bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer
Authors: Clark Gene Chatman , Hampton James David , Koblinski Jennifer E. , Quinn Bridget , Mahmoodi Sitara , Metcalf Olga , Guo Chunqing , Peterson Erica , Fisher Paul B. , Farrell Nicholas P. , Wang Xiang-Yang , Mikkelsen Ross B.
Published: August 2022

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.
Cost-effectiveness analysis of personalised versus standard dosimetry for selective internal radiation therapy with TheraSphere in patients with hepatocellular carcinoma
Authors: Rognoni Carla , Barcellona Maria Rosa , Bargellini Irene , Bavetta Maria Grazia , Bellò Marilena , Brunetto Maurizia , Carucci Patrizia , Cioni Roberto , Crocetti Laura , D’Amato Fabio , D’Amico Mario , Deagostini Simona , Deandreis Désirée , De Simone Paolo , Doriguzzi Andrea , Finessi Monica , Fonio Paolo , Grimaldi Serena , Ialuna Salvatore , Lagattuta Fabio , Masi Gianluca , Moreci Antonio , Scalisi Daniele , Virdone Roberto , Tarricone Rosanna
Published: August 2022

Aims

To perform a cost-effectiveness analysis (CEA) comparing personalised dosimetry with standard dosimetry in the context of selective internal radiation therapy (SIRT) with TheraSphere for the management of adult patients with locally advanced hepatocellular carcinoma (HCC) from the Italian Healthcare Service perspective.

Materials and methods

A partition survival model was developed to project costs and the quality-adjusted life years (QALYs) over a lifetime horizon. Clinical inputs were retrieved from a published randomised controlled trial. Health resource utilisation inputs were extracted from the questionnaires administered to clinicians in three oncology centres in Italy, respectively. Cost parameters were based on Italian official tariffs.

Results

Over a lifetime horizon, the model estimated the average QALYs of 1.292 and 0.578, respectively, for patients undergoing personalised and standard dosimetry approaches. The estimated mean costs per patient were €23,487 and €19,877, respectively. The incremental cost-utility ratio (ICUR) of personalised versus standard dosimetry approaches was €5,056/QALY.

Conclusions

Personalised dosimetry may be considered a cost-effective option compared to standard dosimetry for patients undergoing SIRT for HCC in Italy. These findings provide evidence for clinicians and payers on the value of personalised dosimetry as a treatment option for patients with HCC.
Case report: Intravitreal methotrexate in intraocular acute lymphoblastic leukemia
Authors: Pederzolli Matteo , Giglio Fabio , Cicinelli Maria Vittoria , Marchese Alessandro , Modorati Giulio , Mastaglio Sara , Ciceri Fabio , Bandello Francesco , Miserocchi Elisabetta
Published: August 2022

Direct leukemic infiltration of the eye is most frequently associated with acute lymphoblastic leukemia (ALL), probably due to its well-known central nervous system (CNS) tropism. Systemic treatment alone may not be sufficient for intraocular leukemia. Data on local treatment are scarce. Here, we present two cases of intraocular ALL treated with intravitreal methotrexate (MTX). Initially, anatomical improvement and visual stability were observed. The first patient experienced anatomical and visual worsening after a year of treatment. Treatment was withheld after 2 months for the second patient due to poor systemic conditions. Corneal toxicity and intraocular pressure elevation were observed in the first case. In both cases, eye involvement was associated with CNS or systemic relapse. This highlights the importance of incorporating ocular disease management in a comprehensive approach to therapy. Our experience corroborates previous findings on MTX injections as an effective and safe therapeutic option for intraocular leukemia. Further evidence is needed to consolidate the use of intravitreal MTX to treat such a debilitating localization of leukemia.
Effect of glycated hemoglobin A1c on the survival of patients with oral squamous cell carcinoma: A multi-institutional database cohort study
Authors: Chao Chun-Yuan , Luo Sheng-Dean , Chen Wei-Chih , Wu Shao-Chun , Chiu Tai-Jan , Wang Yu-Ming , Yang Yao-Hsu , Fang Fu-Min , Li Shau-Hsuan , Li Chung-Yi , Wu Ching-Nung
Published: August 2022

Objectives

Few studies have evaluated the impact of blood glucose levels on cancer prognosis. We investigated the association between hemoglobin A1c (HbA1c) and survival in oral squamous cell carcinoma (OSCC) patients.

Materials and Methods

A 19-year retrospective cohort study of OSCC patients was performed using the Chang Gung Research Database to identify and enroll 7279 patients diagnosed with OSCC between January 2001 and June 2020. A total of 3600 patients were recruited after performing 1:2 frequency-matching between patients with DM and non-DM. A Cox’s regression model was used to evaluate the relative hazards of all-cause mortality (ACM) and disease-specific mortality (DSM) in relation to HbA1c.

Results

An unadjusted Cox’s regression model indicated that DM, in addition to high levels of HbA1c, were statistically prognostic of poor survival. An adjusted hazard ratio (aHR) of HbA1c ≥ 8% interval at the initial diagnosis of OSCC was statistically higher for DSM (1.25 to 2.24) compared to the non-DM group in different regression models. Considering the effect of sustained HbA1c control in 699 patients, the aHR of mean HbA1c ≥ 9% interval was statistically higher for ACM (1.78 to 2.13) compared to the reference group (7% ≤ HbA1c< 8%). In addition, increased hazards of ACM (2.09 to 2.18) and DSM (2.20 to 2.41) were consistently observed in the highest quartiles of average real variability of HbA1c.

Conclusion

Poor and unstable control of HbA1c could strongly predict the risks of mortality in OSCC patients with DM.
Is robotic distal pancreatectomy better than laparoscopic distal pancreatectomy after the learning curve? A systematic review and meta-analysis
Authors: Chen Chuwen , Hu Jing , Yang Hao , Zhuo Xuejun , Ren Qiuping , Feng Qingbo , Wang Miye
Published: August 2022

Aim

The aim of this study was to compare the safety and overall effect of robotic distal pancreatectomy (RDP) to laparoscopic distal pancreatectomy (LDP) after the learning curve, especially in perioperative outcome and short-term oncological outcome.

Methods

A literature search was performed by two authors independently using PubMed, Embase, and Web of Science to identify any studies comparing the results of RDP versus LDP published until 5 January 2022. Only the studies where RDP was performed in more than 35 cases were included in this study. We performed a meta-analysis of operative time, blood loss, reoperation, readmission, hospital stay, overall complications, major complications, postoperative pancreatic fistula (POPF), blood transfusion, conversion to open surgery, spleen preservation, tumor size, R0 resection, and lymph node dissection.

Results

Our search identified 15 eligible studies, totaling 4,062 patients (1,413 RDP). It seems that the RDP group had a higher rate of smaller tumor size than the LDP group (MD: −0.15; 95% CI: −0.20 to −0.09; p < 0.00001). Furthermore, compared with LPD, RDP was associated with a higher spleen preservation rate (OR: 2.19; 95% CI: 1.36–3.54; p = 0.001) and lower rate of conversion to open surgery (OR: 0.43; 95% CI: 0.33–0.55; p < 0.00001). Our study revealed that there were no significant differences in operative time, overall complications, major complications, blood loss, blood transfusion, reoperation, readmission, POPF, and lymph node dissection between RDP and LDP.

Conclusions

RDP is safe and feasible for distal pancreatectomy compared with LDP, and it can reduce the rate of conversion to open surgery and increase the rate of spleen preservation, which needs to be further confirmed by quality comparative studies with large samples.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/#recordDetails.
Bioactive peptides from venoms against glioma progression
Authors: Majc Bernarda , Novak Metka , Lah Tamara T. , Križaj Igor
Published: August 2022

Venoms are complex mixtures of different molecules and ions. Among them, bioactive peptides have been found to affect cancer hallmarks, such as cell proliferation, cell invasion, cell migration, and can also modulate the immune response of normal and cancer-bearing organisms. In this article, we review the mechanisms of action on these cancer cell features, focusing on bioactive peptides being developed as potential therapeutics for one of the most aggressive and deadly brain tumors, glioblastoma (GB). Novel therapeutic approaches applying bioactive peptides may contribute to multiple targeting of GB and particularly of GB stem cells. Bioactive peptides selectively target cancer cells without harming normal cells. Various molecular targets related to the effects of bioactive peptides on GB have been proposed, including ion channels, integrins, membrane phospholipids and even immunomodulatory treatment of GB. In addition to therapy, some bioactive peptides, such as disintegrins, can also be used for diagnostics or are used as labels for cytotoxic drugs to specifically target cancer cells. Given the limitations described in the last section, successful application in cancer therapy is rather low, as only 3.4% of such peptides have been included in clinical trials and have passed successfully phases I to III. Combined approaches of added bioactive peptides to standard cancer therapies need to be explored using advanced GB in vitro models such as organoids. On the other hand, new methods are also being developed to improve translation from research to practice and provide new hope for GB patients and their families.
MTBP enhances the activation of transcription factor ETS-1 and promotes the proliferation of hepatocellular carcinoma cells
Authors: Wang Hongbo , Chu Fang , Zhijie Li , Bi Qian , Lixin Li , Zhuang Yunlong , Xiaofeng Zhang , Niu Xiaofeng , Zhang Dali , Xi He , Li Bo-an
Published: August 2022

Increasing evidence indicates that the oncoprotein murine double minute (MDM2) binding protein (MTBP) can be considered a pro-oncogene of human malignancies; however, its function and mechanisms in hepatocellular carcinoma (HCC) are still not clear. In the present work, our results demonstrate that MTBP could function as a co-activator of transcription factor E26 transformation-specific sequence (ETS-1), which plays an important role in HCC cell proliferation and/or metastasis and promotes proliferation of HCC cells. Using luciferase and real-time polymerase chain reaction (qPCR) assays, MTBP was found to enhance the transcription factor activation of ETS-1. The results from chromatin co-immunoprecipitation showed that MTBP enhanced the recruitment of ETS-1 to its downstream gene’s (mmp1’s) promoter region with ETS-1 binding sites. In cellular and nude mice models, overexpression of MTBP was shown to promote the proliferation of MHCC97-L cells with low endogenous MTBP levels, whereas the knockdown of MTBP led to inhibition of the proliferation of MHCC97-H cells that possessed high endogenous levels of MTBP. The effect of MTBP on ETS-1 was confirmed in the clinical specimens; the expression of MTBP was positively correlated with the downstream genes of ETS-1, mmp3, mmp9, and uPA. Therefore, by establishing the role of MTBP as a novel co-activator of ETS-1, this work expands our knowledge of MTBP or ETS-1 and helps to provide new ideas concerning HCC-related research.
Procalcitonin levels in preterm newborns: Reference ranges during the first three days of life
Authors: Tuoni Cristina , Ciantelli Massimiliano , Morganti Riccardo , Violi Martina , Tamagnini Sara , Filippi Luca
Published: August 2022

Background

Sepsis is one of the most important causes of morbidity and mortality in the neonatal period, especially in preterms. Diagnosis is difficult because of specific signs and symptoms. The diagnostic gold standard is blood culture, but its sensibility is low. Much effort has been made to identify early, sensitive, and specific diagnostic markers; among these markers particular attention was paid to procalcitonin. However, reference ranges of serum procalcitonin (PCT) shortly after birth have not been sufficiently studied in healthy preterms, and literature is still contradictory.

Objectives

The aim of the study is to define PCT age-specific reference ranges in the first 72 h of life in uninfected VLBW preterms.

Methods

Serum levels of PCT were assessed for each newborn at birth and every 24 h until the 3rd day of life. The eligible patients were classified into two groups according to their sepsis status.

Results

Approximately 343 patients were enrolled; 28 were septic and 315 non-septic. In non-septic infants, 1,015 determinations of PCT values were performed. Our data showed a trend in average value of PCT to increase after birth up to a peak between 24 and 48 h of life and, subsequently, to fall. The average peak value was 15.12 ng/ml achieved at nearly 36 h of life.

Conclusion

Our study shows a PCT nomogram of healthy preterms, which is different from the one of term newborns. Data agree with what is reported in literature on the reference ranges and trends of PCT in non-septic preterms shortly after birth.
The ethical challenges of palliative care from the perspectives of pediatricians: A qualitative study in Iran
Authors: Zahedi Farzaneh , Kadivar Maliheh , Khanali Mojen Leila , Asadabadi Mahsa , Tajalli Saleheh , Ilkhani Mahnaz , Barasteh Salman , Elahikhah Maryam , Larijani Bagher
Published: August 2022

Background

Adherence to ethical principles is a requirement for palliative care delivery to children and a main concern of healthcare providers. Physicians usually face ethical challenges during their daily practice in hospitals and need adequate skills and the ability to identify and manage them. This study sought to explore the ethical challenges of palliative care from the perspectives of pediatricians.

Methods

This qualitative study was conducted between April and July 2019 using the content analysis approach. Participants were fifteen pediatric medical residents, specialists, and subspecialists purposively recruited from pediatric hospitals in Tehran, Iran. Data were collected using in-depth semi-structured interviews and were analyzed using Graneheim and Lundman's approach to conventional content analysis. Trustworthiness was ensured through the four criteria proposed by Guba and Lincoln.

Results

Participants' experiences of the ethical challenges of palliative care for children were grouped into two main categories, namely “bewilderment in dealing with children and their families” (with two subcategories) and “conflicts in decision making” (with three subcategories). The final five subcategories were: (a) inability to effectively communicate with children and their families, (b) inability to tell the truth about the disease, (c) physician-parent conflicts, (d) parent-child conflicts, and (e) physician-physician conflicts.

Conclusion

The main ethical challenges of palliative care from the perspectives of Iranian pediatricians are the inability to effectively communicate with children and their families, the inability to tell them the truth, and the inability to manage physician-parent, parent-child, and physician-physician conflicts. Identification and management of these challenges may help improve the quality of pediatric palliative care in Iran. Further studies are needed to confirm these findings in other settings.
Differential diagnosis and long-term outcomes of non-atrophic duodenal changes in children
Authors: Kröger Sofia , Repo Marleena , Hiltunen Pauliina , Vornanen Martine , Huhtala Heini , Kivelä Laura , Kurppa Kalle
Published: August 2022

Objectives and study

Gastrointestinal endoscopy is often performed when investigating abdominal complaints in children. While atrophic changes of the duodenal mucosa are usually caused by celiac disease, the prevalence and clinical significance of non-atrophic duodenal changes are less clear. We studied these issues in a large pediatric endoscopic cohort.

Methods

Comprehensive data on clinical features, diagnostic findings and long-term outcomes of children who had undergone upper gastrointestinal endoscopy with systematic duodenal sampling were collected. Study variables were compared between children with non-atrophic changes and normal histology, and between those with non-atrophic changes who did and did not receive a diagnosis.

Results

The study comprised 1,170 consecutive children, of whom 51 (4.4%) had non-atrophic and 315 (26.9%) atrophic duodenal changes and 804 (68.7%) normal histology. The most common non-atrophic findings were non-specific inflammation (n = 19) and intraepithelial lymphocytosis (n = 14). Patients with non-atrophic changes presented more often with blood in stools (23.5 vs. 11.3%; p = 0.009), anemia (43.2 vs. 36.5%; p = 0.028) and positive celiac serology (34.3 vs. 12.9%; p < 0.001) than those with a normal duodenum. Twenty-four (44%) of those with non-atrophic changes received an initial diagnosis, the most common of which were inflammatory bowel disease (IBD) (n = 8), Helicobacter pylori infection (n = 3) and food allergy (n = 3). The prevalence of the diagnoses did not differ from those with a normal duodenum. Those who received a diagnosis had more often blood in stools (37.5 vs. 11.1%; p = 0.027), anemia (70.6 vs. 20.0%; p = 0.002) and negative celiac serology (50.0 vs. 7.7%; p = 0.013) than those without diagnosis. During a follow-up of 6.1–13.3 years, five of the 12 initially undiagnosed seropositive patients developed celiac disease, and one patient also developed ulcerative colitis.

Conclusion

Non-atrophic duodenal changes are relatively common and associated with anemia, blood in stools, and positive celiac disease serology. Excluding potential celiac disease, those without an initial diagnosis have a favorable long-term prognosis.
Evaluation of the safety of using harmonic scalpel during laparoscopic cholecystectomy in children: A preliminary report
Authors: Aboelela Ahmed , Abouheba Mohamed , Khairi Ahmed , Kotb Mostafa
Published: August 2022

Background and objective

In spite of being one of the most common surgical procedures performed in adults, laparoscopic cholecystectomy (LC) is relatively uncommon in the pediatric age group. Most surgeons prefer to dissect the cystic duct using a monopolar electrosurgical hook and occlude it with simple metal clips. Although the safety of using the ultrasonically-activated shears, e.g., harmonic scalpel for dissection of the gallbladder is confirmed in many studies, its efficacy in the closure of the cystic artery and duct in adults is still debatable. Furthermore, very few reports studied its safety in children during LC. The aim of our work is to study the safety and efficacy of ultrasonic shears in controlling the cystic duct and artery during LC in children.

Materials and methods

A prospective study was conducted from May 2017 to April 2020, where all children having symptomatic gallbladder stone disease were included in the study. HS was used as a sole instrument in gallbladder dissection as well as in controlling cystic duct and artery. No metal clips or sutures were used throughout the procedure.

Results

A total of forty-two children having symptomatic gallstone disease were included in the study. The main indication for LC was hemolytic anemia. Their age ranged from 3 to 13 years with a mean of 8.4 ± 3.25 years. All operations were completed laparoscopically, i.e., no conversion to open surgery was needed. The mean operative time was 40 ± 10.42 min. There were no intraoperative complications apart from gall bladder perforation in two cases during dissection from the liver bed while the postoperative recovery was smooth in all patients. Patients started oral feeding after 11.30 ± 3.01 h. The mean time for discharge was 25.47 ± 7.49 h, ranging from 14 to 48 h. Postoperative ultrasound for all cases showed no evidence of minor or major bile leaks or CBD injuries.

Conclusion

This is the first report to evaluate the use of HS as a sole instrument during LC in the pediatric age group. HS is a safe and efficient instrument that can be used alone in gallbladder dissection as well as in controlling cystic duct and artery during LC in children.
Epithelial immunomodulation by aerosolized Toll-like receptor agonists prevents allergic inflammation in airway mucosa in mice
Authors: Goldblatt David L. , Valverde Ha Gabriella , Wali Shradha , Kulkarni Vikram V. , Longmire Michael K. , Jaramillo Ana M. , Chittuluru Rosha P. , Fouts Adrienne , Martinez-Moczygemba Margarita , Lei Jonathan T. , Huston David P. , Tuvim Michael J. , Dickey Burton F. , Evans Scott E.
Published: August 2022

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness, and airway remodeling. Epidemiologic data reveal that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via expression of myriad Toll-like receptors (TLRs) and other pattern-recognition receptors. We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 (“Pam2”, TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 (“ODN”, TLR9 ligand), when delivered together by aerosol (“Pam2ODN”), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae (Ao) mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN immunomodulation lowers the allergic responsiveness of the lung, and reduces the likelihood of inappropriate sensitization to aeroallergens. Furthermore, Pam2 and ODN cooperated synergistically suggesting that this treatment is superior to any single agonist in the setting of allergen immunotherapy.
Exosomes: A novel insight into traditional Chinese medicine
Authors: Mo Chao , Zhao Jie , Liang Jingyan , Wang Huiling , Chen Yu , Huang Guodong
Published: August 2022

Exosomes are small extracellular vesicles and play an essential role in the mediation of intercellular communication both in health and disease. Traditional Chinese medicine (TCM) has historically been used to maintain human health and treat various diseases up till today. The interplay between exosomes and TCM has attracted researchers’ growing attention. By integrating the available evidence, TCM formulas and compounds isolated from TCM as exosome modulators have beneficial effects on multiple disorders, such as tumors, kidney diseases, and hepatic disease, which may associate with inhibiting cells proliferation, anti-inflammation, anti-oxidation, and attenuating fibrosis. Exosomes, a natural delivery system, are essential in delivering compounds isolated from TCM to target cells or tissues. Moreover, exosomes may be the potential biomarkers for TCM syndromes, providing strategies for TCM treatment. These findings may provide a novel insight into TCM from exosomes and serve as evidence for better understanding and development of TCM.
Fluoxetine increases astrocytic glucose uptake and glycolysis in corticosterone-induced depression through restricting GR-TXNIP-GLUT1 Pathway
Authors: Pan Shu-Man , Zhou Yi-Fan , Zuo Na , Jiao Rui-Qing , Kong Ling-Dong , Pan Ying
Published: August 2022

Antidepressant fluoxetine can affect cerebral glucose metabolism in clinic, but the underlying molecular mechanism remains poorly understood. Here, we examined the effect of fluoxetine on brain regional glucose metabolism in a rat model of depression induced by repeated corticosterone injection, and explored the molecular mechanism. Fluoxetine was found to recover the decrease of 18F-fluorodeoxyglucose (18F-FDG) signal in prefrontal cortex (PFC), and increased 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG, a fluorescent glucose analog) uptake in an astrocyte-specific manner in ex vivo cultured PFC slices from corticosterone-induced depressive rats, which were consistent with its improvement of animal depressive behaviors. Furthermore, fluoxetine restricted nuclear translocation of glucocorticoid receptor (GR) to suppress the transcription of thioredoxin interacting protein (TXNIP). Subsequently, it promoted glucose transporter 1 (GLUT1)-mediated glucose uptake and glycolysis of PFC astrocytes through suppressing TXNIP expression under corticosterone-induced depressive state. More importantly, fluoxetine could improve glucose metabolism of corticosterone-stimulated astrocytes via TXNIP-GLUT1 pathway. These results demonstrated that fluoxetine increased astrocytic glucose uptake and glycolysis in corticosterone-induced depression via restricting GR-TXNIP-GLUT1 pathway. The modulation of astrocytic glucose metabolism by fluoxetine was suggested as a novel mechanism of its antidepressant action.
Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE): Protocol for a mixed-methods research study
Authors: Chen Yuanyuan , Tian Ziyu , Wang Shuyan , Liu Hongmei , Liu Yanfang , Peng Wei , Lai Xinxing , Qi Dahe , Kong Lingbo , Gao Ying
Published: August 2022

Background: As the only traditional Chinese medicine injection approved by the China Food and Drug Administration for use as stroke first aid in ambulances, Xingnaojing Injection (XNJI) has been widely used in cases of both acute ischemic stroke (IS) and intracerebral hemorrhage (ICH). However, there is no robust clinical evidence regarding the efficacy and safety of the early use of XNJI during stroke first aid. The main purpose of this trial is to observe whether XNJI, intravenously administered within 24 h of onset in the prehospital ambulance setting, protects against early neurological deterioration (END) on the third day of onset in patients with acute stroke.

Methods: The Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE) is a Mixed-Methods research (MMR) study that involves a combination of quantitative and qualitative research. The quantitative research part of this project is a prospective, multicenter, observational, clinical registry study, for which we aimed to recruit 1,000 patients with acute stroke (IS and ICH). Based on our observation of whether XNJI was intravenously administered within 24 h of onset in the prehospital ambulance setting, patients with acute stroke will be divided into two groups: the exposure group comprising patients who were intravenously administered XNJI and the nonexposure group comprising patients who were not. The primary outcome is early neurological deterioration (END) on the third day of onset defined as an increase of 2 or more points in the National Institute of Health Stroke Scale score between baseline and day 3. In addition, based on the aforementioned quantitative research, qualitative research will be conducted by interviewing emergency doctors about their knowledge and attitude regarding XNJI used for stroke first aid.

Discussion: The results of the TRACE study will provide preliminary evidence for the relationship between XNJI used within 24 h of onset and the presence of END on the third day after stroke onset; it will aid in improving the current knowledge regarding the early use of XNJI for stroke first aid.

Clinical Trial Registration:clinicaltrials.gov, identifier NCT04275349
Optineurin-mediated mitophagy as a potential therapeutic target for intervertebral disc degeneration
Authors: Hu Zhilei , Wang Yu , Gao Xiaoxin , Zhang Yuyao , Liu Chenhao , Zhai Yu , Chang Xian , Li Haiyin , Li Yueyang , Lou Jinhui , Li Changqing
Published: August 2022

Low back pain is thought to be mainly caused by intervertebral disc degeneration (IVDD), and there is a lack of effective treatments. Cellular senescence and matrix degradation are important factors that cause disc degeneration. Mitochondrial dysfunction induced by oxidative stress is an important mechanism of cellular senescence and matrix degradation in the nucleus pulposus (NP), and mitophagy can effectively remove damaged mitochondria, restore mitochondrial homeostasis, and mitigate the damage caused by oxidative stress. Optineurin (OPTN) is a selective mitophagy receptor, and its role in intervertebral disc degeneration remains unclear. Here, we aimed to explore the effect of OPTN on H2O2-induced nucleus pulposus cell (NPCs) senescence and matrix degradation in a rat model of disc degeneration. Western blot analysis showed that OPTN expression was reduced in degenerative human and rat nucleus pulposus tissues and increased in H2O2-induced senescent NPCs. OPTN overexpression significantly inhibited H2O2-induced senescence and increased matrix-associated protein expression in NPCs, but OPTN knockdown showed the opposite effect. As previous reports have suggested that mitophagy significantly reduces mitochondrial damage and reactive oxygen species (ROS) caused by oxidative stress, and we used the mitophagy agonist CCCP, the mitophagy inhibitor cyclosporin A (CsA), and the mitochondrial ROS (mtROS) scavenger mitoTEMPO and confirmed that OPTN attenuated NPCs senescence and matrix degeneration caused by oxidative stress by promoting mitophagy to scavenge damaged mitochondria and excess reactive oxygen species, thereby slowing the progression of IVDD. In conclusion, our research suggests that OPTN is involved in IVDD and exerts beneficial effects against IVDD.
TAIGET: A small-molecule target identification and annotation web server
Authors: Wei Xuxu , Yang Jiarui , Li Simin , Li Boyuan , Chen Mengzhen , Lu Yukang , Wu Xiang , Cheng Zeyu , Zhang Xiaoyu , Chen Zhao , Wang Chunxia , Wang Edwin , Zheng Ruiqing , Xu Xue , Shang Hongcai
Published: August 2022

Background: Accurate target identification of small molecules and downstream target annotation are important in pharmaceutical research and drug development.

Methods: We present TAIGET, a friendly and easy to operate graphical web interface, which consists of a docking module based on AutoDock Vina and LeDock, a target screen module based on a Bayesian–Gaussian mixture model (BGMM), and a target annotation module derived from >14,000 cancer-related literature works.

Results: TAIGET produces binding poses by selecting ≤5 proteins at a time from the UniProt ID-PDB network and submitting ≤3 ligands at a time with the SMILES format. Once the identification process of binding poses is complete, TAIGET then screens potential targets based on the BGMM. In addition, three medical experts and 10 medical students curated associations among drugs, genes, gene regulation, cancer outcome phenotype, 2,170 cancer cell types, and 73 cancer types from the PubMed literature, with the aim to construct a target annotation module. A target-related PPI network can be visualized by an interactive interface.

Conclusion: This online tool significantly lowers the entry barrier of virtual identification of targets for users who are not experts in the technical aspects of virtual drug discovery. The web server is available free of charge at http://www.taiget.cn/.
Development of activated endothelial targeted high-density lipoprotein nanoparticles
Authors: Yu Minzhi , Hong Kristen , Adili Reheman , Mei Ling , Liu Lisha , He Hongliang , Guo Yanhong , Chen Y. Eugene , Holinstat Michael , Schwendeman Anna
Published: August 2022

Endothelial inflammation is an important pathophysiological driving force in various acute and chronic inflammatory diseases. High-density lipoproteins (HDLs) play critical roles in regulating endothelial functions and resolving endothelial inflammation. In the present study, we developed synthetic HDLs (sHDLs) which actively target inflamed endothelium through conjugating vascular cell adhesion protein 1 (VCAM-1) specific VHPK peptide. The active targeting of VHPK-sHDLs was confirmed in vitro on TNF-α activated endothelial cells. VHPK-sHDLs presented potent anti-inflammatory efficacies in vitro through the reduction of proinflammatory cytokine production and inhibition of leukocyte adhesion to activated endothelium. VHPK-sHDLs showed increased binding on inflamed vessels and alleviated LPS-induced lung inflammation in vivo. The activated endothelium-targeted sHDLs may be further optimized to resolve endothelial inflammation in various inflammatory diseases.
Exposure of metal toxicity in Alzheimer’s disease: An extensive review
Authors: Islam Fahadul , Shohag Sheikh , Akhter Shomaya , Islam Md. Rezaul , Sultana Sharifa , Mitra Saikat , Chandran Deepak , Khandaker Mayeen Uddin , Ashraf Ghulam Md , Idris Abubakr M. , Emran Talha Bin , Cavalu Simona
Published: August 2022

Metals serve important roles in the human body, including the maintenance of cell structure and the regulation of gene expression, the antioxidant response, and neurotransmission. High metal uptake in the nervous system is harmful because it can cause oxidative stress, disrupt mitochondrial function, and impair the activity of various enzymes. Metal accumulation can cause lifelong deterioration, including severe neurological problems. There is a strong association between accidental metal exposure and various neurodegenerative disorders, including Alzheimer’s disease (AD), the most common form of dementia that causes degeneration in the aged. Chronic exposure to various metals is a well-known environmental risk factor that has become more widespread due to the rapid pace at which human activities are releasing large amounts of metals into the environment. Consequently, humans are exposed to both biometals and heavy metals, affecting metal homeostasis at molecular and biological levels. This review highlights how these metals affect brain physiology and immunity and their roles in creating harmful proteins such as β-amyloid and tau in AD. In addition, we address findings that confirm the disruption of immune-related pathways as a significant toxicity mechanism through which metals may contribute to AD.
CGX, a standardized herbal syrup, inhibits colon-liver metastasis by regulating the hepatic microenvironments in a splenic injection mouse model
Authors: Lee Sung-Bae , Hwang Seung-Ju , Son Chang-Gue
Published: August 2022

Background: Colon-liver metastasis is observed in approximately 50% of patients with colorectal cancer and is a critical risk factor for a low survival rate. Several clinical studies have reported that colon-liver metastasis is accelerated by pathological hepatic microenvironments such as hepatic steatosis or fibrosis. Chunggan syrup (CGX), a standardized 13-herbal mixture, has been prescribed to patients with chronic liver diseases, including fatty liver, inflammation and fibrotic change, based on preclinical and clinical evidence.

Aim of the study: In the present study, we investigated anti-liver metastatic the effects of CGX in a murine colon carcinoma (MC38)-splenic injection mouse model.

Materials and methods: C57BL/6N mice were administered with CGX (100, 200 or 400 mg/kg) for 14 days before or after MC38-splenic injection under normal and high-fat diet (HFD) fed conditions. Also, above experiment was repeated without MC38-splenic injection to explore underlying mechanism.

Results: The number of tumor nodules and liver weight with tumors were sup-pressed by preadministration of CGX in both normal and HFD fed mice. Regarding its mechanisms, we found that CGX administration significantly activated epithelial-cadherin (E-cadherin), but decreased vascular endothelial-cadherin (VE-cadherin) in hepatic tissues under MC38-free conditions. In addition, CGX administration significantly reduced hepatic steatosis, via modulation of lipolytic and lipogenic molecules, including activated adenosine monophosphate activated protein kinase (AMPK) and peroxisome proliferator activated receptor-alpha (PPARα).

Conclusion: The present data indicate that CGX exerts an anti-colon-liver metastatic property via modulation of hepatic lipid related microenvironments.
Effect of ouabain on calcium signaling in rodent brain: A systematic review of in vitro studies
Authors: Leite Jacqueline Alves , Pôças Elisa , Maia Gisele Silva , Barbosa Leandro , Quintas Luis Eduardo M. , Kawamoto Elisa Mitiko , Silva Maria Luiza Correia da , Scavone Cristoforo , de Carvalho Luciana E. Drumond
Published: August 2022

The Na+/K+-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na+/K+-ATPase. Here, we conducted a systematic review of the in vitro effects of cardiotonic steroids on Ca2+ in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca2+ signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na+/Ca2+ exchanger and increased intracellular Ca2+, other effects have been reported. Ouabain-mediated Ca2+ signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca2+ increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498, identifier CRD42020204498.
A stepwise strategy integrating metabolomics and pseudotargeted spectrum–effect relationship to elucidate the potential hepatotoxic components in Polygonum multiflorum
Authors: Song Yunfei , Yang Jianbo , Hu Xiaowen , Gao Huiyu , Wang Pengfei , Wang Xueting , Liu Yue , Cheng Xianlong , Wei Feng , Ma Shuangcheng
Published: August 2022

Polygonummultiflorum (PM) Thunb., a typical Chinese herbal medicine with different therapeutic effect in raw and processed forms, has been used worldwide for thousands of years. However, hepatotoxicity caused by PM has raised considerable concern in recent decades. The exploration of toxic components in PM has been a great challenge for a long time. In this study, we developed a stepwise strategy integrating metabolomics and pseudotargeted spectrum–effect relationship to illuminate the potential hepatotoxic components in PM. First, 112 components were tentatively identified using ultraperformance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS). Second, based on the theory of toxicity attenuation after processing, we combined the UPLC-Q-TOF-MS method and plant metabolomics to screen out the reduced differential components in PM between raw and processed PM. Third, the proposed pseudotargeted MS of 16 differential components was established and applied to 50 batches of PM for quantitative analysis. Fourth, the hepatocytotoxicity of 50 batches of PM was investigated on two hepatocytes, LO2 and HepG2. Last, three mathematical models, gray relational analysis, orthogonal partial least squares analysis, and back propagation artificial neural network, were established to further identify the key variables affecting hepatotoxicity in PM by combining quantitative spectral information with toxicity to hepatocytes of 50 batches of PM. The results suggested that 16 components may have different degrees of hepatotoxicity, which may lead to hepatotoxicity through synergistic effects. Three components (emodin dianthrones, emodin-8-O-β-D-glucopyranoside, PM 14-17) were screened to have significant hepatotoxicity and could be used as toxicity markers in PM as well as for further studies on the mechanism of toxicity. Above all, the study established an effective strategy to explore the hepatotoxic material basis in PM but also provides reference information for in-depth investigations on the hepatotoxicity of PM.
Dihydropyridine-derived calcium channel blocker as a promising anti-hantavirus entry inhibitor
Authors: Wang Bin , Pei Jiawei , Zhang Hui , Li Jia , Dang Yamei , Liu He , Wang Yuan , Zhang Liang , Qi Libin , Yang Yuewu , Cheng Linfeng , Dong Yangchao , Qian Airong , Xu Zhikai , Lei Yingfeng , Zhang Fanglin , Ye Wei
Published: August 2022

Hantaviruses, the causative agent for two types of hemorrhagic fevers, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are distributed from Eurasia to America. HFRS and HPS have mortality rates of up to 15% or 45%, respectively. Currently, no certified therapeutic has been licensed to treat hantavirus infection. In this study, we discovered that benidipine hydrochloride, a calcium channel blocker, inhibits the entry of hantaviruses in vitro. Moreover, an array of calcium channel inhibitors, such as cilnidipine, felodipine, amlodipine, manidipine, nicardipine, and nisoldipine, exhibit similar antiviral properties. Using pseudotyped vesicular stomatitis viruses harboring the different hantavirus glycoproteins, we demonstrate that benidipine hydrochloride inhibits the infection by both HFRS- and HPS-causing hantaviruses. The results of our study indicate the possibility of repurposing FDA-approved calcium channel blockers for the treatment of hantavirus infection, and they also indicate the need for further research in vivo.
Identification of a potential diagnostic signature for postmenopausal osteoporosis via transcriptome analysis
Authors: Zeng Rui , Ke Tian-Cheng , Ou Mao-Ta , Duan Li-Liang , Li Yi , Chen Zhi-Jing , Xing Zhi-Bin , Fu Xiao-Chen , Huang Cheng-Yu , Wang Jing
Published: August 2022

Purpose: We aimed to establish the transcriptome diagnostic signature of postmenopausal osteoporosis (PMOP) to identify diagnostic biomarkers and score patient risk to prevent and treat PMOP.

Methods: Peripheral blood mononuclear cell (PBMC) expression data from PMOP patients were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the “limma” package. The “WGCNA” package was used for a weighted gene co-expression network analysis to identify the gene modules associated with bone mineral density (BMD). Least absolute shrinkage and selection operator (LASSO) regression was used to construct a diagnostic signature, and its predictive ability was verified in the discovery cohort. The diagnostic values of potential biomarkers were evaluated by receiver operating characteristic curve (ROC) and coefficient analysis. Network pharmacology was used to predict the candidate therapeutic molecules. PBMCs from 14 postmenopausal women with normal BMD and 14 with low BMD were collected, and RNA was extracted for RT-qPCR validation.

Results: We screened 2420 differentially expressed genes (DEGs) from the pilot cohort, and WGCNA showed that the blue module was most closely related to BMD. Based on the genes in the blue module, we constructed a diagnostic signature with 15 genes, and its ability to predict the risk of osteoporosis was verified in the discovery cohort. RT-qPCR verified the expression of potential biomarkers and showed a strong correlation with BMD. The functional annotation results of the DEGs showed that the diagnostic signature might affect the occurrence and development of PMOP through multiple biological pathways. In addition, 5 candidate molecules related to diagnostic signatures were screened out.

Conclusion: Our diagnostic signature can effectively predict the risk of PMOP, with potential application for clinical decisions and drug candidate selection.
SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer
Authors: Koller Stephanie , Kendler Jonatan , Karacs Jasmine , Wolf Andrea , Kreuzinger Caroline , Von Der Decken Isabel , Mungenast Felicitas , Mechtcheriakova Diana , Schreiner Wolfgang , Gleiss Andreas , Jäger Walter , Cacsire Castillo-Tong Dan , Thalhammer Theresia
Published: August 2022

Patients with high-grade serous ovarian cancer (HGSOC) have a very poor overall survival. Current therapeutic approaches do not bring benefit to all patients. Although genetic alterations and molecular mechanisms are well characterized, the molecular pathological conditions are poorly investigated. Solute carrier organic anion transporter family member 4A1 (SLCO4A1) encodes OATP4A1, which is an uptake membrane transporter of metabolic products. Its expression may influence various signaling pathways associated with the molecular pathophysiological conditions of HGSOC and consequently tumor progression. RNA sequencing of 33 patient-derived HGSOC cell lines showed that SLCO4A1 expression was diverse by individual tumors, which was further confirmed by RT-qPCR, Western blotting and immunohistochemistry. Gene Set Enrichment Analysis revealed that higher SLCO4A1 level was associated with inflammation-associated pathways including NOD-like receptor, adipocytokine, TALL1, CD40, NF-κB, and TNF-receptor 2 signaling cascades, while low SLCO4A1 expression was associated with the mitochondrial electron transport chain pathway. The overall gene expression pattern in all cell lines was specific to each patient and remained largely unchanged during tumor progression. In addition, genes encoding ABCC3 along with SLCO4A1-antisense RNA 1, were associated with higher expression of the SLCO4A1, indicating their possible involvement in inflammation-associated pathways that are downstream to the prostaglandin E2/cAMP axis. Taken together, increased SLCO4A1/OATP4A1 expression is associated with the upregulation of specific inflammatory pathways, while the decreased level is associated with mitochondrial dysfunction. These molecular pathophysiological conditions are tumor specific and should be taken into consideration by the development of therapies against HGSOC.