Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.

Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.

Congener-specific fate and impact of microcystins in the soil-earthworm system.

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services.

Ginsenoside Rg3: A Review of its Anticancer Mechanisms and Potential Therapeutic Applications.

BACKGROUND: Traditional Chinese Medicine (TCM) has a long history of treating various diseases and is increasingly being recognized as a complementary therapy for cancer. A promising natural compound extracted from the Chinese herb ginseng is ginsenoside Rg3, which has demonstrated significant anticancer effects. It has been tested in a variety of cancers and tumors and has proven to be effective in suppressing cancer. OBJECTIVE: This work covers various aspects of the role of ginsenoside Rg3 in cancer treatment, including its biological functions, key pathways, epigenetics, and potential for combination therapies, all of which have been extensively researched and elucidated. The study aims to provide a reference for future research on ginsenoside Rg3 as an anticancer agent and a support for the potential application of ginsenoside Rg3 in cancer treatment.

Prognosis prediction and risk stratification of breast cancer patients based on a mitochondria-related gene signature.

As the malignancy with the highest global incidence, breast cancer represents a significant threat to women's health. Recent advances have shed light on the importance of mitochondrial function in cancer, particularly in metabolic reprogramming within tumors. Recognizing this, we developed a novel risk signature based on mitochondrial-related genes to improve prognosis prediction and risk stratification in breast cancer patients. In this study, transcriptome data and clinical features of breast cancer samples were extracted from two sources: the TCGA, serving as the training set, and the METABRIC, used as the independent validation set. We developed the signature using LASSO-Cox regression and assessed its prognostic efficacy via ROC curves. Furthermore, the signature was integrated with clinical features to create a Nomogram model, whose accuracy was validated through clinical calibration curves and decision curve analysis. To further elucidate prognostic variations between high and low-risk groups, we conducted functional enrichment and immune infiltration analyses. Additionally, the study encompassed a comparison of mutation landscapes and drug sensitivity, providing a comprehensive understanding of the differing characteristics in these groups. Conclusively, we established a risk signature comprising 8 mitochondrial-related genes-ACSL1, ALDH2, MTHFD2, MRPL13, TP53AIP1, SLC1A1, ME3, and BCL2A1. This signature was identified as an independent risk predictor for breast cancer patient survival, exhibiting a significant high hazard ratio (HR = 3.028, 95%CI 2.038-4.499, P < 0.001). Patients in the low-risk group showed a more favorable prognosis, with enhanced immune infiltration, distinct mutation landscapes, and greater sensitivity to anti-tumor drugs. In contrast, the high-risk group exhibited an adverse trend in these aspects. This risk signature represents a novel and effective prognostic indicator, suggesting valuable insights for patient stratification in breast cancer.

PET/CT-aided biopsy of lung lesions enhances diagnostic efficacy, especially for lesions >3cm.

Objectives: The purpose of this study was to compare the diagnostic efficacy of PET/CT-aided CT-guided and routine CT-guided transthoracic needle biopsy for lung lesions. Methods: A total of 458 patients with suspicious lung lesions were referred for CT-guided biopsy, with 227 patients assigned to the PET/CT group and 231 patients assigned to the CT group. The clinical characteristics and diagnostic yield were compared between the two groups. Furthermore, conducting subgroup analysis to evaluate the differences of diagnostic success or failure between the two groups. Results: The sensitivity and diagnostic accuracy rate differed significantly (P = 0.035, P = 0.048). In the PET/CT group, the values were 95.7% and 96.3%, respectively, while in the CT group, they were 90.1% and 91.9%. When considering non-diagnostic cases, the overall diagnostic success rate increased markedly in PET/CT group (93.0% vs. 83.1%, P = 0.001). In our subgroup analysis, the PET/CT group demonstrated superiority in detecting lesions larger than 3 cm (OR, 4.81; 95CI%, 2.03 - 11.36), while showing a moderate effect in lesions smaller than 3 cm (OR, 1.09; 95CI%, 0.42 - 2.81). Significant effect modification was observed in large lesions in the PET/CT group (P for interaction = 0.023). Conclusions: 18F-FDG-PET/CT enhances the diagnostic efficacy of CT-guided transthoracic needle biopsy for lung lesions, and the incremental value can be modified by lesion size, particularly when the diameter is larger than 3 cm.

Post-surgery financial toxicity and its influencing factors in colorectal cancer care: A cross-sectional study.

PURPOSE: This study aimed to investigate the influence factors of financial toxicity experienced by colorectal cancer patients after surgery. The results will provide deep insights for developing effective intervention strategies to address this common issue of colorectal cancer care. METHODS: In this cross-sectional study, we recruited 213 postoperative patients with colorectal cancer from February 2023 to July 2023 in two major public hospitals. Patients completed the General Information Questionnaire, Comprehensive Scores for Financial Toxicity (COST), Self-perceived Burden Scale (SPBS), Family Resilience Questionnaire (FaREQ), and Social Support Rating Scale (SSRS). A multiple linear regression model was used to investigate the influence factors of financial toxicity. RESULTS: The mean score of financial toxicity was medium (18.91 ± 7.90) in this study. Financial toxicity score was negatively correlated with self-perceived burden (r = -0.333, P < 0.01) and positively associated with family resilience (r = 0.365, P < 0.01) and social support (r = 0.388, P < 0.01). Via multiple linear regression analysis, we identified seven significant factors associated with financial toxicity, including family income [(95 %CI: 1.075-3.123); P = 0.000], self-perceived burden [(95 %CI: 0.300∼-0.038); P = 0.012], stoma [(95 %CI: 5.309∼-1.682); P = 0.000], social support [(95 %CI:0.058-0.407); P = 0.009], cancer stage [(95 %CI: 2.178∼-0.170); P = 0.022], postoperative duration [(95 %CI: 1.900∼-0.332); P = 0.005], and family resilience [(95 %CI: 0.028-0.203); P = 0.010]. CONCLUSIONS: Financial toxicity was prevalent among postoperative colorectal cancer patients. Additional support and early interventions should be given to high-risk patients, including those with stomas, advanced disease stages, or experiencing longer postoperative duration. Apart from demographic factors, we identified that self-perceived burden, family resilience, and social support were also associated with financial toxicity, providing a new perspective for developing effective strategies against financial toxicity.

The management of non-culprit vessel(s) in patients with unstable angina/non-ST elevation myocardial infarction and chronic kidney dysfunction.

BACKGROUND AND AIMS: The clinical effects of multivessel interventions in patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI), multivessel disease (MVD) and chronic kidney disease (CKD) remain uncertain. This study aimed to investigate the safety and effectiveness of intervention in non-culprit lession(s) among this cohort. METHODS: We consecutively included patients diagnosed with UA/NSTEMI, MVD and CKD between January 2008 and December 2018 at our centre. After successful percutaneous coronary intervention (PCI), we compared 48-month overall mortality between those undergoing multivessel PCI (MV-PCI) through a single-procedure or staged-procedure approach and culprit vessel-only PCI (CV-PCI) after 1:1 propensity score matching. We conducted stratified analyses and tests for interaction to investigate the modifying effects of critical covariates. Additionally, we recorded the incidence of contrast-induced nephropathy (CIN) to assess the perioperative safety of the two treatment strategies. RESULTS: Of the 749 eligible patients, 271 pairs were successfully matched. Those undergoing MV-PCI had reduced all-cause mortality (hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.48-0.67). Subgroup analysis showed that those with advanced CKD (estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 ) could not benefit from MV-PCI (P = 0.250), and the survival advantage also tended to diminish in diabetes (P interaction < 0.01; HR = 0.95, 95% CI = 0.65-1.45). Although the staged-procedure approach (N = 157) failed to bring additional survival benefits compared to single-procedure MV-PCI (N = 290) (P = 0.460), it showed a tendency to decrease the death risk. CIN risks in MV-PCI and CV-PCI groups were not significantly different (risk ratio = 1.60, 95% CI = 0.94-2.73). CONCLUSION: Among patients with UA/NSTEMI and non-diabetic CKD and an eGFR > 30 mL/min/1.73 m2 , MV-PCI was associated with a reduced risk of long-term death but did not increase the incidence of CIN during the management of MVD compared to CV-PCI. And staged procedures might be a preferable option over single-procedure MV-PCI.

Progress, implications, and challenges in using humanized immune system mice in CAR-T therapy-Application evaluation and improvement.

In recent years, humanized immune system (HIS) mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields, better mimicking the human immune system and the tumor immune microenvironment, compared to traditional immunodeficient mice. To better promote the application of HIS mice in preclinical research, we selectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor (CAR) -T cells in various antiviral and antitumor treatments. By exploring its application in preclinical research, we find that it can better reflect the actual clinical patient condition, with the advantages of providing high-efficiency detection indicators, even for progressive research and development. We believe that it has better clinical patient simulation and promotion for the updated design of CAR-T cell therapy than directly transplanted immunodeficient mice. The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction, combining multiple models, and unifying sources and organoid substitution. Strategy study of relapse and toxicity after CAR-T treatment also provides more possibilities for application and development.

Three new glycosides from the stems of Eurya chinensis R. Br.

Two new phenolic glycosides (1 and 2), one known analogue (3), along with a new diterpene glucoside (4) were obtained from ethanolic extract of the stems of Eurya chinensis R. Br. The structures of these isolated compounds were identified by extensive analysis of HRESIMS and NMR spectroscopic data. The cytotoxicities of these compounds were evaluated on MCF-7, A549, HepG2, CaCo2 and 5-8 F cell lines by MTT method, but no obvious activities were observed.

Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016-2021: An observational study.

BACKGROUND: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. METHODS AND FINDINGS: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. CONCLUSIONS: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies.

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy in China.

The aim of this study is to analyze the clinical characteristics and outcomes of Chinese patients with progressive multifocal leukoencephalopathy (PML) who were treated with programmed cell death protein 1 (PD1) blockade therapies. We retrospectively analyzed patients who were admitted to our hospital between October 1, 2020, and October 1, 2022, diagnosed with PML and treated with PD1 blockade therapies. Four patients with PML who were treated with PD1 blockade therapies were identified. All patients were male, and their ages ranged from 19 to 54 years old. One patient (Case 2) exhibited mild pleocytosis, while three patients (Cases 2-4) had markedly reduced T lymphocyte cell counts prior to treatment. The time interval between symptom onset and treatment initiation ranged from six to 54 weeks. All patients received pembrolizumab treatment, with a total of two to four doses administered. Three patients who responded to pembrolizumab treatment showed clinical improvement starting around 8 weeks after the initiation of therapy. Although one patient did not show clinical improvement, they ultimately survived until the last follow-up. None of the patients in this study exhibited immune-related adverse events or immune reconstitution inflammatory syndrome. PD1 blockade appears to be a promising novel therapeutic option for PML; additional prospective studies are necessary to confirm its efficacy.

Overall survival benefits of cancer drugs in the WHO Model List of Essential Medicines, 2015-2021.

INTRODUCTION: We examined overall survival (OS) benefits for targeted cancer drugs recommended for List of Essential Medicines (EMLs) since 2015. We assessed consistency of decisions in 2019 and 2021 with more specific criteria: OS benefit >4 months and high scores on European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: We identified applications for cancer drug in WHO EMLs from 2015 to 2021. We extracted evidence of OS benefit documented in WHO Technical Report Series (TRS) and compared it to evidence from pivotal trial(s) documented in Food and Drug Administration-approved labels. We retrieved published ESMO-MCBS scores. We summarised availability and magnitude of OS benefit and ESMO-MCBS scores and assessed consistency of inclusion decisions against WHO criteria. RESULTS: 22/54 targeted cancer drug indications were recommended. Among them, 68.2% and 31.8% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Among those not recommended, 59.4% and 56.3% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Of 11 cancer drug indications recommended in 2019 and 2021, 54.5% and 9.1% had evidence of OS benefit >4 months in WHO-TRS and pivotal trials, respectively; 45.5% met ESMO-MCBS criteria. Ten targeted cancer drugs had more than one application for the same indications. Five of those were eventually recommended, including three without new evidence of OS benefit. Additional factors, such as reduced cost, and increased treatment options, seemed to be important factors in the selection. CONCLUSION: While WHO has defined approval criteria for cancer drugs EML, we identified areas where adherence of these criteria and communication of the EML approval decision-making processes can be improved.

Appraising causal risk and protective factors for rheumatoid arthritis.

Aims: Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies. Methods: PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines. Results: A total of 517 potentially relevant articles were screened, 35 studies were included in the systematic review, and 19 studies were eligible to be included in the meta-analysis. Pooled estimates of 19 included studies (causality between 15 different risk factors and RA) revealed that obesity, smoking, coffee intake, lower education attainment, and Graves' disease (GD) were related to the increased risk of RA. In contrast, the causality contribution from serum mineral levels (calcium, iron, copper, zinc, magnesium, selenium), alcohol intake, and chronic periodontitis to RA is not significant. Conclusion: Obesity, smoking, education attainment, and GD have real causal effects on the occurrence and development of RA. These results may provide insights into the genetic susceptibility and potential biological pathways of RA.

Context-aware augmentation for liver lesion segmentation: shape uniformity, expansion limit and fusion strategy.

Background: Data augmentation with context has been an effective way to increase the robustness and generalizability of deep learning models. However, to our knowledge, shape uniformity, expansion limit, and fusion strategy of context have yet to be comprehensively studied, particularly in lesion segmentation of medical images. Methods: To examine the impact of these factors, we take liver lesion segmentation based on the well-known deep learning architecture U-Net as an example and thoroughly vary the context shape, the expansion bandwidth as well as three representative fusion methods. In particular, the context shape includes rectangular, circular and polygonal, the expansion bandwidth is scaled by a maximum value of 2 compared to the lesion size, and the context fusion weighting strategy is composed of average, Gaussian and inverse Gaussian. Results: Studies conducted on a newly constructed high-quality and large-volume dataset show that (I) uniform context improves lesion segmentation, (II) expanding the context with either 5 or 7 pixels yields the highest performance for liver lesion segmentation, depending on the lesion size, and (III) an unevenly distributed weighting strategy for context fusion is appreciated but in the opposite direction, depending on lesion size as well. Conclusions: Our findings and newly constructed dataset are expected to be useful for liver lesion segmentation, especially for small lesions.

Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Alleviates Atherosclerotic Plaque by Inhibiting Ox-LDL Uptake, Inflammatory Reaction and Endothelial Damage in Rabbits.

Atherosclerosis (AS) is a chronic inflammatory disease of arteries fueled by lipids. It is a major cause of cardiovascular morbidity and mortality. Mesenchymal stem cells have been used for the treatment of atherosclerotic lesions. Adipose-derived stem cells (ADSCs) have been shown to regulate the activation state of macrophages and exhibit anti-inflammatory capabilities. However, the effect of allogeneic ADSCs in the treatment of AS have not been investigated. In this study, the early treatment effect and preliminary mechanism analysis of allogeneic rabbit ADSCs intravenous transplantation were investigated in a high-fat diet rabbit model. The polarization mechanism of rabbit ADSCs on the macrophage was further analyzed in vitro. Compared with the model group, blood lipid levels declined, the plaque area, oxidized low-density lipoprotein (ox-LDL) uptake, scavenger receptor A1 and cluster of differentiation (CD) 36 levels were all significantly reduced, and the accumulation of inflammatory M1 macrophages, apoptosis, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression were decreased. The endothelial cells (CD31), M2 macrophages, IL-10 and the transforming growth factor (TGF)-ß levels increased. In vitro, ADSCs can promote the M1 macrophage phenotypic switch toward the M2 macrophage through their secreted exosomes, and the main mechanism includes increasing arginase 1 expression and IL-10 secretion, declining inducible nitric oxide synthase (iNOS) expression and TNF-α secretion, and activating the STAT6 pathway. Therefore, allogeneic rabbit ADSC transplantation can transmigrate to the aortic atherosclerotic plaques and show a good effect in lowering blood lipids and alleviating atherosclerotic plaque in the early stage of AS by inhibiting ox-LDL uptake, inflammatory response, and endothelial damage.

Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.

The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Challenges and opportunities in animal models of psoriatic arthritis.

OBJECTIVE: To review the preparation, characteristics and research progress of different PsA animal models. METHODS: Computerized searches were conducted in CNKI, PubMed and other databases to classify and discuss the relevant studies on PsA animal models. The search keywords were "PsA and animal model(s), PsA and animal(s), PsA and mouse, PsA and mice, PsA and rat(s), PsA and rabbit(s), PsA and dog(s)" RESULTS: The experimental animals currently used to study PsA are mainly rodents, including mice and rats. According to the different methods of preparing the models, the retrieved animal models were classified into spontaneous or genetic mutation, transgenic and induced animal models. These PsA animal models involve multiple pathogenesis, some experimental animals' lesions appear in a short and comprehensive cycle, some have a high success rate in molding, and some are complex and less reproducibility. This article summarizes the preparation methods, advantages and disadvantages of different models. CONCLUSIONS: The animal models of PsA aim to mimic the clinicopathological alterations of PsA patients through gene mutation, transgenesis or targeted proinflammatory factor and to reveal new pathogenic pathways and therapeutic targets by exploring the pathological features and clinical manifestations of the disease. This work will have very far-reaching implications for the in-depth understanding of PsA and the development of new drugs.

Evidence of clinical benefit of WHO essential anticancer medicines for children, 2011-2021.

Background: Access to essential cancer medicines is a key determinant of childhood cancer survival. WHO published the Model List of Essential Medicine for Children (EMLc) and updated it every two years since 2007 to promote better access to medicines for children. This study aimed to assess whether the inclusion of essential anticancer medicines for respective indications for children was based on evidence of significant clinical benefit between 2011 and 2021. Methods: We identified all anticancer medicine indications added to the WHO EMLc Section 8 since 2011 and extracted evidence of benefit documented in the corresponding technical reports. Evidence in children was defined as evidence that included participants under 12, and graded into five levels, according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. We analyzed whether each anticancer medicine indication was listed with documented OS benefit or improvements in surrogate measures based on the highest level of documented evidence in children. Findings: A total of 115 anticancer medicine indications were added to the EMLc from 2011 to 2021, of which 101 (87.8%) had some clinical evidence in children and 4 (3.5%) were added without any clinical evidence. Among the 101 medicine indications, none were added with level-1 evidence in children, and 43 (42.6%), 11 (10.9%), 41 (40.6%), and 6 (5.9%) were listed with level-2, level-3, level-4, and level-5 evidence in children, respectively. Only eight (7.9%) medicine indications were reported to have OS benefit, another 12 (11.9%) were reported to have improvements on surrogate measures, and 81 (80.2%) were listed in the EMLc without documented improvements in either OS or surrogate measures. Interpretation: Most anticancer medicine indications of the WHO EMLc were added based on limited evidence of statistically significant clinical benefit in children. Our results suggest that WHO should refine requirements for clinical benefit criteria and permissible forms, quality, and reporting of evidence of essential anticancer medicines for children, specify whether anticancer medicine indications have required evidence of clinical benefit in children, and provide further details in its technical reports that summarise the available evidence. Funding: Not applicable.

Identification of a cuproptosis and copper metabolism gene-related lncRNAs prognostic signature associated with clinical and immunological characteristics of hepatocellular carcinoma.

Background: The relationship between cuproptosis and HCC is still in the exploratory stage. Long noncoding RNAs (lncRNAs) have recently been linked to the progression of hepatocellular carcinoma (HCC). However, the clinical significance of lncRNAs associated with cuproptosis remains unclear. Methods: Based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) dataset, we identified characteristic prognostic lncRNAs by univariate, LASSO, and multifactorial regression analysis, and constructed a prognostic signature of cuproptosis-related lncRNAs in HCC. The role of lncRNAs were identified through CCK-8, clone formation in Huh-7 cells with high expression of FDX1. Prognostic potential of the characteristic lncRNAs was evaluated in each of the two cohorts created by randomly dividing the TCGA cohort into a training cohort and a test cohort in a 1:1 ratio. Immune profiles in defined subgroups of cuproptosis-related lncRNA features as well as drug sensitivity were analyzed. Results: We constructed a multigene signature based on four characteristic prognostic lncRNAs (AL590705.3, LINC02870, KDM4A-AS1, MKLN1-AS). These four lncRNAs participated in the development of cuproptosis. HCC patients were classified into high-risk and low-risk groups based on the median value of the risk score. The receiver operating characteristic curve area under the curve values for 1-, 3-, and 5-year survival were 0.773, 0.728, and 0.647, respectively, for the training cohort, and 0.764, 0.671, and 0.662, respectively, for the test cohort. Univariate and multifactorial regression analyses indicated that this prognostic feature was an independent prognostic factor for HCC. Principal component analysis plots clearly distinguished between low- and high-risk patients in terms of their probability of survival. Furthermore, gene set enrichment analysis showed that a variety of processes associated with tumor proliferation and progression were enriched in the high-risk group compared with the low-risk group. Moreover, there were significant differences in the expression of immune cell subpopulations, immune checkpoint genes, and potential drug screening, which provided distinct therapeutic recommendations for individuals with various risks. Conclusions: We constructed a novel cuproptosis-associated lncRNA signature with a significant predictive value for the prognosis of patients with HCC. Cuproptosis-associated lncRNAs are associated with the tumor immune microenvironment of HCC and even the efficacy of tumor immunotherapy.