bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of stereotactic body radiation therapy for locoregional recurrent pancreatic cancer after radical resection
Authors: Ji Xiaoqin , Zhou Bin , Ding Wei , Wang Jiasheng , Jiang Wanrong , Li Yikun , Hu Jun , Sun Xiangdong
Published: July 2022

Objective

This study aimed to analyze the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for locoregional recurrent pancreatic cancer after radical resection.

Methods

Patients with locoregional recurrent pancreatic cancer after surgery treated with SBRT in our institution were retrospectively investigated from January 2010 to January 2020. Absolute neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) recorded at pretreatment were analyzed. Endpoints included overall survival (OS), progression-free survival (PFS) and cumulative incidences of local failure (LF) and metastatic failure (MF).

Results

A total of 22 patients received SBRT with a median prescribed dose of 40 Gy (range of 30-50 Gy)/4 to 7 fractions. The median OS of all patients was 13.6 months (95% CI, 9.6-17.5 months). 0-1 performance status (HR 12.10, 95% CI 2.04-71.81, P=0.006) and ≤2.1 pre-SBRT NLR (HR 4.05, 95% CI 1.21-13.59, P=0.023) were significant predictors of higher OS on multivariable analysis. The median progression-free survival (PFS) of the cohort was 7.5 months (95% CI, 6.5-8.5 months). The median time to LF and MF were 15.6 months and 6.4 months, respectively. The rate of MF as a first event was higher than that of first event LF. Pain relief was observed in all patients (100%) 6 weeks after SBRT. In terms of acute toxicity, grade 1 including fatigue (6, 27.3%), anorexia (6, 27.3%), nausea (4, 18.2%) and leukopenia (4, 18.2%) was often observed. No acute toxicity of grade 4 or 5 was observed. In terms of late toxicity, no treatment-related toxicity was found during follow-up.

Conclusion

This study showed that SBRT can significantly reduce pain, effectively control local tumor progression, and have acceptable toxicity for patients with locoregional recurrence after radical resection of primary pancreatic cancer. Good performance status and lower pre-SBRT NLR were associated with improved overall survival.
Emerging roles of platelets in cancer biology and their potential as therapeutic targets
Authors: Wang Lei , Wang Xueying , Guo Erliang , Mao Xionghui , Miao Susheng
Published: July 2022

The main role of platelets is to control bleeding and repair vascular damage via thrombosis. They have also been implicated to promote tumor metastasis through platelet-tumor cell interactions. Platelet-tumor cell interactions promote tumor cell survival and dissemination in blood circulation. Tumor cells are known to induce platelet activation and alter platelet RNA profiles. Liquid biopsies based on tumor-educated platelet biomarkers can detect tumors and correlate with prognosis, personalized therapy, treatment monitoring, and recurrence prediction. Platelet-based strategies for cancer prevention and tumor-targeted therapy include developing drugs that target platelet receptors, interfere with the release of platelet particles, inhibit platelet-specific enzymes, and utilize platelet-derived “nano-platelets” as a targeted drug delivery platform for tumor therapy. This review elaborates on platelet-tumor cell interactions and the molecular mechanisms and discusses future research directions for platelet-based liquid biopsy techniques and platelet-targeted anti-tumor strategies.
Application of artificial intelligence to pancreatic adenocarcinoma
Authors: Chen Xi , Fu Ruibiao , Shao Qian , Chen Yan , Ye Qinghuang , Li Sheng , He Xiongxiong , Zhu Jinhui
Published: July 2022

Background and Objectives

Pancreatic cancer (PC) is one of the deadliest cancers worldwide although substantial advancement has been made in its comprehensive treatment. The development of artificial intelligence (AI) technology has allowed its clinical applications to expand remarkably in recent years. Diverse methods and algorithms are employed by AI to extrapolate new data from clinical records to aid in the treatment of PC. In this review, we will summarize AI’s use in several aspects of PC diagnosis and therapy, as well as its limits and potential future research avenues.

Methods

We examine the most recent research on the use of AI in PC. The articles are categorized and examined according to the medical task of their algorithm. Two search engines, PubMed and Google Scholar, were used to screen the articles.

Results

Overall, 66 papers published in 2001 and after were selected. Of the four medical tasks (risk assessment, diagnosis, treatment, and prognosis prediction), diagnosis was the most frequently researched, and retrospective single-center studies were the most prevalent. We found that the different medical tasks and algorithms included in the reviewed studies caused the performance of their models to vary greatly. Deep learning algorithms, on the other hand, produced excellent results in all of the subdivisions studied.

Conclusions

AI is a promising tool for helping PC patients and may contribute to improved patient outcomes. The integration of humans and AI in clinical medicine is still in its infancy and requires the in-depth cooperation of multidisciplinary personnel.
Gonadal tumor risk in pediatric and adolescent phenotypic females with disorders of sex development and Y chromosomal constitution with different genetic etiologies
Authors: Lu Liangsheng , Luo Feihong , Wang Xiang
Published: July 2022

Objectives

This retrospective study sought to investigate the risk and proportion of gonadal neoplasms in phenotypic female pediatric patients with DSD and the presence of the Y chromosome and different genetic backgrounds in a single Chinese center.

Materials and Methods

From January 2012 to December 2020, pediatric and adolescent patients with DSD and the presence of the Y chromosome who had unambiguous female genitalia and underwent bilateral gonadectomy or gonadal biopsy were included in this study. Patients’ demographics, karyotype, laboratory test results, gross pathology, and histology of gonadal tissue were all collected. The patients were divided into three groups based on their different genetic backgrounds, and the percentage of gonadal tumors was calculated to assess the risk of gonadal tumor and malignancy by etiology.

Results

A total of 22 patients with DSD and an unambiguous female phenotype with a Y chromosome were recruited. The mean age was 10.91 ± 4.99 years (9 months to 19 years). Gonadal neoplasia was confirmed in six (27.3%) cases by pathological examination of surgical gonadal tissue samples. Among 44 gonadal samples from these 22 patients, the following were identified: five gonadoblastomas, three dysgerminomas, and two Leydig cell tumors. The youngest patient with a tumor was a 2-year-old girl with 46,XY complete gonadal dysgenesis (46,XY CGD or Swyer syndrome) and bilateral gonadoblastoma. Patients with 46,XY complete gonadal dysgenesis (4/6; 66.7%) had the highest tumor occurrence rate. Among 10 patients with Turner syndrome with the presence of the Y chromosome, only one patient was diagnosed with a gonadal tumor. Leydig cell tumor was diagnosed in only one of six patients with 46,XY androgen synthesis/action disorders.

Conclusion

Pediatric patients with 46,XY complete gonadal dysgenesis had a significantly increased risk of developing gonadal tumors and underwent prophylactic gonadectomy as soon as the diagnosis was confirmed, whereas those with Turner syndrome with Y chromosome and 46,XY androgen synthesis/action disorders had a relatively low risk. In view of the limited number of patients, a large multicenter study with close follow-ups is needed to support these conclusions.
Separation Practices in Children and Adolescents Admitted for Suicidal Behavior: A National Survey of French Psychiatrists
Authors: Payet Maymouna Mourouvaye , Bonfils Nicolas A. , Ouss Lisa , Fourcade Lola J. , Touati-Pellegrin Marie , Golse Bernard , Cohen Jérémie F. , Woestelandt Laure
Published: July 2022

Objectives

To assess practices of French psychiatrists regarding their management of children and adolescents with suicidal behaviors, focusing on the use of a separation protocol in which the youths are separated from their relatives.

Methods

In 2017, we conducted an online cross-sectional survey of French psychiatrists caring for children and adolescents. Participants were asked to describe their practice of a separation protocol in children and adolescents admitted for suicidal behavior. Our main analysis followed a descriptive approach. We also explored whether participant characteristics were associated with the use of a separation protocol.

Results

The response rate was 218/2403 (9,1%); 57.9 % of respondents worked in a University hospital, and 60% of respondents reported routinely hospitalizing children. A separation protocol was set up by 91.1% of survey participants (systematically 39.6%, on a case-by-case basis 51.5%). The mean age from which a separation protocol was indicated was above 11 years; 64% of participants reported a separation period of ≤ 48 h. The most common (87%) criterion cited for establishing a separation period was family relationship difficulties. The most common (80.9%) reason to justify the use of a separation protocol was to allow a better clinical assessment. Exploratory analyses did not identify any participant characteristics associated with the use of a separation protocol (p > 0.2 for all).

Conclusion

The use of a separation protocol in children and adolescents admitted for suicidal behavior is a widespread practice in France, despite the deprivation of liberty it implies. This raises the question of the relevance and usefulness of such a practice.
The second-tier status of fragile X syndrome testing for unexplained intellectual disability/global developmental delay in the era of next-generation sequencing
Authors: Zhang Wen , Li Dong , Pang Nan , Jiang Li , Li Baomin , Ye Fanghua , He Fang , Chen Shimeng , Liu Fangyun , Peng Jing , Yin Jinghua , Yin Fei
Published: July 2022

Objective

Although many unexplained intellectual disability/global developmental delay (ID/GDD) individuals have benefited from the excellent detection yield of copy number variations and next-generation sequencing testing, many individuals still who suffer from ID/GDD of unexplained etiology. In this study, we investigated the applicability of fragile X syndrome (FXS) testing in unexplained ID/GDD individuals with negative or absent genetic testing.

Methods

In this study, we used the triplet repeat primed polymerase chain reaction to evaluate the value and application of fragile X testing in unexplained ID/GDD individuals with negative or absent genetic testing (n = 681) from three hospitals.

Results

Of the 681 ID/GDD individuals with negative or absent genetic testing results detected by FXS testing, 12 men and one woman were positive. This corresponded to a diagnostic yield of 1.9% for FXS testing in our cohort. All FXS individuals had either a family history of ID/GDD or suggestive clinical features. The detection yield of FXS testing in ID/GDD individuals who completed genetic testing (2.70%, 12/438) was significantly higher than in individuals without any genetic testing (0.40%, 1/243).

Conclusions

This is the first report of FXS testing in ID/GDD individuals who lacked previous genetic testing, which promotes standardization of the FXS diagnostic process. These results highlight the utility of FXS testing of unexplained ID/GDD individuals with negative results from standard genetic testing. In the era of next-generation sequencing, FXS testing is more suitable as a second-tier choice and provides clinicians and geneticists with auxiliary references for tracing the etiology of ID/GDD.
Rare cause of coronary artery ectasia in children: A case report of methylmalonic acidemia with hyperhomocysteinemia
Authors: Juan Tu , Chao-ying Chen , Hua-rong Li , Ling Wan
Published: July 2022

Background

Methylmalonic acidemia (MMA) with hyperhomocysteinemia is caused by cobalamin deficiency, mainly due to disturbance of cobalamin C (cblC) metabolism. Its clinical manifestations involve many organs. However, cases of coronary artery ectasia have been rarely reported.

Case presentation

Here, we report the case of a 4-year-old girl who was hospitalized mainly because of pallor, brown urine, and fatigue, followed by hypertension, renal insufficiency, hemolytic anemia, cardiac enlargement, cardiac insufficiency, and coronary artery ectasia. Thrombotic microangiopathy (TMA) was confirmed by renal pathological examination. Metabolic examination showed hyperhomocysteinemia and methylmalonic aciduria. Furthermore, genetic assessment confirmed MMACHC gene variant, which confirmed the final diagnosis of a cblC defect. Intramuscular injection of hydroxy-cobalamin, oral medications of betaine, levocarnitine, folic acid, and aspirin were administered. Three months later, the patient’s condition was significantly improved. Anemia was corrected, and the renal function was normal. Heart size, cardiac function, and coronary artery structure completely returned to normal.

Conclusion

The clinical manifestation of cblC deficiency is atypical. This critical condition may be associated with multiple organ involvement. A rare complication, coronary artery ectasia, can also occur. Early identification, careful evaluation, and appropriate treatment are crucially important for the improvement of this disease prognosis.
Using a route planner to optimize door-to-door visits for a pediatric home-hospitalization program: Feasibility study
Authors: Batlle Astrid , Boada Imma , Thió-Henestrosa Santiago , Sevilla Mariona Fernández de , García-García Juan José
Published: July 2022

Background

Hospital Sant Joan de Déu (Barcelona) initiated a pediatric acute home-hospitalization program. Due to high patient turnover and the health staff's lack of planning training, daily scheduling was a time-consuming task. Home-hospitalization planning is a vehicle routing problem that can be solved with a technological solution. It was therefore decided to evaluate the efficacy and necessity of the SmartMonkey.io planner.

Objectives

To compare traditional manual route planning with a route optimizer, and to evaluate the technical feasibility of the implementation of a route planner into a homecare program.

Methods

Eight participants (experienced homecare staff and inexperienced hospital staff) were included. Personal interviews were performed to assess their eagerness to try a technological solution to the planning problem. Objective benefits including reduced travel time (time planning, distance traveled, and time traveled) were evaluated. Paired t-test, t-test, and Pearson's correlation were used to compare manual and route planner scheduling. Participants then answered a questionnaire to assess planning difficulty and the acceptance of the route planner.

Results

Homecare staff were initially reluctant to use the technology. Significant differences (P < 0.0001) in three variables were found between manual planning and the route planner. A moderate correlation between time planning and plan difficulty (r = 0.59, P < 0.0001) was found with manual planning but not with the route planner. All route planner schedules saved time and distance. No significant differences were found between expertise and planning method. It was noted that it was easy to create plans with the route planner, while difficulty with manual planning increased as more locations were added. All participants evaluated the route planning tool favorably.

Conclusions

Route-planning technology saved planning time and generated better plans than manual planning. The route planner's learning curve was fast and results were obtained in the same amount of time regardless of difficulty and expertise. SmartMonkey.io also has the potential to reduce internal and environmental costs and increase staff productivity.
The relationship of domestic pet ownership with the risk of childhood asthma: A systematic review and meta-analysis
Authors: Ji Xiaoyi , Yao Yuan , Zheng Ping , Hao Chuangli
Published: July 2022

Background and Objective

The relationship between pet ownership and childhood asthma remains controversial. In recent years, there have been increasing studies with large sample size. Therefore, we conducted this systematic review and meta-analysis to evaluate the relationship between pet ownership and childhood asthma.

Method

Relevant research was retrieved from PubMed, Cochrane, EMBASE, and Web of science. The retrieval was as of October 1, 2021. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies. Stata 15.0 was used to conduct the meta-analysis.

Results

A total of 60 studies with large sample size published between 1995 and 2021 were included in this systematic review and meta-analysis, which included 18 cohort studies and 42 case-control studies covering 27 countries and 1,871,295 children. As shown by meta-analysis results, cat ownership (OR = 1.18, 95%CI: 1.05∼1.33) and dog ownership (OR = 1.12, 95%CI: 1.0 0∼1.24) have a significant bearing on the occurrence of childhood asthma. Pet ownership was also positively correlated with the occurrence of severe childhood asthma (OR = 1.15, 95%CI: 1.11∼1.20).

Conclusion

Pet ownership, especially cats and dogs, is associated with the occurrence of asthma in children.
The extended clinical and genetic spectrum of CTNNB1-related neurodevelopmental disorder
Authors: Lee Seungbok , Jang Se Song , Park Soojin , Yoon Jihoon G. , Kim Soo Yeon , Lim Byung Chan , Chae Jong Hee
Published: July 2022

Purpose

Loss-of-function mutations ofCTNNB1have been established as the cause of neurodevelopmental disorder with spastic diplegia and visual defects. Although most patients share key phenotypes such as global developmental delay and intellectual disability, patients withCTNNB1-related neurodevelopmental disorder show a broad spectrum of clinical features.

Methods

We enrolled 13 Korean patients withCTNNB1-related neurodevelopmental disorder who visited Seoul National University Children’s Hospital (5 female and 8 male patients with ages ranging from 4 to 22 years). They were all genetically confirmed as having pathogenic loss-of-function variants inCTNNB1using trio or singleton whole exome sequencing. Variants called from singleton analyses were confirmed to bede novothrough parental Sanger sequencing.

Results

We identified 11de novotruncating variants inCTNNB1in 13 patients, and two pathogenic variants, c.1867C > T (p.Gln623Ter) and c.1420C > T (p.Arg474Ter), found in two unrelated patients, respectively. Five of them were novel pathogenic variants not listed in the ClinVar database. While all patients showed varying degrees of intellectual disability, impaired motor performance, and ophthalmologic problems, none of them had structural brain abnormalities or seizure. In addition, there were three female patients who showed autistic features, such as hand stereotypy, bruxism, and abnormal breathing. A literature review revealed a female predominance of autistic features inCTNNB1-related neurodevelopmental disorder.

Conclusion

This is one of the largest single-center cohorts ofCTNNB1-related neurodevelopmental disorder. This study investigated variable clinical features of patients and has expanded the clinical and genetic spectrum of the disease.
Population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency undergoing hematopoietic stem cell transplantation
Authors: Chen Xiao , Wang Dongdong , Zheng Feng , Zhai Xiaowen , Xu Hong , Li Zhiping
Published: July 2022

The present study aimed to explore the population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency (SCID) undergoing hematopoietic stem cell transplantation (HSCT). Children with SCID undergoing HSCT treated with tacrolimus were enrolled for analysis. Population pharmacokinetics of tacrolimus was built up by a nonlinear mixed-effects model (NONMEM), and initial dose optimization of tacrolimus was simulated with the Monte Carlo method in children weighing <20 kg at different doses. A total of 18 children with SCID undergoing HSCT were included for analysis, with 130 tacrolimus concentrations. Body weight was included as a covariable in the final model. Tacrolimus CL/F was 0.36–0.26 L/h/kg from body weights of 5–20 kg. Meanwhile, we simulated the tacrolimus concentrations using different body weights (5–20 kg) and different dose regimens (0.1–0.8 mg/kg/day). Finally, the initial dose regimen of 0.6 mg/kg/day tacrolimus was recommended for children with SCID undergoing HSCT whose body weights were 5–20 kg. It was the first time to establish tacrolimus population pharmacokinetics in children with SCID undergoing HSCT; in addition, the initial dose optimization of tacrolimus was recommended.
Isoliensinine Suppresses Osteoclast Formation Through NF-κB Signaling Pathways and Relieves Ovariectomy-Induced Bone Loss
Authors: Liu Huijiang , Gu Ronghe , Huang Qian , Liu Yun , Liu Chong , Liao Shijie , Feng Wenyu , Xie Tianyu , Zhao Jinmin , Xu Jiake , Liu Qian , Zhan Xinli
Published: July 2022

Osteoporosis is among the major contributors of pathologic fracture in postmenopausal women, which is caused by the bone metabolic disorder owing to the over-activation of osteoclasts. Inhibition of osteoclast differentiation and maturation has become a mainstream research interest in the prevention of osteoporosis. Isoliensinine (Iso) is a dibenzyl isoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-cancer activities. However, whether it can be used as a potential treatment for osteoporosis remains undiscovered. Here, we investigated whether Iso might suppress the differentiation of osteoclasts in vitro and in vivo to play an anti-osteoporosis role. Our results showed that Iso inhibits the formation of mature multinuclear osteoclasts induced by RANKL, the bone resorption, and the osteoclast-specific genes expression by blocking the nuclear translocation of NF-κB p65, and the effect was in a dosage-dependent way. Furthermore, we investigated the therapeutic effect of Iso on osteoporosis in ovariectomized (OVX) mice. We found that Iso attenuated bone loss in the OVX mice and significantly promoted BS, Conn. DN, Tb.Th, TB.N, and BV/TV Index. All in all, Iso showed a prominent effect of osteoclast inhibition, with great promise for treating osteoporosis.
Cost-Effectiveness Analysis of Capecitabine Plus Oxaliplatin Versus Gemcitabine Plus Oxaliplatin as First-Line Therapy for Advanced Biliary Tract Cancers
Authors: Chen Ruijia , Zhang Yalan , Lin Kongying , Huang Defu , You MaoJin , Lai Yanjin , Wang Jinye , Hu Yingying , Li Na
Published: July 2022

Background: In the first-line treatment of biliary tract cancers (BTCs), XELOX (capecitabine plus oxaliplatin) showed comparable clinical efficacy and safety to gemcitabine and oxaliplatin (GEMOX), with fewer visits and better treatment management. Our study aims to investigate the cost-effectiveness of XELOX and GEMOX as the first-line therapy for BTCs from the perspective of the Chinese healthcare systems and to provide valuable suggestions for clinical decision-making.

Methods: A Markov model was developed using the phase 3 randomized clinical trial (ClinicalTrials.gov number, NCT01470443) to evaluate the cost-effectiveness of XELOX and GEMOX. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used as the primary outcomes of the model. Uncertainty was assessed using univariate and probabilistic sensitivity analysis.

Results: The QALYs for the XELOX and GEMOX groups were 0.66 and 0.54, respectively. In China, the total cost of XELOX treatment is US $12,275.51, which is lower than that of the GEMOX regimen. In addition, XELOX is more effective than GEMOX, making it the preferred regimen. A sensitivity analysis determined that XELOX therapy has a stable economic advantage in China.

Conclusion: Compared to GEMOX, XELOX is a more cost-effective treatment as a first-line treatment for advanced BTC from the perspective of the Chinese health service system.
The potential application of natural products in cutaneous wound healing: A review of preclinical evidence
Authors: Liu E , Gao Hongjin , Zhao YiJia , Pang Yaobing , Yao Yejing , Yang Zhengru , Zhang Xueer , Wang YanJin , Yang Siming , Ma Xiao , Zeng Jinhao , Guo Jing
Published: July 2022

Under normal circumstances, wound healing can be summarized as three processes. These include inflammation, proliferation, and remodeling. The vast majority of wounds heal rapidly; however, a large percentage of nonhealing wounds have still not been studied significantly. The factors affecting wound nonhealing are complex and diverse, and identifying an effective solution from nature becomes a key goal of research. This study aimed to highlight and review the mechanisms and targets of natural products (NPs) for treating nonhealing wounds. The results of relevant studies have shown that the effects of NPs are associated with PI3K-AKT, P38MAPK, fibroblast growth factor, MAPK, and ERK signaling pathways and involve tumor growth factor (TNF), vascular endothelial growth factor, TNF-α, interleukin-1β, and expression of other cytokines and proteins. The 25 NPs that contribute to wound healing were systematically summarized by an inductive collation of the six major classes of compounds, including saponins, polyphenols, flavonoids, anthraquinones, polysaccharides, and others, which will further direct the attention to the active components of NPs and provide research ideas for further development of new products for wound healing.
The human cathelicidin peptide LL-37 inhibits pancreatic cancer growth by suppressing autophagy and reprogramming of the tumor immune microenvironment
Authors: Zhang Zhu , Chen Wen-Qing , Zhang Shi-Qing , Bai Jing-Xuan , Lau Ching-Lam , Sze Stephen Cho-Wing , Yung Ken Kin-Lam , Ko Joshua Ka-Shun
Published: July 2022

Pancreatic cancer is amongst the most lethal malignancies, while its poor prognosis could be associated with promotion of autophagy and the tumor immune microenvironment. Studies have confirmed the pro-tumorigenic nature of the cathelicidin family of peptide LL-37 in several types of cancer. However, at higher doses, LL-37 exerts significant cytotoxicity against gastrointestinal cancer cells. In our study, we investigated the anti-tumorigenic potential of LL-37 in pancreatic cancer and the underlying mechanisms. Our results have shown that LL-37 inhibited the growth of pancreatic cancer both in vitro and in vivo. Mechanistic studies have demonstrated that LL-37 induced DNA damage and cell cycle arrest through induction of reactive oxygen species (ROS). Further study indicates that LL-37 suppressed autophagy in pancreatic cancer cells through activation of mTOR signaling, leading to more accumulation of ROS production and induction of mitochondrial dysfunctions. With combined treatment of LL-37 with the mTOR inhibitor rapamycin, LL-37-induced ROS production and cancer cell growth inhibition were attenuated. Subsequent in vivo study has shown that LL-37 downregulated the immunosuppressive myeloid-derived suppressor cells and M2 macrophages while upregulated the anti-cancer effectors CD8+ and CD4+ T cells in the tumor microenvironment. By using an in vitro co-culture system, it was shown that promotion of M2 macrophage polarization would be suppressed by LL-37 with inhibition of autophagy, which possessed significant negative impact on cancer growth. Taken together, our findings implicate that LL-37 could attenuate the development of pancreatic cancer by suppressing autophagy and reprogramming of the tumor immune microenvironment.
Human Umbilical Cord Blood Mononuclear Cells Ameliorate CCl4-Induced Acute Liver Injury in Mice via Inhibiting Inflammatory Responses and Upregulating Peripheral Interleukin-22
Authors: Zhang Jinming , Zhai Hengben , Yu Pei , Shang Dabao , Mo Ruidong , Li Ziqiang , Wang Xiaolin , Lu Jie , Xie Qing , Xiang Xiaogang
Published: July 2022

Background: Human umbilical cord blood mononuclear cells (hUCBMNCs) show therapeutic effects on many inflammatory diseases. The deterioration of acute liver injury is attributed to excessive inflammatory responses triggered by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Whether hUCBMNCs treatment is a promising strategy for acute liver injury/failure needs to be investigated.

Methods: Liver injury mice induced by PAMPs, DAMPs, or DAMPs plus PAMPs were developed. DAMPs included CCl4 (carbon tetrachloride), APAP (acetaminophen), and ConA (Concanavalin A). PAMPs included Klebsiella pneumoniae (K.P.) and Salmonella typhimurium (S. Typhimurium). DAMP plus PAMP-induced liver injury was developed by sequential CCl4 and K.P. administration. hUCBMNCs were injected intravenously.

Results: hUCBMNCs significantly prolonged mice survival time in DAMP plus PAMP-induced liver failure but had no benefit in bacteria-infected mice. hUCBMNCs significantly alleviated hepatic necrosis post CCl4/ConA insult. In CCl4-induced acute liver injury, peripheral levels of interleukin (IL)-22 were upregulated and liver regeneration was enhanced after treating with hUCBMNCs at 48h. The levels of p62 and LC3B-II, autophagy markers, were also upregulated in the hUCBMNC-treated group.

Conclusion: hUCBMNCs as a kind of cell therapeutic strategy could attenuate acute liver injury in mice, which is executed by enhancing autophagy and regeneration in the liver via inhibiting inflammatory responses and upregulating peripheral IL-22.
Uncovering the Effect and Mechanism of Rhizoma Corydalis on Myocardial Infarction Through an Integrated Network Pharmacology Approach and Experimental Verification
Authors: Li Jingyan , Wu Junxuan , Huang Junying , Cheng Yuanyuan , Wang Dawei , Liu Zhongqiu
Published: July 2022

Background: Myocardial infarction (MI), characterized by reduced blood flow to the heart, is a coronary artery disorder with the highest morbidity and mortality among cardiovascular diseases. Consequently, there is an urgent need to identify effective drugs to treat MI. Rhizoma Corydalis (RC) is the dry tuber of Corydalis yanhusuo W.T. Wang, and is extensively applied in treating MI clinically in China. Its underlying pharmacological mechanism remains unknown. This study aims to clarify the molecular mechanism of RC on MI by utilizing network pharmacology and experimental verification.

Methods: Based on network pharmacology, the potential targets of the RC ingredients and MI-related targets were collected from the databases. Furthermore, core targets of RC on MI were identified by the protein-protein interaction (PPI) network and analyzed with Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecular docking was used to validate the binding affinity between the core targets and the bioactive components. Oxygen-glucose deprivation (OGD) was performed on H9c2 cells to mimic MI in vitro. A Cell Counting Kit-8 assay was used to assess the cardioprotective effect of the active ingredient against OGD. Western blot analysis and RT-qPCR were used to measure the cell apoptosis and inflammation level of H9c2 cells.

Results: The network pharmacology obtained 60 bioactive components of RC, 431 potential targets, and 1131 MI-related targets. In total, 126 core targets were screened according to topological analysis. KEGG results showed that RC was closely related to the phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (PKB, also called Akt) signaling pathway. The experimental validation data showed that tetrahydropalmatine (THP) pretreatment preserved cell viability after OGD exposure. THP suppressed cardiomyocyte apoptosis and inflammation induced by OGD, while LY294002 blocked the inhibition effect of THP on OGD-induced H9c2 cell injury. Moreover, the molecular docking results indicated that THP had the strongest binding affinity with Akt over berberine, coptisine, palmatine, and quercetin.

Conclusion: THP, the active ingredient of RC, can suppress OGD-induced H9c2 cell injury by activating the PI3K/Akt pathway, which in turn provides a scientific basis for a novel strategy for MI therapy and RC application.
Dimethyl Itaconate Attenuates CFA-Induced Inflammatory Pain via the NLRP3/ IL-1β Signaling Pathway
Authors: Lin Jiaqi , Ren Jinxuan , Zhu Bin , Dai Yi , Gao Dave Schwinn , Xia Suyun , Cheng Zhenzhen , Huang Yangyuxin , Yu Lina
Published: July 2022

Itaconate plays a prominent role in anti-inflammatory effects and has gradually been ushered as a promising drug candidate for treating inflammatory diseases. However, its significance and underlying mechanism for inflammatory pain remain unexplored. In the current study, we investigated the effects and mechanisms of Dimethyl Itaconate (DI, a derivative of itaconate) on Complete Freund’s adjuvant (CFA)-induced inflammatory pain in a rodent model. Here, we demonstrated that DI significantly reduced mechanical allodynia and thermal hyperalgesia. The DI-attenuated neuroinflammation was evident with the amelioration of infiltrative macrophages in peripheral sites of the hind paw and the dorsal root ganglion. Concurrently, DI hindered the central microglia activation in the spinal cord. Mechanistically, DI inhibited the expression of pro-inflammatory factors interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) and upregulated anti-inflammatory factor IL-10. The analgesic mechanism of DI was related to the downregulation of the nod-like receptor protein 3 (NLRP3) inflammasome complex and IL-1β secretion. This study suggested possible novel evidence for prospective itaconate utilization in the management of inflammatory pain.
Nodosin Exerts an Anti-Colorectal Cancer Effect by Inhibiting Proliferation and Triggering Complex Cell Death in Vitro and in Vivo
Authors: Fan Huixia , Hao Xiaopeng , Gao Yuan , Yang Jian , Liu Aojun , Su Yarui , Xia Yong
Published: July 2022

Colorectal cancer (CRC) is one of the most common digestive system cancer in the world. Its incidence and mortality are increasing annually. Presently, CRC lacks long-term effective treatment methods and drugs. Therefore, finding new treatment methods and drugs is of great significance for CRC treatment. Compounds derived from natural plants have been widely used in tumor research and treatment because of their good antitumor activity these years. This study found that nodosin, a diterpenoid extracted from the medicinal plant Rabdosia serra (Maxim.) Hara, inhibited the growth of CRC cells SW480, HT-29 and LoVo in a dose- and time-dependent manner, with inhibitory concentrations (IC50) of 7.4, 7.7, and 6.6 μM respectively. We selected highly metastatic and poorly differentiated SW480 cells for further studies. We found that nodosin could inhibit cell proliferation by inhibiting DNA synthesis and induce cell death by inducing oxidative stress, apoptosis and autophagy in cells. Through in vitro assays combined with transcriptomic analysis, it was found that nodosin could downregulate tribbles pseudokinase 3 and upregulate oxidative stress-induced growth inhibitor 1 to induce oxidative stress in cells; nodosin-induced reactive oxygen species were able to upregulate the expression of heme oxygenase 1 to induce apoptosis and the expression of cathepsin L. and light chain-3 to induce autophagy. In vivo, we found that nodosin inhibited tumor growth and induced cells to undergo apoptosis and autophagy without significant toxic effects. In conclusion, our findings suggest that nodosin exerts anti-CRC effects mainly through its ability to induce apoptosis and autophagy in vitro and in vivo. Therefore, our study contributes to the development of nodosin-based potential CRC therapeutic drugs.
ATP indirectly stimulates hippocampal CA1 and CA3 pyramidal neurons via the activation of neighboring P2X7 receptor-bearing astrocytes and NG2 glial cells, respectively
Authors: Zhang Ying , Yin Hai-Yan , Rubini Patrizia , Illes Peter , Tang Yong
Published: July 2022

There is ongoing dispute on the question whether CNS neurons possess ATP-sensitive P2X7 receptors (Rs) or whether only non-neuronal cells bear this receptor-type and indirectly signal to the neighboring neurons. We genetically deleted P2X7Rs specifically in astrocytes, oligodendrocytes and microglia, and then recorded current responses in neurons to the prototypic agonist of this receptor, dibenzoyl-ATP (Bz-ATP). These experiments were made in brain slice preparations taken from the indicated variants of the P2X7R KO animals. In hippocampal CA3, but not CA1 pyramidal neurons, the deletion of oligodendrocytic (NG2 glial) P2X7Rs abolished the Bz-ATP-induced current responses. In contrast to the Bz-ATP-induced currents in CA3 pyramidal neurons, current amplitudes evoked by the ionotropic glutamate/GABAAR agonists AMPA/muscimol were not inhibited at all. Whereas in the CA3 area NG2 glia appeared to mediate the P2X7R-mediated stimulation of pyramidal neurons, in the CA1 area, astrocytic P2X7Rs had a somewhat similar effect. This was shown by recording the frequencies and amplitudes of spontaneous excitatory currents (sPSCs) in brain slice preparations. Bz-ATP increased the sPSC frequency in CA1, but not CA3 pyramidal neurons without altering the amplitude, indicating a P2X7R-mediated increase of the neuronal input. Micro-injection of the selective astrocytic toxin L-α-aminoadipate into both hippocampi, or the in vitro application of the GABAAR antagonistic gabazine, completely blocked the frequency increases of sPSCs. Hence, CA1 and CA3 pyramidal neurons of the mouse did not possess P2X7Rs, but were indirectly modulated by astrocytic and oligodendrocytic P2X7Rs, respectively.
Postoperative Long-Term Outcomes and Independent Risk Factors of Non-Small-Cell Lung Cancer Patients With Propofol versus Sevoflurane Anesthesia: A Retrospective Cohort Study
Authors: Gao Zhenglian , Xu Jian , Coburn Mark , Ma Daqing , Wang Kun
Published: July 2022

Background: Existing studies have shown that the relationship between anesthetic agents and non-small-cell lung cancer (NSCLC) prognosis remains controversial. Therefore, this retrospective cohort study was designed to investigate the effects of propofol or sevoflurane anesthesia on the long-term oncologic outcomes of NSCLC patients.

Methods: We identified 1,778 eligible patients (propofol-based total intravenous anesthesia (TIVA) group, n = 686; sevoflurane-based inhalation anesthesia (INHA) group, n = 1,092) out of 2,388 patients undergoing elective NSCLC surgery from June 2013 to June 2016 in the Harbin Medical University Cancer Hospital. The primary endpoints were five-year overall survival and recurrence-free survival. The secondary endpoints were independent risk factors of cancer recurrence or all-cause mortality. The data were analyzed with propensity score matching, Kaplan–Meier survival, and Cox multivariate analyses as appropriate.

Results: After propensity score matching, there were 672 patients in each group. The median follow-up period was 69 months (interquartile range: 68–70 months) for all patients. Five-year overall survival was 75.7% (95% confidence interval (CI) 72.4–79.1) in the TIVA group and 71.8% (68.4–75.4) in the INHA group (p = 0.160) (hazard ratio (HR), 0.86; 95% CI, 0.70–1.06; p = 0.158), and five-year recurrence-free survival was 68.5% (65.0–72.2) and 62.7% (59.1–66.5 (p = 0.108) (HR, 0.90; 95% CI, 0.75–1.08; p = 0.253), respectively. Subgroup analyses showed there were no significant difference in the overall survival or recurrence-free survival between the two groups in each TNM stage of NSCLC. The independent risk factors included age ≥60 years, male, blood transfusion, segmental/wedge resection and pneumonectomy, thoracotomy, postoperative complications, lung adenocarcinoma, TNM stages, high CEA and CYFRA211 levels, and postoperative radiotherapy.

Conclusions: Our data indicated no difference between the propofol-based TIVA and sevoflurane-based INHA in terms of five-year overall survival and recurrence-free survival after NSCLC surgery.
Comparison of the efficiency of anti-VEGF drugs intravitreal injections treatment with or without retinal laser photocoagulation for macular edema secondary to retinal vein occlusion: A systematic review and meta-analysis
Authors: Zou Weijie , Du Yuanyuan , Ji Xiaoyan , Zhang Ji , Ding Hongping , Chen Jingqiao , Wang Tao , Ji Fangfang , Huang Jiang
Published: July 2022

Objective: To compare the efficiency of anti-VEGF drugs intravitreal injections(IVI) treatment with or without retinal laser photocoagulation(LPC) for macular edema(ME) secondary to retinal vein occlusion(RVO).

Methods: The randomized controlled trials and retrospective studies including anti-VEGF drug IVI combined with retinal LPC and single IVI in the treatment of macular edema secondary to RVO were collected in PubMed, Medline, Embase, Cochrane Library, and Web of Science. We extracted the main outcome indicators including the best corrected visual acuity (BCVA), central macular thickness(CMT), the number of injections and the progress of retinal non-perfusion areas(NPAs) for systematic evaluation, to observe whether IVI + LPC could be more effective on the prognosis of RVO. We use Review Manager 5.4 statistical software to analyze the data

Results: 527 articles were initially retrieved. We included 20 studies, with a total of 1387 patients who were divided into the combination(IVI + LPC) treatment group and the single IVI group. All the patients completed the ocular examination including BCVA, slit-lamp test, fundus examination and Optical Coherence Tomography(OCT) test before and after each treatment. There was no statistical difference between the combination treatment group and single IVI group on BCVA(WMD = 0.12,95%CI = -3.54–3.78,p = 0.95),CMT(WMD = -4.40,95%CI = -21.33–12.53,p = 0.61) and NPAs(WMD = 0.01,95%CI = -0.28–0.30,p = 0.94).However, the number of IVI was decreased significantly in the combination treatment group in BRVO patients, compared to that in the single IVI group(WMD = -0.69,95%CI = -1.18∼-0.21,p = 0.005).

Conclusion: In the treatment of RVO patients with macular edema, the combination of IVI and retinal LPC neither improves BCVA nor reduces CMT significantly compared with the single IVI treatment. However, the combination treatment can decrease the number of intravitreal injections in patients with BRVO, while it is not observed in CRVO patients.
Fluorescent Tracers for In Vivo Imaging of Lymphatic Targets
Authors: Russell P. S. , Velivolu R. , Maldonado Zimbrón V. E. , Hong J. , Kavianinia I. , Hickey A. J. R. , Windsor J. A. , Phillips A. R. J.
Published: July 2022

The lymphatic system continues to gain importance in a range of conditions, and therefore, imaging of lymphatic vessels is becoming more widespread for research, diagnosis, and treatment. Fluorescent lymphatic imaging offers advantages over other methods in that it is affordable, has higher resolution, and does not require radiation exposure. However, because the lymphatic system is a one-way drainage system, the successful delivery of fluorescent tracers to lymphatic vessels represents a unique challenge. Each fluorescent tracer used for lymphatic imaging has distinct characteristics, including size, shape, charge, weight, conjugates, excitation/emission wavelength, stability, and quantum yield. These characteristics in combination with the properties of the target tissue affect the uptake of the dye into lymphatic vessels and the fluorescence quality. Here, we review the characteristics of visible wavelength and near-infrared fluorescent tracers used for in vivo lymphatic imaging and describe the various techniques used to specifically target them to lymphatic vessels for high-quality lymphatic imaging in both clinical and pre-clinical applications. We also discuss potential areas of future research to improve the lymphatic fluorescent tracer design.
The cost-effectiveness of different types of educational interventions in type II diabetes mellitus: A systematic review
Authors: Wan Rohimi Wan Nur Liyana Hazwani , Mohd Tahir Nurul Ain
Published: July 2022

Aims: Educational interventions are effective to improve peoples’ self-efficacy in managing diabetes complications and lifestyle changes. This systematic review aims to assess and compare various aspects of educational interventions and to provide updated pharmacoeconomics data.

Methods: Literature searches were conducted using databases such as EBSCOhost, Ovid, PubMed, Scopus, and Web of Science. Outcomes such as study characteristics, costs, medication adherence, effectiveness and were narratively summarized, and the quality of each article was assessed.

Results: A total of 27 studies were retrieved. The types of educational interventions were classified as face-to-face strategy, structured programs, telemedicine health education, a combination approach, and others. All types of educational interventions (N = 24, 89%) were reported to be cost-effective. The cost-effectiveness of the other two studies was considered to be not cost-effective while the outcome of one study could not be determined. The majority of the studies (N = 24, 89%) had moderate-quality evidence whereas thirteen (48%) studies were regarded to provide high-quality economic evaluations.

Conclusion: All types of educational interventions are highly likely to be cost-effective. The quality of economic evaluations is moderate but the most cost-effective types of educational interventions could not be determined due to variations in the reporting and methodological conduct of the study. A high-quality approach, preferably utilizing the societal perspective over a long period, should be standardized to conduct economic evaluations for educational interventions in T2DM.

Systematic Review Registration: website, identifier registration number.
A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress
Authors: Correia da Silva Daniela , Valentão Patrícia , Andrade Paula B. , Pereira David M.
Published: July 2022

The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while it is also the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterizes the pathogenesis of neurodegenerative diseases. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The protective potential of these compounds against ER stress was evaluated at the levels of calcium homeostasis, key gene and protein expression, and levels of protein aggregation in fibroblasts. The most promising compounds were subsequently tested in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it. Delphinidin stands out as the most promising candidate against neurodegeneration. This compound significantly inhibited the expression of UPR biomarkers, and displayed a strong potential to inhibit protein aggregation in the two aforementioned cell models. Our results indicate that natural products may be a valuable resource in the development of an effective therapeutic strategy against ER stress-related diseases.