bluuebunny/crossref_metadata_2025 huggingface dataset:
Colorectal Cancer Screening With High Risk-Factor Questionnaire and Fecal Immunochemical Tests Among 5, 947, 986 Asymptomatic Population: A Population-Based Study
Authors: Zhang Mingqing , Zhao Lizhong , Zhang Yongdan , Jing Haoren , Wei Lianbo , Li Zhixuan , Zhang Haixiang , Zhang Yong , Zhu Siwei , Zhang Shiwu , Zhang Xipeng
Published: June 2022

Background

The recent uptrend in colorectal cancer (CRC) incidence in China is causing an increasingly overwhelming social burden. And its occurrence can be effectively reduced by sensitizing CRC screening for early diagnosis and treatment. However, a large number of people in China do not undergo screening due to multiple factors. To address this issue, since 2012, a CRC screening program has been initiated in Tianjin.

Methods

Residents aged 40-74 years were eligible for CRC screening. The first was to complete the high-risk factor questionnaire (HRFQ) and undergo fecal immunochemical test (FIT). Then those with a positive result in any of the two screening methods were recommended for a free colonoscopy.

Results

The detection rate of intestinal diseases increased with age, had a male predominance, and was higher in residents from central urban areas and those with primary school above education level. The sensitivity of predicting CRC after colonoscopy in the high-risk group was 76.02%; the specificity was 25.33%.A significant decrease in the detection rate of intestinal disease, CRC and advanced adenoma was observed from positive FIT, the high-risk group and positive HRFQ, 47.13%, 44.79%, 42.30%; 3.15%, 2.44%, 1.76%; 7.72%, 6.42%, 5.08%, in that order, while no inter-group difference was found for the detection of polyps. In addition, the different combinations of HRFQ and FIT can enroll more high-risk population than FIT or (and) HRFQ only, and thus detect more intestinal diseases (include CRC/AA/Polyp).

Conclusion

The superimposition of different screening method for HRFQ and FIT is an effective strategy for the detection of CRC, AA, and Polyp, compared to HRFQ or FIT alone. However, further improvements in screening and interventions are needed to promote colonoscopy compliance.
Application of a Novel 68Ga-HER2 Affibody PET/CT Imaging in Breast Cancer Patients
Authors: Miao Haitao , Sun Yuyun , Jin Yizi , Hu Xichun , Song Shaoli , Zhang Jian
Published: June 2022

Background

Breast cancer is a heterogeneous disease, and the human epidermal growth factor receptor 2 (HER2) expression may vary considerably between primary and metastatic lesions, or even within a single lesion. Repeated biopsies cannot always be performed. In this feasibility trial, we assessed whether a novel 68Ga-NOTA-MAL-MZHER2 (68Ga-HER2) affibody PET/CT could determine the HER2 status of each lesion if there was a clinical need for it.

Methods

68Ga-HER2 affibody PET/CT was performed in breast cancer patients if HER2 status remained unclear after standard examinations (including bone scan, 18F-FDG PET/CT, CT, and feasible biopsy). All available images for each patient were evaluated through an independent review of two committee-certified radiologists with nuclear medicine expertise. In case of discrepancy, adjudication by a third radiologist was performed as needed. All radiologists were blinded to the clinical information.

Results

Twenty-four patients were enrolled. 68Ga-HER2 affibody PET/CT was requested by physicians due to the following reasons: 6 with multiple primary cancers, 13 with metastases not amenable to biopsy or repeated biopsy, 6 with inconsistent HER2 status between primary and metastatic lesions, and 4 with different HER2 status within different metastases. The final PET report revealed that the 68Ga-HER2 affibody tumor uptake was considered positive in 16 patients, negative in 7 patients, and equivocal in one patient. The heterogeneity of 68Ga-HER2 affibody uptake was observed, with a maximal 8.5-fold difference within one patient and a maximal 11-fold difference between patients. 68Ga-HER2 affibody PET/CT demonstrated a high diagnostic accuracy in differentiating HER2-enriched breast cancer, with a sensitivity of 91.7% and a specificity of 84.6%, regardless of prior lines of anti-HER2 therapies.

Conclusion

68Ga-HER2 affibody PET/CT imaging could provide valuable information on HER2 expression of each tumor in the body of patients, which may help in personalized clinical decision-making. Its value is now under systemic assessment.
Current Trends and Research Hotspots in Pancreatic Stellate Cells: A Bibliometric Study
Authors: Yang Zhaoming , Xie Zhiqin , Wan Jian , Yi Bo , Xu Tao , Shu Xiaorong , Zhao Zhijian , Tang Caixi
Published: June 2022

Background

Pancreatic stellate cells (PSCs) play crucial roles in acute/chronic pancreatitis and pancreatic cancer. In this study, bibliometric analysis was used to quantitatively and qualitatively analyze the literature related to PSCs from 1998-2021 to summarize the current trends and research topics in this field.

Methods

Relevant literature data were downloaded from the Science Citation Index Expanded Web of Science Core Collection (WoSCC) on April 07, 2021, using Clarivate Analytics. Biblioshiny R packages, VOSviewer, Citespace, BICOMB, gCLUTO, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com) were used to analyze the manually selected data.

Results

A total of 958 relevant studies published in 48 countries or regions were identified. The United States of America (USA) had the highest number of publications, followed by the People’s Republic of China, Germany, and Japan. Tohoku University (Japan), the University of New South Wales (Australia), the University of Texas MD Anderson Cancer Center (USA), Technical University of Munich (Germany), and University of Rostock (Germany) were the top five institutions with most publications. Nine major clusters were generated using reference co-citation analysis. Keyword burst detection revealed that progression (2016-2021), microenvironment (2016-2021), and tumor microenvironment (2017-2021) were the current frontier keywords. Biclustering analysis identified five research hotspots in the field of PSCs during 1998-2021.

Conclusion

In this study, a scientometric analysis of 958 original documents related to PSCs showed that the research topics of these studies are likely in the transition from acute/chronic pancreatitis to pancreatic cancer. The current research trends regarding PSCs are related to pancreatic cancer, such as tumor microenvironment. This study summarizes five research hotspots in the field of PSCs between 1998 and 2021 and thus may provide insights for future research.
Long Non-Coding RNA TMPO-AS1 Promotes GLUT1-Mediated Glycolysis and Paclitaxel Resistance in Endometrial Cancer Cells by Interacting With miR-140 and miR-143
Authors: Dong Peixin , Wang Feng , Taheri Mohammad , Xiong Ying , Ihira Kei , Kobayashi Noriko , Konno Yosuke , Yue Junming , Watari Hidemichi
Published: June 2022

Increased glycolysis in tumor cells is frequently associated with drug resistance. Overexpression of glucose transporter-1 (GLUT1) promotes the Warburg effect and mediates chemoresistance in various cancers. Aberrant GLUT1 expression is considered as an essential early step in the development of endometrial cancer (EC). However, its role in EC glycolysis and chemoresistance and the upstream mechanisms underlying GLUT1 overexpression, remain undefined. Here, we demonstrated that GLUT1 was highly expressed in EC tissues and cell lines and that high GLUT1 expression was associated with poor prognosis in EC patients. Both gain-of-function and loss-of-function studies showed that GLUT1 increased EC cell proliferation, invasion, and glycolysis, while also making them resistant to paclitaxel. The long non-coding RNA TMPO-AS1 was found to be overexpressed in EC tissues and to be negatively associated with EC patient outcomes. RNA-immunoprecipitation and luciferase reporter assays confirmed that TMPO-AS1 elevated GLUT1 expression by directly binding to two critical tumor suppressor microRNAs (miR-140 and miR-143). Downregulation of TMPO-AS1 remarkably reduced EC cell proliferation, invasion, glycolysis, and paclitaxel resistance in EC cells. This study established that dysregulation of the TMPO-AS1-miR-140/miR-143 axis contributes to glycolysis and drug resistance in EC cells by up-regulating GLUT1 expression. Thus, inhibiting TMPO-AS1 and GLUT1 may prove beneficial in overcoming glycolysis-induced paclitaxel resistance in patients with EC.
Clinical Features, Management, and Prognostic Factors of Intracranial Solitary Fibrous Tumor
Authors: Liu Jingdian , Wu Sisi , Zhao Kai , Wang Junwen , Shu Kai , Lei Ting
Published: June 2022

Background

Because of the low incidence and the constantly changing diagnostic and classification criteria, the clinical features, management, and prognostic factors of intracranial solitary fibrous tumor (ISFT) remain unclear and were thus analyzed in this study.

Method

A total of 38 patients with ISFTs who were diagnosed in our institution were enrolled in this study. Patient data including age, gender, clinical presentation, histopathological features, immunohistochemistry staining, tumor location, tumor size, treatment methods, and prognosis were extracted and retrospectively analyzed.

Results

The median age at diagnosis was 45.5 years (range 28–66 years) and the male-to-female ratio was 1:1.53 in our series. The 3-, 5-, and 10-year progression-free survival (PFS) rate was 82.2%, 62.8%, and 21.4%, respectively; and the 3-, 5-, and 10-year overall survival rate was 97.1%, 86.9%, and 64.2%, respectively. Patients with high WHO grade (grade 3) ISFTs experienced impaired PFS (p < 0.05) and OS (p < 0.01). Subtotal resection (STR) was associated with worse PFS and OS (p < 0.001, respectively). Postoperative radiotherapy (PORT) improved PFS, especially local control rate, in patients with WHO grade 3 ISFTs (P = 0.025) or STR (p = 0.027). Moreover, CD34-negative immunostaining and a high Ki-67 index (>10%) were associated with impaired PFS in ISFTs.

Conclusion

Our study provides evidence that high tumor grade, subtotal tumor resection, CD34 negative immunostaining, and high Ki-67 index (>10%) were independent predictors for the poor prognosis of ISFTs. PORT can improve local control rate, and should be recommended for patients with high-grade ISFTs or STR.
Constant Multi-Tasking With Time Constraint to Preserve Across-Network Dynamics Throughout Awake Surgery for Low-Grade Glioma: A Necessary Step to Enable Patients Resuming an Active Life
Authors: Duffau Hugues , Ng Sam , Lemaitre Anne-Laure , Moritz-Gasser Sylvie , Herbet Guillaume
Published: June 2022

Awake surgery for brain gliomas improves resection while minimizing morbidity. Although intraoperative mapping was originally used to preserve motor and language functions, the considerable increase of life expectancy, especially in low-grade glioma, resulted in the need to enhance patients’ long-term quality of life. If the main goal of awake surgery is to resume normal familial and socio-professional activities, preventing hemiparesis and aphasia is not sufficient: cognitive and emotional functions must be considered. To monitor higher-order functions, e.g., executive control, semantics or mentalizing, further tasks were implemented into the operating theater. Beyond this more accurate investigation of function-specific neural networks, a better exploration of the inter-system communication is required. Advances in brain connectomics led to a meta-network perspective of neural processing, which emphasizes the pivotal role of the dynamic interplay between functional circuits to allow complex and flexible, goal-directed behaviors. Constant multi-tasking with time constraint in awake patients may be proposed during intraoperative mapping, since it provides a mirror of the (dys)synchronization within and across neural networks and it improves the sensitivity of behavioral monitoring by increasing cognitive demand throughout the resection. Electrical mapping may hamper the patient to perform several tasks simultaneously whereas he/she is still capable to achieve each task in isolation. Unveiling the meta-network organization during awake mapping by using a more ecological multi-demand testing, more representative of the real-life conditions, constitutes a reliable way to tailor the surgical onco-functional balance based upon the expectations of each patient, enabling him/her to resume an active life with long-lasting projects.
Identification and Validation of lncRNA-SNHG17 in Lung Adenocarcinoma: A Novel Prognostic and Diagnostic Indicator
Authors: Li Xinyan , Yuan Yixiao , Pal Mintu , Jiang Xiulin
Published: June 2022

Background

Lung cancer has the highest death rate among cancers globally. Accumulating evidence has indicated that cancer-related inflammation plays an important role in the initiation and progression of lung cancer. However, the prognosis, immunological role, and associated regulation axis of inflammatory response-related gene (IRRGs) in non-small-cell lung cancer (NSCLC) remains unclear.

Methods

In this study, we perform comprehensive bioinformatics analysis and constructed a prognostic inflammatory response-related gene (IRRGs) and related competing endogenous RNA (ceRNA) network. We also utilized the Pearson’s correlation analysis to determine the correlation between IRRGs expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor-immune infiltration, and the drug sensitivity in NSCLC. Growth curve and Transwell assay used to verify the function of SNHG17 on NSCLC progression.

Results

First, we found that IRRGs were significantly upregulated in lung cancer, and its high expression was correlated with poor prognosis; high expression of IRRGs was significantly correlated with the tumor stage and poor prognosis in lung cancer patients. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that these IRRGs are mainly involved in the inflammatory and immune response-related signaling pathway in the progression of NSCLC. We utilized 10 prognostic-related genes to construct a prognostic IRRGs model that could predict the overall survival of lung adenocarcinoma (LUAD) patients possessing high specificity and accuracy. Our evidence demonstrated that IRRGs expression was significantly correlated with the TMB, MSI, immune-cell infiltration, and diverse cancer-related drug sensitivity. Finally, we identified the upstream regulatory axis of IRRGs in NSCLC, namely, lncRNA MIR503HG/SNHG17/miR-330-3p/regulatory axis. Finally, knockdown of SNHG17 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and migration. Our findings confirmed that SNHG17 is a novel oncogenic lncRNA and may be a biomarker for the prognosis and diagnosis of LUAD.

Conclusion

DNA hypomethylation/lncRNA MIR503HG/SNHG17/microRNA-330-3p/regulatory axis may be a valuable biomarker for prognosis and is significantly correlated with immune cell infiltration in lung cancer.
Serum Vitamin D Insufficiency in Hospitalized Full-Term Neonates at a Tertiary Hospital in Eastern China
Authors: Wang Huawei , Du Yiming , Wu Zhixin , Geng Haifeng , Zhu Xueping , Zhu Xiaoli
Published: June 2022

Objective

This study explored the status of serum vitamin D in hospitalized full-term neonates at a tertiary hospital in eastern China.

Methods

A prospective study was conducted among 471 hospitalized full-term neonates at the Children's Hospital of Soochow University between January 1 and June 20, 2020. Perinatal clinical data, serum 25-hydroxyvitamin D (25(OH)D3), laboratory examinations, serum calcium levels, and immune function were obtained and analyzed. We explored and analyzed the risk factors for vitamin D insufficiency or deficiency, and we also attempted to determine correlations between vitamin D and its influence on immunity.

Results

The mean serum 25(OH)D3 was 33.65±6.07ng/ml.The prevalence of vitamin D insufficiency was 28.24%,vitamin D sufficiency was 71.76%, there was no vitamin D deficiency. The serum 25-(OH)D3 in singleton neonate was higher than twins or multiple infants (t = −10.918, P = 0.000). The serum 25-(OH)D3 were higher in neonates who born in spring and summer than in winter (H = 13.443, P = 0.001). The serum 25-(OH)D3 in appropriate for gestational age (AGA) and large for gestational age (LGA) neonates were higher than small for gestational age (SGA) (H = 7.686, P = 0.021). The serum 25-(OH)D3 were higher in neonates whose mothers had no underlying diseases than those with certain immunological and infectious diseases (F = 12.417, P = 0.000). The serum 25-(OH)D3 in neonates whose mothers had none or one perinatal complication were higher than those with two or more (F = 13.299, P = 0.000). The neonates with eosinophils ≤5% or normal platelet counts or serum Ca++ ≥0.9 mmol/L have higher serum 25-(OH)D3. Neonates born in winter were at risk for vitamin D insufficiency, and the incidence of infectious pneumonia, sepsis, cytomegalovirus infection, and hypocalcemia in the vitamin D insufficiency group were higher than sufficiency group (P < 0.05). The serum CD3+, CD3+CD4+, and IgA levels in vitamin D sufficiency neonates were significantly higher than those in insufficiency group (P < 0.05).

Conclusion

The prevalence of vitamin D insufficiency was 28.24%, and birth in winter was a risk factor for vitamin D insufficiency in hospitalized full-term neonates in Suzhou area. Neonates with infectious pneumonia, sepsis, cytomegalovirus infection, and hypocalcemia exhibited a high risk of vitamin D insufficiency. The serum CD3+, CD3+CD4+, and IgA levels in neonates with vitamin D insufficiency were lower.
New Insights on Juvenile Psoriatic Arthritis
Authors: Brunello Francesco , Tirelli Francesca , Pegoraro Luca , Dell'Apa Filippo , Alfisi Alessandra , Calzamatta Giulia , Folisi Camilla , Zulian Francesco
Published: June 2022

Juvenile psoriatic arthritis (JPsA) is a relatively rare condition in childhood as it represents approximately 5% of the whole Juvenile Idiopathic Arthritis (JIA) population. According to International League of Associations of Rheumatology (ILAR) classification, JPsA is defined by the association of arthritis and psoriasis or, in the absence of typical psoriatic lesions, with at least two of the following: dactylitis, nail pitting, onycholysis or family history of psoriasis in a first-degree relative. However, recent studies have shown that this classification system could conceal more homogeneous subgroups of patients differing by age of onset, clinical characteristics and prognosis. Little is known about genetic factors and pathogenetic mechanisms which distinguish JPsA from other JIA subtypes or from isolated psoriasis without joint involvement, especially in the pediatric population. Specific clinical trials testing the efficacy of biological agents are lacking for JPsA, while in recent years novel therapeutic agents are emerging in adults. In this review, we summarize the clinical features and the current evidence on pathogenesis and therapeutic options for JPsA in order to provide a comprehensive overview on the clinical management of this complex and overlapping entity in childhood.
Clinical Characteristics, Renal Involvement, and Therapeutic Options of Pediatric Patients With Fabry Disease
Authors: Muntean Carmen , Starcea Iuliana Magdalena , Stoica Cristina , Banescu Claudia
Published: June 2022

Inherited renal diseases represent 20% of the causes of end-stage renal diseases. Fabry disease, an X-linked lysosomal storage disorder, results from α-galactosidase A deficient or absent activity followed by globotriaosylceramide (Gb3) accumulation and multiorgan involvement. In Fabry disease, kidney involvement starts early, during intrauterine life by the Gb3 deposition. Even if chronic kidney disease (CKD) is discovered later in adult life in Fabry disease patients, a decline in glomerular filtration rate (GFR) can occur during adolescence. The first clinical sign of kidney involvement is represented by albuminuria. So, early and close monitoring of kidneys function is required: albuminuria and proteinuria, urinary albumin-to-creatinine ratio, serum creatinine, or cystatin C to estimate GFR, while urinary sediment with phase-contrast microscopy under polarized light may be useful in those cases where leucocyte α-Gal A activity and GLA genotyping are not available. Children with Fabry disease and kidney involvement should receive enzyme replacement therapy and nephroprotective drugs (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) to prevent or slow the progressive loss of kidney functions. Early diagnosis of Fabry disease is important as enzyme replacement therapy reduces symptoms, improves clinical features and biochemical markers, and the quality of life. More importantly, early treatment could slow or stop progressive organ damage in later life.
Evidence on Indications and Techniques to Increase the Future Liver Remnant in Children Undergoing Extended Hepatectomy: A Systematic Review and Meta-Analysis of Individual Patient Data
Authors: Fuchs Juri , Murtha-Lemekhova Anastasia , Rabaux-Eygasier Lucas , Kessler Markus , Ruping Fabian , Günther Patrick , Hoffmann Katrin
Published: June 2022

Background

Techniques to increase the future liver remnant (FLR) have fundamentally changed the indications and criteria of resectability in adult liver surgery. In pediatric patients however, these procedures have rarely been applied and the potential benefit or harm as well as suited indications are unclear.

Methods

A systematic literature search of MEDLINE, Web of Science, and CENTRAL was conducted. Based on a PRISMA-compliant, predefined methodology, all studies reporting pediatric patients (< 18y) undergoing liver resection with either associating liver partition and portal vein ligation for stages hepatectomy (ALPPS) or preoperative portal vein embolization or ligation (PVE/PVL) were included. Baseline data, periinterventional morbidity, increase of FLR and outcomes were analyzed.

Results

15 studies reporting on 21 pediatric patients with a mean age of 4 years and 7 months (range 1.8 months – 17 years) were included. 12 ALPPS procedures, 8 PVE and 1 PVL were performed. The applied criteria for performing ALPPS or PVE were heterogenous and thresholds for minimally acceptable FLR varied. Mean FLR [% of total liver volume] before the intervention was 23.6% (range 15.0 – 39.3%) in the ALPPS group and 31.4% (range 21.5 – 56.0%) in the PVE group. Mean increase of FLR before stage 2 resection was 69.4% (range 19.0 – 103.8%) for ALPPS and 62.8% (range 25.0 – 108.0%) after PVE. No postoperative death occurred, one early intrahepatic recurrence after an ALPPS procedure was reported. Overall postoperative morbidity was 23.8%.

Conclusion

Validated criteria for minimal FLR in pediatric liver resection are lacking and so are clear indications for ALPPS or PVE. In special cases, ALPPS and PVE can be valuable techniques to achieve complete resection of pediatric liver tumors. However, more data are needed, and future studies should focus on a definition and validation of posthepatectomy liver failure as well as the minimally needed FLR in pediatric patients undergoing extended hepatectomy.

Systematic Review Registration

[www.clinicaltrials.gov], identifier [PROSPERO 2021 CRD42021274848].
Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
Authors: Hua Yaping , Yuan Xing , Shen Yun-heng , Wang Jinxin , Azeem Waqas , Yang Shuo , Gade Alexandra , Lellahi Seyed Mohammad , Øyan Anne Margrete , Ke Xisong , Zhang Wei-dong , Kalland Karl-Henning
Published: June 2022

Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323–1 and 323–2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3.
Hyaluronic Acid Hydrogels Hybridized With Au-Triptolide Nanoparticles for Intraarticular Targeted Multi-Therapy of Rheumatoid Arthritis
Authors: Li Chenxi , Liu Rui , Song Yurong , Chen Youwen , Zhu Dongjie , Yu Liuchunyang , Huang Qingcai , Zhang Zhengjia , Xue Zeyu , Hua Zhenglai , Lu Cheng , Lu Aiping , Liu Yuanyan
Published: June 2022

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by synovial inflammation in multiple joints. Triptolide (TP) is a disease-modifying anti-rheumatic drug (DMARD) highly effective in patients with RA and has anti-inflammatory properties. However, its clinical application has been limited owing to practical disadvantages. In the present study, hyaluronic acid (HA) hydrogel-loaded RGD-attached gold nanoparticles (AuNPs) containing TP were synthesized to alleviate the toxicity and increase therapeutic specificity. The hydrogels can be applied for targeted photothermal-chemo treatment and in vivo imaging of RA. Hydrogel systems with tyramine-modified HA (TA-HA) conjugates have been applied to artificial tissue models as surrogates of cartilage to investigate drug transport and release properties. After degradation of HA chains, heat was locally generated at the inflammation region site due to near-infrared resonance (NIR) irradiation of AuNPs, and TP was released from nanoparticles, delivering heat and drug to the inflamed joints simultaneously. RA can be penetrated with NIR light. Intraarticular administration of the hydrogels containing low dosage of TP with NIR irradiation improved the inflamed conditions in mice with collagen-induced arthritis (CIA). Additionally, in vitro experiments were applied to deeply verify the antirheumatic mechanisms of TP-PLGA-Au@RGD/HA hydrogels. TP-PLGA-Au@RGD/HA hydrogel treatment significantly reduced the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS) in vitro, through the decrease of phosphorylation of mTOR and its substrates, p70S6K1, thus inhibiting the mTOR pathway.
Mechanism of Multi-Organ Injury in Experimental COVID-19 and Its Inhibition by a Small Molecule Peptide
Authors: Paidas Michael J. , Sampath Natarajan , Schindler Emma A. , Cosio Daniela S. , Ndubizu Chima Obianuju , Shamaladevi Nagarajarao , Kwal Jaclyn , Rodriguez Suset , Ahmad Anis , Kenyon Norma Sue , Jayakumar Arumugam R.
Published: June 2022

Severe disease from SARS-CoV-2 infection often progresses to multi-organ failure and results in an increased mortality rate amongst these patients. However, underlying mechanisms of SARS- CoV-2-induced multi-organ failure and subsequent death are still largely unknown. Cytokine storm, increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs contribute to the pathogenesis of COVID-19. One potential consequence of immune/inflammatory events is the acute progression of generalized edema, which may lead to death. We, therefore, examined the involvement of water channels in the development of edema in multiple organs and their contribution to organ dysfunction in a Murine Hepatitis Virus-1 (MHV-1) mouse model of COVID-19. Using this model, we recently reported multi-organ pathological abnormalities and animal death similar to that reported in humans with SARS-CoV-2 infection. We now identified an alteration in protein levels of AQPs 1, 4, 5, and 8 and associated oxidative stress, along with various degrees of tissue edema in multiple organs, which correlate well with animal survival post-MHV-1 infection. Furthermore, our newly created drug (a 15 amino acid synthetic peptide, known as SPIKENET) that was designed to prevent the binding of spike glycoproteins with their receptor(s), angiotensin- converting enzyme 2 (ACE2), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively), ameliorated animal death and reversed altered levels of AQPs and oxidative stress post-MHV-1 infection. Collectively, our findings suggest the possible involvement of altered aquaporins and the subsequent edema, likely mediated by the virus-induced inflammatory and oxidative stress response, in the pathogenesis of COVID- 19 and the potential of SPIKENET as a therapeutic option.
Cannabinoids as Glial Cell Modulators in Ischemic Stroke: Implications for Neuroprotection
Authors: Vicente-Acosta Andrés , Ceprian Maria , Sobrino Pilar , Pazos Maria Ruth , Loría Frida
Published: June 2022

Stroke is the second leading cause of death worldwide following coronary heart disease. Despite significant efforts to find effective treatments to reduce neurological damage, many patients suffer from sequelae that impair their quality of life. For this reason, the search for new therapeutic options for the treatment of these patients is a priority. Glial cells, including microglia, astrocytes and oligodendrocytes, participate in crucial processes that allow the correct functioning of the neural tissue, being actively involved in the pathophysiological mechanisms of ischemic stroke. Although the exact mechanisms by which glial cells contribute in the pathophysiological context of stroke are not yet completely understood, they have emerged as potentially therapeutic targets to improve brain recovery. The endocannabinoid system has interesting immunomodulatory and protective effects in glial cells, and the pharmacological modulation of this signaling pathway has revealed potential neuroprotective effects in different neurological diseases. Therefore, here we recapitulate current findings on the potential promising contribution of the endocannabinoid system pharmacological manipulation in glial cells for the treatment of ischemic stroke.
In vitro Inhibition of HIV-1 by Cyclotide-Enriched Extracts of Viola tricolor
Authors: Conzelmann Carina , Muratspahić Edin , Tomašević Nataša , Münch Jan , Gruber Christian W.
Published: June 2022

Since viral infectious diseases continue to be a global health threat, new antiviral drugs are urgently needed. A unique class of therapeutic compounds are antimicrobial peptides (AMPs). They can be found in humans, bacteria and plants. Plants express a wide variety of such defense peptides as part of their innate immune system to protect from invading pathogens. Cyclotides are non-classical AMPs that share a similar structure. Their unique topology consists of a circular peptide backbone and disulfide bonds. In previous studies they have been attributed to a wide range of biological activities. To identify novel cyclotides with antiviral activity, we established a library of plant extracts largely consisting of cyclotide-rich species and screened them as inhibitors of HIV-1 infection. Subsequent extraction and fractionation revealed four cyclotide-containing subfractions from Viola tricolor with antiviral activity. These subfractions inhibited HIV-1 infection with IC50 values between 0.6 and 11.2 μg/ml, and selectivity indices of up to 8.1. The identification and characterization of antiviral cyclotides and the determination of the antiviral mechanisms may allow to develop novel agents to combat viral infections. Therefore, cyclotides represent a natural source of bioactive molecules with prospects for development as therapeutics.
The Ion Channel-Related Gene Signatures Correlated With Diagnosis, Prognosis, and Individualized Treatment in Patients With Clear Cell Renal Cell Carcinoma
Authors: Zhu Zhenpeng , Lei Zhenchuan , Qian Jinqin , Zhang Cuijian , Gong Yanqing , Yin Guicao , Li Yifan , Li Xuesong , Lin Jian , Zhou Liqun
Published: June 2022

Background: Early detection and precise prognostic evaluation of clear cell renal cell carcinoma (ccRCC) are crucial for patient life expectancy. Ion channel-related genes (ICRGs) are of great diagnostic and prognostic value as components that maintain the normal structure of the kidney. Therefore, we systematically explored the diagnostic, prognostic, and therapeutic value of ICRGs in ccRCC using the multi-database.

Methods: RNA transcriptome profiles and clinical data of ccRCC patients were extracted and integrated from public databases including The Cancer Genome Atlas, ICGC, GEO, and E-MTAB databases. Ion channel-related genes were obtained from the literature collection. The diagnostic signature was performed using the LASSO and SVM-REF analyses. Meanwhile, the prognostic signature was conducted using the LASSO analyses. Molecular subtyping was performed using the ConsensusClusterPlus and the corresponding therapeutic targets were evaluated using the pRRophetic package. In addition, a prognostic nomogram was constructed based on the results of cox regression analyses.

Results: We successfully constructed diagnostic signatures for five ICRGs and prognostic signatures for 10 ICRGs with AUC values greater than 0.7, showing good predictive performance. Based on the median risk score, we found that high-risk patients had a significantly worse prognosis. We also divided ccRCC patients into two clusters according to prognostic ICRGs, and there was a significant survival outcome between the two clusters and different sensitivity to diverse clinical therapeutic strategies. Meanwhile, we constructed a nomogram based on clinical molecules and signatures, and its predictive efficacy was better than the signature or the present tumor-node-metastasis staging system.

Conclusion: In this study, we established useful signatures for early detection, prognosis evaluation, and individualized treatment for ccRCC. Moreover, KCNJ16 deserves to be explored comprehensively in the future.
Immune Checkpoint Inhibitors Plus an Anti-VEGF Antibody as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis and Cost-Effectiveness Analysis
Authors: Li Lu , Yang Shilei , Chen Yanwei , Tian Li , He Ying , Wu Bin , Dong Deshi
Published: June 2022

Background: Sintilimab + a bevacizumab biosimilar (IBI305) (SB) and atezolizumab + bevacizumab (AB) have been approved for the treatment of unresectable hepatocellular carcinoma (HCC). At present, oncologists and their patients remain indecisive on their preferred treatment regime. Therefore, assessing their efficacy via a network meta-analysis and determining their comparative cost-effectiveness is necessary.

Objective: To evaluate the cost-effectiveness of SB and AB compared with sorafenib alone for the treatment of unresectable HCC.

Materials and Methods: The data used in our analysis were obtained from patients in ORIENT-32 and IMbrave150 phase III randomized clinical trials. A Bayesian network meta-analysis and cost-effectiveness analysis that included 1,072 patients were performed in this study. A partitioned survival model was applied to the patients with unresectable HCC. The model was designed with a 15-year time horizon, 1-month cycle, and 5% discount rate for costs and outcomes. In China, an incremental cost-effectiveness ratio (ICER) value of less than $33,500 (three times the GDP per capita in 2020) per quality-adjusted life-year (QALY) is considered cost-effective. The influence of parameter uncertainty on the results was verified by one-way deterministic sensitivity analysis and probability sensitivity analysis. Furthermore, scenario analyses of the patient assistance program (PAP) were conducted to explore the cost-effectiveness of SB and AB.

Results: For the model of 1,072 patients, treatment with SB produced an additional 0.617 QALYs compared with sorafenib, resulting in an ICER of $39,766.86/QALY. Similarly, treatment with AB produced an additional 0.596 QALYs compared with sorafenib, resulting in an ICER of $103,037.66/QALY. The probability sensitivity analysis showed that when the willingness-to-pay (WTP) threshold was $33,500/QALY, the cost-effectiveness of SB and AB was 15.4 and 0.4%, respectively. However, in the scenario analyses, the probability of SB and AB regimens being cost-effective was 65.4 and 15.8%, respectively, at a WTP of $33,500/QALY.

Conclusion: The findings from our study showed that sintilimab + a bevacizumab biosimilar is a cost-effective regimen compared with sorafenib as the first-line therapy for unresectable HCC in China at a $33,500 WTP threshold if sintilimab PAP is considered. However, the atezolizumab + bevacizumab regimen is not cost-effective whether atezolizumab PAP is considered or not.
The Antimicrobial Potential of the Neem Tree Azadirachta indica
Authors: Wylie Marina R. , Merrell D. Scott
Published: June 2022

Azadirachta indica(A. Juss), also known as the neem tree, has been used for millennia as a traditional remedy for a multitude of human ailments. Also recognized around the world as a broad-spectrum pesticide and fertilizer, neem has applications in agriculture and beyond. Currently, the extensive antimicrobial activities ofA. indicaare being explored through research in the fields of dentistry, food safety, bacteriology, mycology, virology, and parasitology. Herein, some of the most recent studies that demonstrate the potential of neem as a previously untapped source of novel therapeutics are summarized as they relate to the aforementioned research topics. Additionally, the capacity of neem extracts and compounds to act against drug-resistant and biofilm-forming organisms, both of which represent large groups of pathogens for which there are limited treatment options, are highlighted. Updated information on the phytochemistry and safety of neem-derived products are discussed as well. Although there is a growing body of exciting evidence that supports the use ofA. indicaas an antimicrobial, additional studies are clearly needed to determine the specific mechanisms of action, clinical efficacy, andin vivosafety of neem as a treatment for human pathogens of interest. Moreover, the various ongoing studies and the diverse properties of neem discussed herein may serve as a guide for the discovery of new antimicrobials that may exist in other herbal panaceas across the globe.
Effect of Chinese Herbal Medicine Therapy on Risks of Overall, Diabetes-Related, and Cardiovascular Diseases-Related Mortalities in Taiwanese Patients With Hereditary Hemolytic Anemias
Authors: Chiu Mu-Lin , Chiou Jian-Shiun , Chen Chao-Jung , Liang Wen-Miin , Tsai Fuu-Jen , Wu Yang-Chang , Lin Ting-Hsu , Liao Chiu-Chu , Huang Shao-Mei , Chou Chen-Hsing , Lin Cheng-Wen , Li Te-Mao , Hsu Yu-Lung , Lin Ying-Ju
Published: June 2022

Hereditary Hemolytic Anemias (HHAs) are a rare but heterogeneous group of erythrocytic diseases, characterized by intrinsic cellular defects due to inherited genetic mutations. We investigated the efficacy of Chinese herbal medicine (CHM) in reducing the overall, diabetes-related, and cardiovascular diseases (CVDs)-related mortalities among patients with HHAs using a nationwide population database. In total, we identified 33,278 patients with HHAs and included 9,222 non-CHM and 9,222 CHM matched pairs after matching. The Cox proportional hazards model was used to compare the risk of mortality between non-CHM and CHM users. The Kaplan-Meier method and log-rank test were used to compare the cumulative incidence mortality between non-CHM and CHM users. The CHM prescription patterns were presented by the association rules and network analyses, respectively. The CHM prescription patterns were presented by the association rules and network analyses, respectively. CHM users showed significant reduced risks for of overall (adjusted hazard ratio [aHR]: 0.67, 95% confidence interval [CI]: 0.61–0.73, p < 0.001), diabetes-related (aHR: 0.57, 95% CI: 0.40–0.82, p < 0.001), and CVDs-related (aHR: 0.59, 95% CI: 0.49–0.72, p < 0.001) mortalities compared with non-CHM users. Two CHM clusters are frequently used to treat Taiwanese patients with HHAs. Cluster 1 is composed of six CHMs: Bei-Mu (BM; Fritillaria cirrhosa D.Don), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Hai-Piao-Xiao (HPX; Endoconcha Sepiae), Jie-Geng (JG; Platycodon grandiflorus (Jacq.) A.DC.), Yu-Xing-Cao (YXC; Houttuynia cordata Thunb.), and Xin-Yi-Qing-Fei-Tang (XYQFT). Cluster 2 is composed of two CHMs, Dang-Gui (DG; Angelica sinensis (Oliv.) Diels) and Huang-Qi (HQi; Astragalus membranaceus (Fisch.) Bunge). Further randomized clinical trials are essential to evaluate the safety and effectiveness of above CHM products and to eliminate potential biases in the current retrospective study.
Lenvatinib Combined With a PD-1 Inhibitor as Effective Therapy for Advanced Intrahepatic Cholangiocarcinoma
Authors: Xie Lulu , Huang Jingzheng , Wang Linling , Ren Wenrui , Tian Hao , Hu Anhong , Liang Jun , Jiao Yuqing , Li Yali , Zhou Qunfang , Zhang Wenjing
Published: June 2022

Background: Lenvatinib combined with a PD-1 inhibitor has obtained a satisfactory antitumor effect in several solid tumors. However, the efficacy and tumor response of lenvatinib with a PD-1 inhibitor in advanced intrahepatic cholangiocarcinoma still need further exploration.

Methods: This is a single-arm study for the assessment of the efficacy and tolerability of lenvatinib with a PD-1 inhibitor in intrahepatic cholangiocarcinoma patients who had chemotherapy failure. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1).

Results: A total of 40 patients with advanced intrahepatic cholangiocarcinoma were enrolled after the chemorefractory effect. The median progression-free survival was 5.83 ± 0.76 months. The 3-month and 6-month progression-free survival rates were 80.0% and 32.5%, respectively. The median overall survival was 14.30 ± 1.30 months. The 12-month and 18-month overall survival rates were 61.4% and 34.7%. The 3-month RECIST 1.1 evaluation was that seven patients (17.5%) showed partial response, 23 patients (57.5%) had stable disease, and 10 patients (25.0%) had progressive disease. The objective response rate was 17.5%, and the disease control rate was 75.0%. All the recorded any-grade adverse events inducing treatment termination were controllable, and there were no AE-related deaths.

Conclusion: Our study showed that a combination of lenvatinib with the PD-1 inhibitor could be an effective treatment for advanced intrahepatic cholangiocarcinoma after the chemorefractory effect.
Effectiveness and Nephrotoxicity of Intravenous Polymyxin B in Carbapenem-Resistant Gram-Negative Bacterial Infections Among Chinese Children
Authors: Jia Xuedong , Yin Zhao , Zhang Wan , Guo Conghui , Du Shuzhang , Zhang Xiaojian
Published: June 2022

Background: No clinical study on the use of polymyxin B in Chinese children has been reported, thus making it difficult for pediatric clinicians to rationally select these drugs.

Methods: A retrospective analysis of children treated with polymyxin B during hospitalization in a hospital from June 2019 to June 2021 was conducted to analyze its effectiveness and the incidence of acute kidney injury (AKI) during treatment with polymyxin B.

Results: A total of 55 children were included in this study, and the results showed that the intravenous polymyxin B-based regimen had an effective rate of 52.7% in the treatment of Carbapenem-resistant Gram-negative bacterial (CR-GNB) infection in children. The results of the subgroup analysis showed that the course of treatment was longer in the favorable clinical response group than in the unfavorable outcome group (p = 0.027) and that electrolyte disturbances in children during the course of treatment could lead to unfavorable clinical outcomes (p = 0.042). The risk of incidence of AKI during treatment was 27.3%, and the all-cause mortality rate in the children on their discharge from the hospital was 7.3%.

Conclusion: Polymyxin B can be used as a salvage therapy for CR-GNB infection in children when no other susceptible antibiotics are available, and the monitoring of kidney function should be strengthened.
Receptor of Advanced Glycation End Products Deficiency Attenuates Cisplatin-Induced Acute Nephrotoxicity by Inhibiting Apoptosis, Inflammation and Restoring Fatty Acid Oxidation
Authors: Wang Qiang , Xi Yuemei , Chen Binyang , Zhao Hairong , Yu Wei , Xie De , Liu Weidong , He Furong , Xu Chenxi , Cheng Jidong
Published: June 2022

Cisplatin is a widely used and potent anti-neoplastic agent, but severe and inescapable side effects in multiple normal tissues and organs limit its application, especially nephrotoxicity. Molecular mechanisms of cisplatin nephrotoxicity involve mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, necroptosis, etc. Receptor of advanced glycation end products (RAGE) is a multiligand pattern recognition receptor, engaged in inflammatory signaling and mitochondrial homeostasis. Whether inhibition of RAGE alleviates cisplatin-induced nephropathy has not been investigated. Here, we revealed that RAGE deficiency attenuates cisplatin-induced acute nephrotoxicity, as evidenced by reduced apoptosis, inflammation, lipid accumulation, restored mitochondrial homeostasis and fatty acid oxidation in renal tubular epithelial cells (TECs). In vitro studies showed that, the RAGE-specific inhibitor FPS-ZM1 attenuated the cisplatin-induced decrease of cell viability and fatty acid oxidation in the normal rat renal TEC line NRK-52E cells. Taken together, RAGE knockout mitigated cisplatin-induced acute nephrotoxicity by inhibiting apoptosis, inflammation, and restoring fatty acid oxidation in TECs, suggesting that RAGE inhibition could be a therapeutic option for cisplatin-induced acute nephrotoxicity.