bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics
Authors: Shu Yuan , Peng Jie , Feng Zuxi , Hu Kaibo , Li Ting , Zhu Peijun , Cheng Tao , Hao Liang
Published: September 2022

Background

Osteosarcoma is a common metastatic tumor in children and adolescents. Because of its easy metastasis, patients often show a poor prognosis. Recently, researchers have found that platelets are closely related to metastasis of a variety of malignant tumors, but the role of platelets related characteristics in osteosarcoma is still unknown. The purpose of this study is to explore the characteristics of platelet-related subtypes and cell infiltration in tumor microenvironment.

Methods

We collected osteosarcoma cohorts from TCGA and GEO databases, and explored the molecular subtypes mediated by platelet-related genes and the related TME cell infiltration according to the expression of platelet-related genes in osteosarcoma. In addition, we also explored the differentially expressed genes (DEGs) among different molecular subtypes and established a protein-protein interaction network (PPI). Then we constructed a platelet scoring model by Univariate cox regression and least absolute shrinkage and selection operator (Lasso) cox regression model to quantify the characteristics of platelet in a single tumor. RT-PCR was used to investigate the expression of six candidate genes in osteosarcoma cell lines and normal osteoblast lines. Finally, we also predicted potential drugs with therapeutic effects on platelet-related subtypes.

Results

We found that platelet-related genes (PRGs) can distinguish osteosarcoma into two different platelet-related subtypes, C1 and C2. And the prognosis of the C2 subtype was significantly worse than that of C1 subtype. The results of ESTIMATE analysis and GO/KEGG enrichment showed that the differences between different subtypes were mainly concentrated in immune response pathways, and the immune response of C2 was inhibited relative to C1. We further studied the relationship between platelet-related subtypes and immune cell infiltration. We found that the distribution of most immune cells in C1 subtype was higher than that in C2 subtype, and there was a correlation between C1 subtype and more immune cells. Finally, we screened the PRGs related to the prognosis of osteosarcoma through Univariate Cox regression, established independent prognostic platelet characteristics consisting of six genes to predict the prognosis of patients with OS, and predicted the drugs that may be used in the treatment of osteosarcoma. RT-PCR was used to verify the expression of candidate genes in osteosarcoma cells.

Conclusion

Platelet scoring model is a significant biomarker, which is of great significance to determine the prognosis, molecular subtypes, characteristics of TME cell infiltration and therapy in patients with OS.
Prognostic role of indoleamine 2,3-dioxygenase 1 expression in solid tumors: A systematic review and meta-analysis
Authors: Zhang Haiyan , Li Jing , Zhou Qi
Published: September 2022

Background

As an emerging immune checkpoint molecule, indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive rate-limiting enzyme in metabolism of tryptophan to kynurenine. The expression of IDO1 affected the prognosis of patients in cancers by regulating the kynurenine pathway, inhibiting the proliferation of T cells. However, the association between IDO1 and solid tumor prognosis was controversial. To further investigate the role of IDO1 expression in solid tumors, we conducted the systematic review and meta-analysis.

Methods

We searched the Web of Science, PubMed, Embase, and Cochrane Library databases and China National Knowledge Infrastructure (CNKI) to identify studies evaluating the prognostic value of IDO1 in solid tumors. Overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) were extracted as the outcome. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by using the fixed-effect/random-effect model, while heterogeneity, publication bias, and sensitivity between studies were also analyzed.

Results

Eighteen studies with 2,168 patients were included in this systematic review and meta-analysis. The results indicated that the high expression of IDO1 was associated with a shorter OS (n = 1926, HR = 1.60, 95% CI: 1.22–2.11, P = 0.001) and DFS (n = 327, HR = 2.65, 95% CI: 1.52–4.63, P = 0.001), while it was uncorrelated with PFS (n = 428, HR = 1.76, 95% CI: 0.99–3.14, P = 0.240). There was significant heterogeneity between studies on OS (I2 = 77.8%, P < 0.001). Subgroup analysis showed that age, gender, tumor type, follow-up period, and study quality were possible reasons for high heterogeneity. The result of the trim-and-fill method indicated that publication bias for OS had no impact on our results. Egger’s test suggested no publication bias for PFS (P = 0.553) and DFS (P = 0.273). Furthermore, sensitivity analysis indicated the result was stable.

Conclusion

High expression of IDO1 was associated with poor clinical outcomes, indicating that it could be a potential prognostic marker in various cancer types.
Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma
Authors: Sahashi Hidenori , Kato Akihisa , Yoshida Michihiro , Hayashi Kazuki , Naitoh Itaru , Hori Yasuki , Natsume Makoto , Jinno Naruomi , Kachi Kenta , Asano Go , Toyohara Tadashi , Kito Yusuke , Ammanamanchi Sudhakar , Kataoka Hiromi
Published: September 2022

Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA.
Construction and validation of a prognostic model with RNA binding protein-related mRNAs for the HBV-related hepatocellular carcinoma patients
Authors: Xu Shaohua , Liu Hui , Tian Renyun , Xie Jiahui , Chen Su , Luo Junyun , Zhu Haizhen , Wang Yirong , Li Zhaoyong
Published: September 2022

Hepatocellular carcinoma (HCC) is a common malignancy worldwide with poor clinical outcomes, and the infection of hepatitis B virus (HBV) is the leading cause of this disease. Mounting evidence shows that RNA binding proteins (RBPs) can modulate the progression of cancers. However, the functions and clinical implications of RBP-related mRNAs in HBV-related HCC remain largely unclear. Therefore, we aim to develop a prognostic model based on the RBP-related mRNAs for HBV-related HCC patients. Firstly, we identified 626 differentially expressed RBP-related mRNAs in the HBV-related HCC through the Pearson correlation analysis. Subsequently, the Kaplan-Meier survival, univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses were used to construct a prognostic model comprised of five RBP-related mRNAs. Furthermore, the patients were categorized into the high- and low-risk groups by the prognostic model and the patients in the high-risk group had a poor prognosis. Additionally, the prognostic model was an independent predictor of prognosis, and the accuracy of the prognostic model was proved by the receiver operator characteristic (ROC) analysis. Furthermore, the functional enrichment analysis revealed that various cancer-promoting processes were enriched in the high-risk group. Taken together, our study may provide the HBV-related HCC biomarkers of prognosis to improve the clinical outcomes of patients.
Glucocorticoid receptor and androgen receptor-targeting therapy in patients with castration-resistant prostate cancer
Authors: Pak Sahyun , Suh Jungyo , Park Seo Young , Kim Yunlim , Cho Yong Mee , Ahn Hanjong
Published: September 2022

Objective

The glucocorticoid receptor (GR) promotes resistance to androgen receptor (AR)-targeting therapies in castration-resistant prostate cancer (CRPC) by bypassing AR blockade. However, the clinical relevance of evaluating GR expression in patients with CRPC has not been determined. The present study investigated the association of relative GR expression in CRPC tissue samples with treatment response to AR-targeting therapy.

Methods

Levels of GR, AR-FL, and AR-V7 mRNAs were measured in prostate cancer tissue from prospectively enrolled CRPC patients who were starting treatment. Patients were divided into groups with high and low AR-V7/AR-FL ratios and with high and low GR/AR-FL ratios. The primary endpoint was prostate-specific antigen (PSA) response rate to treatment.

Results

Evaluation of 38 patients treated with AR-targeting therapies showed that the PSA response rate was significantly higher in patients with low than high AR-V7/AR-FL ratios (77.8% vs. 25.0%, p=0.003) and in patients with low than high GR/AR-FL ratios (81.3% vs. 27.3%, p=0.003). Patients with low GR/AR-FL ratios had higher rates of PSA progression-free survival (46.0% vs. 22.4%, p=0.006), radiologic progression-free survival (28.9% vs. 10.0%, p=0.02), and overall survival (75.2% vs. 48.0%, p=0.037) than patients with high GR/AR-FL ratios. The association of GR/AR-FL ratio with PSA response to AR-targeting therapy remained significant in multivariable models. Evaluation of the 14 patients who received taxane chemotherapy showed that PSA response rates did not differ significantly in those with low and high AR-V7/AR-FL and GR/AR-FL ratios, although no definitive conclusions can be drawn due to the small number of patients.

Conclusion

Relative GR expression is associated with sensitivity to AR-targeting therapy and survival in patients with CRPC. Large-scale prospective validation and liquid biopsy-based studies are warranted.
Percutaneous thermal ablation combined with transcatheter arterial chemoembolization for hepatitis C virus-related hepatocellular carcinoma: Efficacy and survival
Authors: Sun Yu , Zhang Honghai , Long Jiang , Zhang Yonghong , Zheng Jiasheng , Yuan Chunwang
Published: September 2022

Objective

The aim of this study was to investigate the efficacy and survival of Hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) undergoing percutaneous thermal ablation combined with transcatheter arterial chemoembolization (TACE).

Methods

A total of 83 HCV-related HCC patients who were treated with percutaneous thermal ablation combined with TACE were retrospectively analyzed. The demographic and clinical data were collected. The overall survival (OS) and recurrence free survival (RFS) rates were assessed by the Kaplan-Meier method. Univariate and multivariate Cox regression analysis was used to assess independent risk factors of OS and RFS.

Results

92.8% patients (77/83) and 96.6% (170/176) tumor lesions achieved complete response (CR) 1 month after all treatment, and 10.8% (9/83) patients had minor complications. The median OS was 60 months (95% confidence interval (CI)= 48.0-72.0), and the 1-, 2-, 3-, 5- and 10-year cumulative OS rates were 94%, 78.3%, 72.3%, 43.4% and 27.5%, respectively. The cumulative RFS rates at 1-, 2-, 3- and 5-year were 74.7%, 49.3%, 30.7% and 25.3%, respectively. Sex (HR =0.529, P=0.048), ablation result (HR=5.824, P=0.000) and Albumin-bilirubin (ALBI) score (HR=2.725, P=0.011) were independent prognostic factors for OS. Alpha-fetoprotein (AFP) (HR =2.360, P = 0.005) and tumor number(HR=2.786, P=0.000) were independent prognostic factors for RFS.

Conclusions

Percutaneous thermal ablation combined with TACE is a safe and effective treatment for HCV-related HCC. Sex, ablation result and ALBI are significant prognostic factors for OS. AFP and tumor number are significant prognostic factors for RFS.
Case Report: Neoadjuvant immunotherapy with pembrolizumab alone for bilateral upper tract urothelial carcinoma is a feasible strategy for kidney sparing and avoidance of hemodialysis
Authors: Chan Wai-Nga , Huang Yun-Ching , Ho Dong-Ru , Chen Chih-Shou
Published: September 2022

In Taiwan, the incidence of upper-tract urothelial carcinomas (UTUCs) is higher than in western countries (20%–31% vs. 5%–10%), as is bilateral disease. The standard management for high-grade UTUC is radical nephroureterectomy with bladder cuff excision and regional lymphadenectomy. The challenges in managing bilateral UTUCs are how to retain renal function and avoid permanent hemodialysis. We present two cases of developed bilateral high-grade renal pelvis urothelial carcinoma, cT3N0M0 stage III, that revealed excellent results in tumor regression after three cycles of half-dose pembrolizumab. One case received unilateral retroperitoneal laparoscopic nephroureterectomy with bladder cuff excision; thereafter, renal function has been good until now, and the remaining right kidney has been free of tumor recurrence in the 3 years of follow-up. The other patient, however, expired from an immune-related adverse event (irAE) 22 days after the third cycle of pembrolizumab, although tumor remission was evident also. Neoadjuvant pembrolizumab alone could be a potential strategy in positive of selected biomarkers for high-grade bilateral UTUC with remaining neglectable nephrotoxicity and may avoid permanent hemodialysis.
Association of sarcopenia with survival in advanced NSCLC patients receiving concurrent immunotherapy and chemotherapy
Authors: Bolte Fabian J. , McTavish Sloane , Wakefield Nathan , Shantzer Lindsey , Hubbard Caroline , Krishnaraj Arun , Novicoff Wendy , Gentzler Ryan D. , Hall Richard D.
Published: September 2022

Background

Frailty, sarcopenia and malnutrition are powerful predictors of clinical outcomes that are not routinely measured in patients with non-small cell lung cancer (NSCLC). The primary aim of this study was to investigate the association of sarcopenia, determined by the psoas muscle index (PMI) with overall survival (OS) in patients with advanced NSCLC treated with concurrent immune checkpoint inhibitor (ICI) and chemotherapy (CTX).

Methods

We retrospectively reviewed data from a cohort of patients with locally advanced or metastatic NSCLC who were treated between 2015 and 2021 at the University of Virginia Medical Center. The cross-sectional area of the psoas muscle was assessed on CT or PET/CT imaging prior to treatment initiation. Multivariate analysis was performed using Cox proportional hazards regression models.

Results

A total of 92 patients (median age: 64 years, range 36-89 years), 48 (52.2%) men and 44 (47.8%) women, were included in the study. The median follow-up was 29.6 months. The median OS was 17.8 months. Sarcopenia, defined by a PMI below the 25th percentile, was associated with significantly lower OS (9.1 months in sarcopenic patients vs. 22.3 months in non-sarcopenic patients, P = 0.002). Multivariate analysis revealed that sarcopenia (HR 2.12, P = 0.0209), ECOG ≥ 2 (HR 2.88, P = 0.0027), prognostic nutritional index (HR 3.02, P = 0.0034) and the absence of immune related adverse events (HR 2.04, P = 0.0185) were independently associated with inferior OS.

Conclusions

Sarcopenia is independently associated with poor OS in patients with advanced NSCLC undergoing concurrent ICI and CTX.
Metabolite-derived protein modifications modulating oncogenic signaling
Authors: Liu Yawen , Vandekeere Anke , Xu Min , Fendt Sarah-Maria , Altea-Manzano Patricia
Published: September 2022

Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these.
Successes and failures of angiogenesis blockade in gastric and gastro-esophageal junction adenocarcinoma
Authors: Salati Massimiliano , Caputo Francesco , Bocconi Alessandro , Cerri Sara , Baldessari Cinzia , Piacentini Federico , Dominici Massimo , Gelsomino Fabio
Published: September 2022

Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients’ outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.
LncmiRHG-MIR100HG: A new budding star in cancer
Authors: Wu Yingnan , Wang Zhenzhen , Yu Shan , Liu Dongzhe , Sun Litao
Published: September 2022

MIR100HG, also known as lncRNA mir-100-let-7a-2-mir-125b-1 cluster host gene, is a new and critical regulator in cancers in recent years. MIR100HG is dysregulated in various cancers and plays an oncogenic or tumor-suppressive role, which participates in many tumor cell biology processes and cancer-related pathways. The errant expression of MIR100HG has inspired people to investigate the function of MIR100HG and its diagnostic and therapeutic potential in cancers. Many studies have indicated that dysregulated expression of MIR100HG is markedly correlated with poor prognosis and clinicopathological features. In this review, we will highlight the characteristics and introduce the role of MIR100HG in different cancers, and summarize the molecular mechanism, pathways, chemoresistance, and current research progress of MIR100HG in cancers. Furthermore, some open questions in this rapidly advancing field are proposed. These updates clarify our understanding of MIR100HG in cancers, which may pave the way for the application of MIR100HG-targeting approaches in future cancer diagnosis, prognosis, and therapy.
Splint Duration and Not the Mode of Anesthesia Is the Main Factor Influencing Avascular Necrosis After Closed Reduction for Developmental Dysplasia of the Hip in Kosovo
Authors: Sllamniku Sabit , Beqo Besiana P. , Krasniqi Islam , Tërshana Azem , Murtezani Ardiana , Quehenberger Franz , Haxhija Emir Q.
Published: September 2022

The aim of this study was to determine whether the use of analgesia and sedation (AS) as opposed to general anesthesia (GA) for closed reduction and spica casting of children with severe developmental dysplasia of the hip (DDH) influenced the long-term incidence of avascular necrosis (AVN). In a prospective, randomized, single-blinded clinical trial we investigated 100 pediatric patients with DDH type IIIa, IIIb, and IV (according to Graf classification), who were randomly assigned into the group receiving AS, and the group receiving GA. Baseline demographics, splint duration, and type of DDH were carefully assessed. The presence of AVN was assessed at the follow-up visits at 1 and 7 years after the end of treatment. The AS-group consisted of 50 patients (46 girls) with 76 hips affected (n = 11/Type-IIIa, n = 32/Type-IIIb, and n = 33/Type-IV). The GA-group consisted also of 50 patients (44 girls) with 78 hips involved (n = 15/Type-IIIa, n = 34/Type-IIIb, and n = 29/Type-IV). At 7-years follow-up, AVN was diagnosed in 9 of 154 hips (5.8%), 5 hips in the AS-group and 4 hips in the GA group. The logistic regression model showed no significant difference in AVN incidence between the AS and GA groups at 7-years follow-up (p = 0.27). The multivariate regression analysis showed that neither the type of DDH nor the age at diagnosis influenced the incidence of AVN (p = 0.48 and p = 0.28, respectively). Splint duration was identified as the only significant factor for the long-term incidence of AVN in the treatment of severe DDH. For every month of longer splint duration, the odds of AVN at 7-years follow-up increased by a factor of 3.81 (95%CI: 1.35–13.73, p = 0.02). Closed reduction and spica casting of children with severe DDH under AS can be considered a feasible alternative to management under GA. All efforts must be made to diagnose patients with DDH as early as possible and shorten the duration of splint treatment to prevent the development of AVN. Level of Evidence. Level II-1.
Approaches to Preventing Intrapartum Fetal Injury
Authors: Schifrin Barry S. , Koos Brian J. , Cohen Wayne R. , Soliman Mohamed
Published: September 2022

Electronic fetal monitoring (EFM) was introduced into obstetric practice in 1970 as a test to identify early deterioration of fetal acid-base balance in the expectation that prompt intervention (“rescue”) would reduce neonatal morbidity and mortality. Clinical trials using a variety of visual or computer-based classifications and algorithms for intervention have failed repeatedly to demonstrate improved immediate or long-term outcomes with this technique, which has, however, contributed to an increased rate of operative deliveries (deemed “unnecessary”). In this review, we discuss the limitations of current classifications of FHR patterns and management guidelines based on them. We argue that these clinical and computer-based formulations pay too much attention to the detection of systemic fetal acidosis/hypoxia and too little attention not only to the pathophysiology of FHR patterns but to the provenance of fetal neurological injury and to the relationship of intrapartum injury to the condition of the newborn. Although they do not reliably predict fetal acidosis, FHR patterns, properly interpreted in the context of the clinical circumstances, do reliably identify fetal neurological integrity (behavior) and are a biomarker of fetal neurological injury (separate from asphyxia). They provide insight into the mechanisms and trajectory (evolution) of any hypoxic or ischemic threat to the fetus and have particular promise in signaling preventive measures (1) to enhance the outcome, (2) to reduce the frequency of “abnormal” FHR patterns that require urgent intervention, and (3) to inform the decision to provide neuroprotection to the newborn.
EFMSDTI: Drug-target interaction prediction based on an efficient fusion of multi-source data
Authors: Zhang Yuanyuan , Wu Mengjie , Wang Shudong , Chen Wei
Published: September 2022

Accurate identification of Drug Target Interactions (DTIs) is of great significance for understanding the mechanism of drug treatment and discovering new drugs for disease treatment. Currently, computational methods of DTIs prediction that combine drug and target multi-source data can effectively reduce the cost and time of drug development. However, in multi-source data processing, the contribution of different source data to DTIs is often not considered. Therefore, how to make full use of the contribution of different source data to predict DTIs for efficient fusion is the key to improving the prediction accuracy of DTIs. In this paper, considering the contribution of different source data to DTIs prediction, a DTIs prediction approach based on an effective fusion of drug and target multi-source data is proposed, named EFMSDTI. EFMSDTI first builds 15 similarity networks based on multi-source information networks classified as topological and semantic graphs of drugs and targets according to their biological characteristics. Then, the multi-networks are fused by selective and entropy weighting based on similarity network fusion (SNF) according to their contribution to DTIs prediction. The deep neural networks model learns the embedding of low-dimensional vectors of drugs and targets. Finally, the LightGBM algorithm based on Gradient Boosting Decision Tree (GBDT) is used to complete DTIs prediction. Experimental results show that EFMSDTI has better performance (AUROC and AUPR are 0.982) than several state-of-the-art algorithms. Also, it has a good effect on analyzing the top 1000 prediction results, while 990 of the first 1000DTIs were confirmed. Code and data are available at https://github.com/meng-jie/EFMSDTI.
Efficacy of pharmacologic therapies in patients with acute heart failure: A network meta-analysis
Authors: Dai Hengheng , Li Haisong , Wang Bin , Zhang Jingjing , Chen Ying , Zhang Xuecheng , Liu Yan , Shang Hongcai
Published: September 2022

Background: A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy.

Methods: We used PubMed, EMBASE, Cochrane Clinical Trials Register, and Web of Science systems to search studies of randomized controlled trials (RCT) for the treatment of AHF recommended by the guidelines and expert consensus until 1 December 2020. The primary outcome was all-cause mortality within 30 days. The secondary outcomes included 30-days all-cause rehospitalization, rates of HF-related rehospitalization, rates of adverse events, and rates of serious adverse events. A Bayesian NMA based on random effects model was performed.

Results: After screening 14,888 citations, 23 RCTs (17,097 patients) were included, focusing on nesiritide, placebo, serelaxin, rhANP, omecamtiv mecarbil, tezosentan, KW-3902, conivaptan, tolvaptan, TRV027, chlorothiazide, metolazone, ularitide, relaxin, and rolofylline. Omecamtiv mecarbil had significantly lower all-cause mortality rates than the placebo (odds ratio 0.04, 0.01–0.22), rhANP (odds ratio 0.03, 0–0.40), serelaxin (odds ratio 0.05, 0.01–0.38), tezosentan (odds ratio 0.04, 0–0.22), tolvaptan (odds ratio 0.04, 0.01–0.30), and TRV027 (odds ratio 0.03, 0–0.36). No drug was superior to the other drugs for the secondary outcomes and safety outcomes.

Conclusion: No drug was superior to the other drugs for the secondary outcomes and safety outcomes. Current drugs for AHF show similar efficacy and safety.
Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis
Authors: Griffin Robert J. , Avery Ethan , Xia Cindy Q.
Published: September 2022

The correlation between efficacious doses in human tumor-xenograft mouse models and the human clinical doses of approved oncology agents was assessed using published preclinical data and recommended clinical doses. For 90 approved small molecule anti-cancer drugs, body surface area (BSA) corrected mouse efficacious doses were strongly predictive of human clinical dose ranges with 85.6% of the predictions falling within three-fold (3×) of the recommended clinical doses and 63.3% within 2×. These results suggest that BSA conversion is a useful tool for estimating human doses of small molecule oncology agents from mouse xenograft models from the early discovery stage. However, the BSA based dose conversion poorly predicts for the intravenous antibody and antibody drug conjugate anti-cancer drugs. For antibody-based drugs, five out of 30 (16.7%) predicted doses were within 3× of the recommended clinical dose. The body weight-based dose projection was modestly predictive with 66.7% of drugs predicted within 3× of the recommended clinical dose. The correlation was slightly better in ADCs (77.7% in 3×). The application and limitations of such simple dose estimation methods in the early discovery stage and in the design of clinical trials are also discussed in this retrospective analysis.
ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression
Authors: Li Yilan , Yan Jingru , Zhao Qianqian , Zhang Yan , Zhang Yao
Published: September 2022

Sorafenib is the unique recommended molecular-targeted drug for advanced hepatocellular carcinoma, but its clinical use is limited due to cardiotoxicity. As sorafenib is an efficient ferroptosis inducer, the pathogenesis of this compound to ferroptosis-mediated cardiotoxicity is worth further study. Mice were administered 30 mg/kg sorafenib intraperitoneally for 2 weeks to induce cardiac dysfunction and Ferrostatin-1 (Fer-1) was used to reduce ferroptosis of mice with sorafenib-induced cardiotoxicity. Sorafenib reduced levels of anti-ferroptotic markers involving Slc7a11 and glutathione peroxidase 4 (GPX4), increased malonaldehyde malondialdehyde, apart from causing obvious mitochondria damage, which was alleviated by Fer-1. In vitro experiments showed that Fer-1 inhibited lipid peroxidation and injury of H9c2 cardiomyoblasts induced by sorafenib. Both in vitro and in vivo experiments confirmed that the expression of Slc7a11 was down regulated in sorafenib-induced cardiotoxicity, which can be partially prevented by treatment with Fer-1. Overexpression of Slc7a11 protected cells from ferroptosis, while knock-down of Slc7a11 made cardiomyoblasts sensitive to ferroptosis caused by sorafenib. Finally, by comparing data from the GEO database, we found that the expression of ATF3 was significantly increased in sorafenib treated human cardiomyocytes. In addition, we demonstrated that ATF3 suppressed Slc7a11 expression and promoted ferroptosis. Based on these findings, we concluded that ATF3/Slc7a11 mediated ferroptosis is one of the key mechanisms leading to sorafenib-induced cardiotoxicity. Targeting ferroptosis may be a novel therapeutic approach for preventing sorafenib-induced cardiotoxicity in the future.
Multifaceted Roles of Chemokine C-X-C Motif Ligand 7 in Inflammatory Diseases and Cancer
Authors: Wu Qianmiao , Tu Huaijun , Li Jian
Published: September 2022

Over recent years, C-X-C motif ligand 7 (CXCL7) has received widespread attention as a chemokine involved in inflammatory responses. Abnormal production of the chemokine CXCL7 has been identified in different inflammatory diseases; nevertheless, the exact role of CXCL7 in the pathogenesis of inflammatory diseases is not fully understood. Persistent infection or chronic inflammation can induce tumorigenesis and progression. Previous studies have shown that the pro-inflammatory chemokine CXCL7 is also expressed by malignant tumor cells and that binding of CXCL7 to its cognate receptors C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2) can influence tumor biological behavior (proliferation, invasion, metastasis, and tumor angiogenesis) in an autocrine and paracrine manner. CXCL7 and its receptor CXCR1/CXCR2, which are aberrantly expressed in tumors, may represent new targets for clinical tumor immunotherapy.
Synergistic Effect of Huangqin Decoction Combined Treatment With Radix Actinidiae chinensis on DSS and AOM-Induced Colorectal Cancer
Authors: Huang Jianbo , Jiang Tao , Kang Jingyi , Xu Jiayi , Dengzhang Yiting , Zhao Zhengqi , Yang Chuqi , Wu Mengting , Xu Xiaoping , Zhang Guangji , Lou Zhaohuan
Published: September 2022

Objective: To demonstrate the effectiveness of Huangqin decoction (Huangqin Tang in Chinese, HQT) combined with Radix Actinidiae chinensis (Tengligen in Chinese, TLG) under the guidance of “dampness–heat theory” in preventing and treating colorectal cancer (CRC) with dampness–heat accumulation and to preliminarily reveal its mechanism.

Methods: The mice model of CRC was established by intraperitoneal injection of AOM combined with consumption of 2.5% DSS solution, and celecoxib, HQT, TLG, and their combination (HQT + TLG) were administered at the same time. The physical signs and death of the mice were observed daily. At the end of the experiment, the colorectal tissue was dissected, and the tumor was observed and counted. HE staining and Masson’s staining were used to observe the histopathological changes of colon. Expression levels of TNF-α, IL-6, and IL-10 in colorectal tissue were detected by ELISA, and the expression of TNF-α was observed by immunofluorescence. TUNEL assay was used to observe the apoptosis of tumor tissues, and immunohistochemistry was used to observe the expression of Ki-67 and occludin. The mRNA expression levels of claudin-1, occludin, ZO-1, and IL-6 and IL-17 were detected by RT-PCR, and occludin, ZO-1, NF-κB, and STAT3 protein levels were detected by Western blot. The composition of intestinal flora was analyzed by 16S rRNA.

Results: HQT + TLG could significantly reduce the mortality of model mice and improve the intestinal mucosal inflammatory cell infiltration and high-grade intraepithelial neoplasia in model mice. All administration groups show a great reduction in the levels of IL-6 and TNF-α in the colorectal tissues of model mice, and increase in the level of IL-10, the total number of CD3+ T cells, the proportion of CD3+CD4+ T cells, and the ratio of CD4/CD8. HQT and HQT + TLG could significantly change the composition of intestinal flora and increase the abundance of Firmicutes and Patescibacteria.

Conclusion: HQT and TLG combination has a good effect on inhibiting AOM-DSS-induced CRC. This function may be related to improving the composition of the intestinal flora, regulating the proportion of T-cell subsets in colorectal lymphoid tissue to improve inflammatory response, and downregulating the expression of claudin-1, inhibiting the activation of IL-6/STAT3 signaling pathway to improving abnormal hyperplasia.
Multi-component pharmacokinetic study of prunus mume fructus extract after oral administration in rats using UPLC-MS/MS
Authors: Zhu Yameng , Wei Shujie , Cao Xiunan , Wang Songrui , Chang Yanxu , Ouyang Huizi , He Jun
Published: September 2022

Prunus mume fructus (MF) is used in traditional Chinese medicine and food, as it exerts pharmacological effects, such as antibacterial, antioxidant, antitumour, thirst-relieving, and antidiarrheal effects. In the present study, a reliable and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of 16 prototype components (L-(-)-malic acid, 3,4-dihydroxybenzaldehyde, protocatechuic acid, vanillic acid, caffeic acid, D-(-)-quinic acid, citric acid, ferulic acid, syringic acid, cryptochlorogenic acid, neochlorogenic acid, chlorogenic acid, amygdalin, maslinic acid, corosolic acid, and rutin) in rat plasma after oral administration of the MF extract. Plasma samples were prepared via protein precipitation using acetonitrile. The 16 components were separated on an ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) with a gradient mobile phase system of methanol and 0.1% (v/v) formic acid aqueous solution at a flow rate of 0.3 ml/min. All components were quantitated using Agilent Jet Stream electrospray ionisation in negative ion mode. The intra-day and inter-day accuracies ranged from-9.4 to 9.4%, and the precision of the analytes was less than 14.8%. The extraction recovery rate of the analytes ranged from 63.59 to 109.44% and the matrix effects ranged from 49.25 to 109.28%. Stability studies proved that the analytes were stable under the tested conditions, with a relative standard deviation lower than 13.7%. Hence, the developed method was successfully applied to evaluate the pharmacokinetics of 16 components in the MF extract after oral administration in rats using UPLC-MS/MS.
Efficacy and safety of total glucosides of paeony as an add-on treatment in adolescents and adults with chronic urticaria: A systematic review and meta-analysis
Authors: Li Ming , Li Yan , Xiang Lujing , Li Linfeng
Published: September 2022

Background:Total glycosides of paeony (TGP), an active compound extracted from the dried roots ofPaenoia lactifloraPall., has been widely used to treat chronic urticaria (CU) in China. This study aims to systematically evaluate the efficacy and safety of TGP as an add-on treatment for the treatment of CU in adolescents and adults.

Methods:Eight literature databases and two clinical trial registries were searched from their inception to 31 May 2022. Randomized controlled trials on TGP as an add-on treatment for CU in adolescents and adults were included. The Cochrane Collaboration’s risk of bias tool was used for the methodological quality assessment, and RevMan 5.3 software and Stata 12.0 software were used for data analyses.

Results:A total of 30 studies with 2,973 participants were included in this meta-analysis. The methodological qualities of all included studies were suboptimal. The pooled results showed that TGP combined with H1-antihistamine was superior to H1-antihistamine alone in the cure rate (risk ratio (RR) = 1.54, 95% confidence interval (CI) = 1.39 to 1.71,p< 0.00001), total efficacy rate (RR = 1.33, 95%CI = 1.26 to 1.40,p< 0.00001), urticaria activity score 7 (mean difference (MD) = -4.03, 95%CI = -6.62 to -1.44,p= 0.002), recurrence rate (RR = 0.31, 95%CI = 0.20 to 0.46,p< 0.00001), and the level of IgE in serum (standardized mean difference (SMD) = -1.96, 95%CI = -3.02 to -0.90,p= 0.0003). In terms of safety, the incidence of diarrhea (RR = 6.19, 95%CI = 3.39 to 11.29,p< 0.00001) was significantly increased in the TGP plus H1-antihistamine groups, and no abnormal results of laboratory tests and electrocardiogram were reported in two groups. The qualities of evidences were evaluated as moderate to low.

Conclusions:TGP as an add-on treatment could provide a good effect for CU in adolescents and adults with mild and tolerable adverse events. However, in view of poor methodological quality, high-quality and long-term clinical trials are needed in the future to confirm and update the evidence.
Remodeling an existing rare disease registry to be used in regulatory context: Lessons learned and recommendations
Authors: Mordenti Marina , Boarini Manila , D’Alessandro Fabio , Pedrini Elena , Locatelli Manuela , Sangiorgi Luca
Published: September 2022

Disease registries have been used as an interesting source of real-world data for supporting regulatory decision-making. In fact, drug studies based on registries cover pre-approval investigation, registry randomized clinical trials, and post-authorization studies. This opportunity has been investigated particularly for rare diseases—conditions affecting a small number of individuals worldwide—that represent a peculiar scenario. Several guidelines, concepts, suggestions, and laws are already available to support the design or improvement of a rare disease registry, opening the way for implementation of a registry capable of managing regulatory purposes. The present study aims to highlight the key stages performed for remodeling the existing Registry of Multiple Osteochondromas—REM into a tool consistent with EMA observations and recommendations, as well as to lead the readers through the entire adapting, remodeling, and optimizing process. The process included a variety of procedures that can be summarized into three closely related categories: semantic interoperability, data quality, and governance. At first, we strengthened interoperability within the REM registry by integrating ontologies and standards for proper data collection, in accordance with FAIR principles. Second, to increase data quality, we added additional parameters and domains and double-checked to limit human error to a bare minimum. Finally, we established two-level governance that has increased the visibility for the scientific community and for patients and carers. In conclusion, our remodeled REM registry fits with most of the scientific community’s needs and indications, as well as the best techniques for providing real-world evidence for regulatory aspects.
A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients
Authors: Asiimwe Innocent G. , Blockman Marc , Cohen Karen , Cupido Clint , Hutchinson Claire , Jacobson Barry , Lamorde Mohammed , Morgan Jennie , Mouton Johannes P. , Nakagaayi Doreen , Okello Emmy , Schapkaitz Elise , Sekaggya-Wiltshire Christine , Semakula Jerome R. , Waitt Catriona , Zhang Eunice J. , Jorgensen Andrea L. , Pirmohamed Munir
Published: September 2022

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.
Scheme for implementing nonlocal high-fidelity quantum controlled-not gates on quantum-dot-confined electron spins using optical microcavities and photonic hyperentanglement
Authors: Han Yu-Hong , Cao Cong , Fan Ling , Zhang Ru
Published: September 2022

Quantum information networks can transmit quantum states and perform quantum operations between different quantum network nodes, which are essential for various applications of quantum information technology in the future. In this paper, a potentially practical scheme for implementing nonlocal quantum controlled-not (CNOT) gate operations on quantum-dot-confined electron spins between two quantum network nodes is presented. The scheme can realize parallel teleportation of two nonlocal quantum CNOT gates simultaneously by employing hyperentangled photon pairs to establish quantum channel, which can effectively improve the channel capacity and operational speed. The core of the scheme are two kinds of photon-spin hybrid quantum CNOT gate working in a failure-heralded and fidelity-robust fashion. With the heralded mechanism, the nonlocal CNOT gates can be implementated with unity fidelities in principle, even if the particularly ideal conditions commonly used in other schemes are not satisfied strictly. Our analysis and calculations indicate that the scheme can be demonstrated efficiently (with efficiency exceeding 99%) with current or near-future technologies. Moreover, the utilized photon-spin hybrid quantum gates can be regarded as universal modules for many other quantum information processing (QIP) tasks. Therefore, the scheme is potential for constructing elementary quantum networks, and realizing nolocal QIP with high channel capacities, high fidelities, and high efficiencies.