of nivolumab in combination with lenvatinib to prevent recurrence of HCC after liver transplantation.
Embryonic esophageal rhabdomyosarcoma in an adult male: A case report and literature review
Authors: Zhang Xiaoman , Li Guang 
Published: September 2022

Basic principleThere exists a rare aggressive neoplasm called esophageal rhabdomyosarcoma. It originates in cells of the striated muscle or mesenchymal cells which differ from the striated muscle. This tumor has a high degree of malignancy and extensive metastasis. Masses of the sick people are at a high phase when going to hospital. Consequently, the prognosis is exceedingly bad.Patient concernsA 54-year-old male presented with dysphagia as the initial symptom. Gastroscopy showed an irregular protuberant lesion about 18–22 cm from the incisor. The lesion was observed to be pathological under gastroscopy and was diagnosed as an (esophageal) sarcoma.DiagnosisEmbryonic esophageal rhabdomyosarcoma.InterventionsAfter receiving two cycles of DP (docetaxel and cisplatin) chemotherapy in the local hospital, the patient received 60 Gy of radiotherapy in 30 fractions combined with chemotherapy at our hospital. Dysphagia was relieved, and the tumor appeared significantly shrunken on imaging after the treatment.OutcomesLung metastasis occurred 1 month after radiotherapy, and the patient died of pulmonary edema on March 11, 2022.LessonsPreviously reported cases of embryonic esophageal rhabdomyosarcoma are few. Theoretically, the disease should occur in adolescents; nevertheless, our case was a man who was in middle-aged; the neoplasm was in an unusual position: the upper part of the esophagus. Moreover, the patient initially had good response to the combination of radiotherapy and chemotherapy. Although he died 8 months after diagnosis, the presented data represent a valuable resource for understanding the survival benefits of treating embryonic esophageal rhabdomyosarcoma patients with radiotherapy combined with chemotherapy. In addition, we reviewed the previously reported literature, and a total of 17 cases of esophageal rhabdomyosarcoma were identified and analyzed.
Pediatric acute liver failure: An experience of a pediatric intensive care unit from resource limited settings
Authors: Amatya Puja , Kapalavai Sudeep Kumar , Deep Akash , Sankaranarayanan Srinivas , Krupanandan Ravikumar , Sadasivam Kalaimaran , Ramachandran Bala 
Published: September 2022

IntroductionPediatric acute liver failure is a rare and serious disease. Though liver transplantation is considered as the established treatment option for patients who are unlikely to recover with medical management, however, with the advancement of medical care there has been an increase in spontaneous regeneration of liver, obviating the need for liver transplantation. We identified the etiologies, outcome and prognostic factors of acute liver failure and the validity of the existing liver transplantation criteria to predict the outcome of pediatric acute liver failure.Materials and methodsThis was a retrospective study done from January 2014 to December 2019 in a tertiary pediatric critical care unit in South India. All children aged between 1 month to 18 years admitted with acute liver failure were enrolled.ResultsOf 125 children with acute liver failure, the main etiologies were infections (32%), indeterminate (23%), paracetamol toxicity (21%), metabolic (13%) and others (11%). Dengue was the most common infection (55%). The median pediatric logistic organ dysfunction score at admission was 12 (4–27). Of 125 patients, 63.2% (n = 79) had spontaneous regeneration which was higher in paracetamol induced (92.3%) compared to non-paracetamol induced acute liver failure (55.5%). Only two patients underwent liver transplantation and 35% died. Peak alanine transaminase and use of inotropes significantly predicted the outcome of disease. Of 38 children meeting King's College Hospital criteria for liver transplantation, 57.9% had spontaneous regeneration and 36.8% died. Of 74 children meeting INR &gt; 4 criteria, 54% (n = 40) had spontaneous regeneration and 43.2% died. INR &gt;4 criteria was more sensitive than King's College Hospital criteria for predicting the need for liver transplantation.ConclusionPediatric acute liver failure is caused by varied etiologies and infections were the commonest cause. Despite having a seriously ill cohort of patients, medical management resulted in spontaneous regeneration in the majority of children with acute liver failure. The use of inotropes, advanced hepatic encephalopathy, and peak alanine transaminase were predictors of poor outcome in children with acute liver failure and these patients could be considered for liver transplantation as available. Therefore, we may need to develop better predictors of pediatric acute liver failure in resource limited settings.
Reduced activity of adenylyl cyclase 1 attenuates morphine induced hyperalgesia and inflammatory pain in mice
Authors: Johnson Kayla , Doucette Alexis , Edwards Alexis , Verdi Aleeya , McFarland Ryan , Hulke Shelby , Fowler Amanda , Watts Val J. , Klein Amanda H. 
Published: September 2022

Opioid tolerance, opioid-induced hyperalgesia during repeated opioid administration, and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10–40 mg/kg, 4 days). Systemic treatment with an AC1 inhibitor, ST03437 (2.5–10 mg/kg, IP), reduced morphine-induced hyperalgesia in mice. Lumbar intrathecal administration of a viral vector incorporating a short-hairpin RNA targeting Adcy1 reduced morphine-induced hypersensitivity compared to control mice. In contrast, acute morphine antinociception, along with thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecal Adcy1 knockdown. Knockdown of Adcy1 by intrathecal injection also decreased inflammatory mechanical hyperalgesia and increased burrowing and nesting activity after intraplantar administration of Complete Freund’s Adjuvant (CFA) one-week post-injection.
KangPiLao decoction modulates cognitive and emotional disorders in rats with central fatigue through the GABA/Glu pathway
Authors: Xu Yifei , Lian Yajun , Li Jie , Zhang Yifei , Liu Yan , Wang Xuejiao , Ma Jie , Li Feng 
Published: September 2022

Background: Central fatigue (CF) is a subjective sense of tiredness associated with cognitive and memory disorders, accompanied by reduced physical endurance and negative emotions, such as anxiety and depression. Disease progression and prognosis with regards to CF have been unfavorable and possibly contribute to dementia, schizophrenia, and other diseases. Additionally, effective treatments for CF are lacking. KangPiLao decoction (KPLD) has been widely applied in clinical treatment and is composed of six Chinese herbal medicines, some of which have confirmed anti-fatigue effects. While glutamic acid (Glu) is the main excitatory transmitter in the central nervous system (CNS), gamma-aminobutyric acid (GABA) is the major inhibitory transmitter. Both are involved in emotional, cognitive, and memory functions. This research was designed to explore how KPLD regulates cognitive and emotional disorders in rats with CF and to identify the relationship between the regulatory effect and the GABA/Glu pathway.Methods: The compounds comprising KPLD were analyzed using high-performance liquid chromatography-mass spectrometry. Sixty Wistar rats were randomly divided into six groups. The modified multiple platform method was used to induce CF. Cognitive, emotional, and fatigue states were evaluated by performing behavioral tests (Morris water maze [MWM], open-field test [OFT], and grip strength test). Histomorphology, western blotting, immunohistochemistry, and RT-qPCR were performed to investigate protein and mRNA expression levels in the hippocampus and prefrontal cortexes involved in the GABA/Glu pathway.Results: Rats with CF exhibited impaired spatial cognition and increased negative emotions in the MWM and OFT. KPLD enabled the improvement of these symptoms, especially in the high-concentration group. Western blotting and RT-qPCR demonstrated that the expression of GABAARα1, GABAARγ2, GABABR1, and GAD67 in rats with CF was higher, whereas GAT-1 and NMDAR2B were lower in the hippocampus and prefrontal cortex. KPLD decreased the expression of GABAARα1, GABABR1, GABAARγ2, and GAD67 in the hippocampus and prefrontal cortex and enhanced the expression of NR2B in the prefrontal cortex.Conclusion: KPLD significantly improved cognitive and emotional disorders in rats with CF by regulating the GABA/Glu pathway. Overall, KPLD may be a promising candidate for developing a drug for treating CF.
Efficacy and safety of a Chinese herbal formula Maxing Ganshi Decoction in children with community-acquired pneumonia: A randomized, double-blind, placebo-controlled, multicenter trial
Authors: Zheng Yujiao , Shi Changren , Han Yaowei , Li Xinmin , Dong Lijing , Li Yan , Chen Hui , Wang Yushui , Li Jinsong , Liu Geli , Ma Rong , Lian Fengmei , Tong Xiaolin 
Published: September 2022

Background: As one of the most commonly used Chinese medicine formula in the manage of respiratory diseases, Maxing Ganshi Decoction (MGD) has been demonstrated to improve the clinical symptoms of pneumonia. To evaluate the efficacy and safety of MGD in treating children with community-acquired pneumonia (CAP), we conducted the clinical trial.Methods: A randomized, double-blind, placebo-controlled, multicenter trial was conducted in 3 study sites in Tianjin, China. MDG or placebo were randomly given to patients aged 3–6 years with onset of CAP within 48 h. Changes in disease efficacy during the study period (which was measured as recovery, significant effect, improvement and no effect) was evaluated as the primary outcome. Time from enrollment to fever resolution was assessed as the secondary outcome. The adverse event was analyzed as safety evaluation.Results: A total of 71 patients (36 in MGD and 35 in placebo) were randomized and completed the whole study. The patient demographics and other characteristics at baseline were similar between the 2 groups (p &gt; 0.05). After 10 days of intervention, the proportion of recovered and significant effective patients was increased significantly in the MGD group (34.85% [95% CI, 12.44%–57.26%]; p &lt; 0.05) compared with the control group. Besides, the symptom score of the MGD group was lowered significantly (p &lt; 0.001). The estimated time to fever resolution in the MGD group was also reduced compared with the control group (p &lt; 0.05). During the whole study, no side effects were observed in both MGD and control groups.Conclusion: MGD was effective in improving disease efficacy, clinical symptoms and reducing time to fever resolution in patients with childhood CAP, which suggested that MGD may be used as an alternative therapy in the treatment of childhood CAP.Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=5612, identifier 13003955.
Performance of a pharmaceutical services regionalization strategy policy in Minas Gerais, Brazil: Pre-post analysis from ERAF project
Authors: Luz Tatiana Chama Borges , Castro Ana Karine Sarvel de , Marques Isabela Cristina , Cota Betania Barros , Alves Jèssica de Castro , Law Michael Robert 
Published: September 2022

Background: In 2016, the Brazilian state of Minas Gerais (∼20 million people), implemented the ERAF policy (“Regionalization Strategy of Pharmaceutical Services”) in an effort to improve medicine procurement and distribution within primary care. We evaluated the impact of the policy on three main goals: price reductions, volume increases, and expansion of therapeutic options.Methods: We analyzed the procurement data from the Integrated System of Management of Pharmaceutical Services database in 2012 and 2018. We estimated the volume, drug mix, and expenditure indicators for all major therapeutic classes, and, in detail, for cardiovascular and nervous system drugs. We evaluated the expenditure drivers using decomposition analyses.Results: Overall, the expenditure increased by 14.5%, drug mix almost doubled, while the volume decreased by a third. Cardiovascular and neurological system drugs followed similar patterns. Decomposition analyses showed that prices and drug mix had positive effects while the volume had negative effects, resulting in an overall increase in expenditure.Conclusion: Our findings suggest that the ERAF policy cannot be considered effective as it has not fulfilled its intended purposes so far. Strategies to address the identified problems and to build a platform for a more sustainable long-lasting policy should be put in place by the government.
Study on the mechanism of American ginseng extract for treating type 2 diabetes mellitus based on metabolomics
Authors: Liu Tiantian , Wang Dan , Zhou Xinfeng , Song Jiayin , Yang Zijun , Shi Chang , Li Rongshan , Zhang Yanwen , Zhang Jun , Yan Jiuxing , Zhu Xuehui , Li Ying , Gong Min , Wang Chongzhi , Yuan Chunsu , Cui Yan , Wu Xiaohui 
Published: September 2022

American ginseng extract (AGE) is an efficient and low-toxic adjuvant for type 2 diabetes mellitus (T2DM). However, the metabolic mechanisms of AGE against T2DM remain unknown. In this study, a rat model of T2DM was created and administered for 28 days. Their biological (body weight and serum biochemical indicators) and pathological (pancreatic sections stained with HE) information were collected for further pharmacodynamic evaluation. Moreover, an ultra-performance liquid chromatography–mass spectrometry–based (UHPLC–MS/MS–based) untargeted metabolomics method was used to identify potential biomarkers of serum samples from all rats and related metabolic pathways. The results indicated that body weight, fasting blood glucose (FBG), fasting blood insulin (FINS), blood triglyceride concentration (TG), high-density lipoprotein cholesterol (HDL-C), insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI), and impaired islet cells were significantly improved after the high dose of AGE (H_AGE) and metformin treatment. Metabolomics analysis identified 101 potential biomarkers among which 94 metabolites had an obvious callback. These potential biomarkers were mainly enriched in nine metabolic pathways linked to amino acid metabolism and lipid metabolism. Tryptophan metabolism and glutathione metabolism, as differential metabolic pathways between AGE and metformin for treating T2DM, were further explored. Further analysis of the aforementioned results suggested that the anti-T2DM effect of AGE was closely associated with inflammation, oxidative stress, endothelial dysfunction, dyslipidemia, immune response, insulin resistance, insulin secretion, and T2DM-related complications. This study can provide powerful support for the systematic exploration of the mechanism of AGE against T2DM and a basis for the clinical diagnosis of T2DM.