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Background: China accounts for 24% of newly diagnosed cancer cases and 30% of cancer-related deaths worldwide. Comprehensive analyses of the economic burden on patients across different cancer treatment phases, based on empirical data, are lacking. This study aims to estimate the financial burden borne by patients and analyze the cost compositions of the leading cancers with the highest number of new cases in China., Methods: This cross-sectional cost-of-illness study analyzed patients diagnosed with lung, breast, colorectal, esophageal, liver, or gastric cancer, identified through electronic health records (EHRs) from 84 hospitals across 17 provinces in China. Patients completed any one of the initial treatment phase, follow-up phase, and relapse/metastasis phase were recruited by trained attending physicians through a stratified sampling procedure to ensure enough cases for each cancer progression stage and cancer treatment phase. Direct and indirect costs by treatment phase were collected from the EHRs and self-reported surveys. We estimated per case cost for each type of cancer, and employed subgroup analyses and multiple linear regression models to explore cost drivers., Results: We recruited a total of 13,745 cancer patients across three treatment phases. The relapse/metastasis phase incurred the highest per case costs, varying from $8,890 to $14,572, while the follow-up phase was the least costly, ranging from $1,840 to $4,431. Being in the relapse/metastasis phase and having an advanced clinical stage of cancer at diagnosis were associated with significantly higher cost, while patients with low socioeconomic status borne lower costs., Conclusions: There were substantial financial burden on patients with six leading cancers in China. Health policymakers should emphasize comprehensive healthcare coverage for marginalized populations such as the uninsured, less educated, and those living in underdeveloped regions., (© 2024. The Author(s).)

Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68 Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [ 68 Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [ 68 Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [ 68 Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies., (© 2024. The Author(s).)

Tumor immunotherapy is a promising approach for addressing the limitations of conventional tumor treatments, such as chemotherapy and radiotherapy, which often have side effects and fail to prevent recurrence and metastasis. However, the effectiveness and sustainability of immune activation in tumor immunotherapy remain challenging. Tumor immunogenic cell death, characterized by the release of immunogenic substances, damage associated molecular patterns (DAMPs), and tumor associated antigens, from dying tumor cells (DTCs), offers a potential solution. By enhancing the immunogenicity of DTCs through the inclusion of more immunogenic antigens and stimulating factors, immunogenic cell death (ICD) based cancer vaccines can be developed as a powerful tool for immunotherapy. Integrating ICD nanoinducers into conventional treatments like chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, and radiotherapy presents a novel strategy to enhance treatment efficacy and potentially improve patient outcomes. Preclinical research has identified numerous potential ICD inducers. However, effectively translating these findings into clinically relevant applications remains a critical challenge. This review aims to contribute to this endeavor by providing valuable insights into the in vitro preparation of ICD-based cancer vaccines. We explored established tools for ICD induction, followed by an exploration of personalized ICD induction strategies and vaccine designs. By sharing this knowledge, we hope to stimulate further development and advancement in the field of ICD-based cancer vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Ma, Xie, Miao, lv, Huang, Zhang, Yu, Tai, Zhu and Bao.)

Existing antibody-drug conjugate (ADC) linkers, whether cleavable or non-cleavable, are designed to release highly toxic payloads or payload derivatives upon internalisation of the ADCs into cells. However, clinical studies have shown that only <1 % of the dosed ADCs accumulate in tumour cells. The remaining >99 % of ADCs are nonspecifically distributed in healthy tissue cells, thus inevitably leading to off-target toxicity. Herein, we describe an intelligent tumour-specific linker strategy to address these limitations. A tumour-specific linker is constructed by introducing a hypoxia-activated azobenzene group as a toxicity controller. We show that this azobenzene-based linker is non-cleavable in healthy tissues (O 2 >10 %), and the corresponding payload derivative, cysteine-appended azobenzene-linker-monomethyl auristatin E (MMAE), can serve as a safe prodrug to mask the toxicity of MMAE (switched off). Upon exposure to the hypoxic tumour microenvironment (O 2 <1 %), this linker is cleaved to release MMAE and fully restores the high cytotoxicity of the ADC (switched on). Notably, the azobenzene linker-containing ADC exhibits satisfactory antitumour efficacy in vivo and a larger therapeutic window compared with ADCs containing traditional cleavable or non-cleavable linkers. Thus, our azobenzene-based linker sheds new light on the development of next-generation ADC linkers., (© 2024 Wiley‐VCH GmbH.)

Aim: To determine the associations between the Chinese visceral adiposity index (CVAI) and the risks of all-cause and cause-specific mortality., Materials and Methods: A total of 3 916 214 Chinese adults were enrolled in a nationwide population cohort covering all 31 provinces of mainland China. The CVAI was calculated based on age, body mass index, waist circumference, and triglyceride and high-density lipoprotein cholesterol concentrations. We used a Cox proportional hazards regression model to determine the hazard ratios and 95% confidence intervals (CIs) for risk of mortality associated with different CVAI levels., Results: The median follow-up duration was 3.8 years. A total of 86 158 deaths (34 867 cardiovascular disease [CVD] deaths, 29 884 cancer deaths, and 21 407 deaths due to other causes) were identified. In general, after adjusting for potential confounding factors, a U-shaped relationship between CVAI and all-cause mortality was observed by restricted cubic spline (RCS). Compared with participants in CVAI quartile 1, those in CVAI quartile 4 had a 23.0% (95% CI 20.0%-25.0%) lower risk of cancer death, but a 23.0% (95% CI 19.0-27.0) higher risk of CVD death. In subgroup analysis, a J-shaped and inverted U-shaped relationship for all-cause mortality and cancer mortality was observed in the group aged < 60 years., Conclusions: The CVAI, an accessible indicator reflecting visceral obesity among Chinese adults, has predictive value for all-cause, CVD, and cancer mortality risks. Moreover, the CVAI carries significance in the field of health economics and secondary prevention. In the future, it could be used for early screening purposes., (© 2024 John Wiley & Sons Ltd.)

Small intestinal stromal tumor (SIST) is a common gastrointestinal tumor. Currently, SIST diagnosis relies on clinical radiologists reviewing CT images from medical imaging sensors. However, this method is inefficient and greatly affected by subjective factors. The automatic detection method for stromal tumors based on computer vision technology can better solve these problems. However, in CT images, SIST have different shapes and sizes, blurred edge texture, and little difference from surrounding normal tissues, which to a large extent challenges the use of computer vision technology for the automatic detection of stromal tumors. Furthermore, there are the following issues in the research on the detection and recognition of SIST. After analyzing mainstream target detection models on SIST data, it was discovered that there is an imbalance in the features at different levels during the feature fusion stage of the network model. Therefore, this paper proposes an algorithm, based on the attention balance feature pyramid (ABFP), for detecting SIST with unbalanced feature fusion in the target detection model. By combining weighted multi-level feature maps from the backbone network, the algorithm creates a balanced semantic feature map. Spatial attention and channel attention modules are then introduced to enhance this map. In the feature fusion stage, the algorithm scales the enhanced balanced semantic feature map to the size of each level feature map and enhances the original feature information with the original feature map, effectively addressing the imbalance between deep and shallow features. Consequently, the SIST detection model's detection performance is significantly improved, and the method is highly versatile. Experimental results show that the ABFP method can enhance traditional target detection methods, and is compatible with various models and feature fusion strategies.

Fibroblast activation protein (FAP) is a promising molecular target for imaging in various types of cancers. Several 18 F-labeled FAP inhibitor (FAPI) tracers have been evaluated in clinical study. However, these tracers display high physiological uptake in gallbladder and bile duct system. To overcome the limitation, we herein designed a novel radiotracer named 18 F-FAPTG. 18 F-FAPTG was produced with a non-decay-corrected radiochemical yield of 24.0 ± 6.0% and 22.0 ± 7.0% for manual and automatic synthesis, respectively. 18 F-FAPTG exhibited high hydrophilicity and stability in vitro. The studies of cellular uptake, internalization, efflux properties and competitive binding to FAP of 18 F-FAPTG indicated that the tracer showed high specificity, rapid internalization and low cellular efflux in FAP-positive cells. Biodistribution studies and microPET in mice bearing FAP-positive xenografts demonstrated extremely low uptake in the majority of other organs and main excretion of 18 F-FAPTG through the urinary system. Furthermore, compared to 18 F-FAPI-42, 18 F-FAPTG showed significantly lower uptake in gallbladder, higher tumor uptake and longer tumor retention. In the pilot clinical study, 18 F-FAPTG PET/CT demonstrated favorable tumor-to-background ratios in most organs and clearly displayed the malignant lesions. Our findings indicated that 18 F-FAPTG had an advantage over 18 F-FAPI-42 in PET imaging for cancers located in gallbladder the bile duct system. Thus, 18 F-FAPTG could be an alternative to the currently available FAPI tracers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Cancer-associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro-tumourigenic or anti-tumourigenic functions. Their inherent phenotypic and functional diversity allows for the subdivision of CAFs into various subpopulations. While several classification systems have been suggested for different cancer types, a unified molecular classification of CAFs on a single-cell pan-cancer scale has yet to be established., Methods: We employed a comprehensive single-cell transcriptomic atlas encompassing 12 solid tumour types. Our objective was to establish a novel molecular classification and to elucidate the evolutionary trajectories of CAFs. We investigated the functional profiles of each CAF subtype using Single-Cell Regulatory Network Inference and Clustering and single-cell gene set enrichment analysis. The clinical relevance of these subtypes was assessed through survival curve analysis. Concurrently, we employed multiplex immunofluorescence staining on tumour tissues to determine the dynamic changes of CAF subtypes across different tumour stages. Additionally, we identified the small molecule procyanidin C1 (PCC1) as a target for matrix-producing CAF (matCAF) using molecular docking techniques and further validated these findings through in vitro and in vivo experiments., Results: In our investigation of solid tumours, we identified four molecular clusters of CAFs: progenitor CAF (proCAF), inflammatory CAF (iCAF), myofibroblastic CAF (myCAF) and matCAF, each characterised by distinct molecular traits. This classification was consistently applicable across all nine studied solid tumour types. These CAF subtypes displayed unique evolutionary pathways, functional roles and clinical relevance in various solid tumours. Notably, the matCAF subtype was associated with poorer prognoses in several cancer types. The targeting of matCAF using the identified small molecule, PCC1, demonstrated promising antitumour activity., Conclusions: Collectively, the various subtypes of CAFs, particularly matCAF, are crucial in the initiation and progression of cancer. Focusing therapeutic strategies on targeting matCAF in solid tumours holds significant potential for cancer treatment., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Shared decision-making is useful to facilitate cancer treatment decisions. However, it is difficult to make treatment decisions when physician and patient preferences are different. This review aimed to summarize and compare the preferences for cancer treatments between physicians and patients., Methods: A systematic literature search was conducted on PubMed, Embase, PsycINFO, CINAHL and Scopus. Studies elicited and compared preferences for cancer treatments between physicians and patients were included. Information about the study design and preference measuring attributes or questions were extracted. The available relative rank of every attribute in discrete choice experiment (DCE) studies and answers to preference measuring questions in non-DCE studies were summarized followed by a narrative synthesis to reflect the preference differences., Results: Of 12,959 studies identified, 8290 were included in the title and abstract screening and 48 were included in the full text screening. Included 37 studies measured the preferences from six treatment-related aspects: health benefit, adverse effects, treatment process, cost, impact on quality of life, and provider qualification. The trade-off between health benefit and adverse effects was the main focus of the included studies. DCE studies showed patients gave a higher rank on health benefit and treatment process, while physicians gave a higher rank on adverse effects. Non-DCE studies suggested that patients were willing to take a higher risk of adverse effects or lower health benefit than physicians when accepting a treatment., Conclusions: Physicians and patients had important preference differences for cancer treatment. More sufficient communication is needed in cancer treatment decision-making., (© 2023. The Author(s).)

Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed., Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion., Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks., Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761., Competing Interests: Authors WF, LL, BZ, and XK are full time employees of the company Qilu Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Qilu Pharmaceutical Co., Ltd. The funder(s) had the following involvement in the study project management, data analyses, review, and editing of this manuscript. Medical writing assistance was provided by Qilu Pharmaceutical Co., Ltd. and Happy Life Tech. Co., Ltd., (Copyright © 2023 Huang, Xu, Hong, Gong, Chen, Qin, Xie, Wang, Tian, Meng, Feng, Li, Zhang, Kang and Fan.)

The sensitive and accurate detection of tumor cells is essential for successful cancer therapy and improving cancer survival rates. However, current tumor cell detection technologies have some limitations for clinical applications due to their complexity, low specificity, and high cost. Herein, we describe the design of a terahertz anti-resonance hollow core fiber (THz AR-HCF) biosensor that can be used for tumor cell detection. Through simulation and experimental comparisons, the low-loss property of the THz AR-HCF was verified, and the most suitable fiber out of multiple THz AR-HCFs was selected for biosensing applications. By measuring different cell numbers and different types of tumor cells, a good linear relationship between THz transmittance and the numbers of cells between 10 and 10 6 was found. Meanwhile, different types of tumor cells can be distinguished by comparing THz transmission spectra, indicating that the biosensor has high sensitivity and specificity for tumor cell detection. The biosensor only required a small amount of sample (as low as 100 μL), and it enables label-free and nondestructive quantitative detection. Our flow cytometry results showed that the cell viability was as high as 98.5 ± 0.26% after the whole assay process, and there was no statistically significant difference compared with the negative control. This study demonstrates that the proposed THz AR-HCF biosensor has great potential for the highly sensitive, label-free, and nondestructive detection of circulating tumor cells in clinical samples.

HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Transformer has been widely used in histopathology whole slide image analysis. However, the design of token-wise self-attention and positional embedding strategy in the common Transformer limits its effectiveness and efficiency when applied to gigapixel histopathology images. In this paper, we propose a novel kernel attention Transformer (KAT) for histopathology WSI analysis and assistant cancer diagnosis. The information transmission in KAT is achieved by cross-attention between the patch features and a set of kernels related to the spatial relationship of the patches on the whole slide images. Compared to the common Transformer structure, KAT can extract the hierarchical context information of the local regions of the WSI and provide diversified diagnosis information. Meanwhile, the kernel-based cross-attention paradigm significantly reduces the computational amount. The proposed method was evaluated on three large-scale datasets and was compared with 8 state-of-the-art methods. The experimental results have demonstrated the proposed KAT is effective and efficient in the task of histopathology WSI analysis and is superior to the state-of-the-art methods.

Purpose: The presence and functional competence of intratumoral CD8 + T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8 + T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting. Here, we took advantage of immuno-PET imaging using 89 Zr-IAB42M1-14, anti-mouse CD8 minibody, to characterize CD8 + T-cell tumor infiltration dynamics following ICOS (inducible T-cell co-stimulator) agonist antibody treatment alone and in combination with PD-1 blocking antibody in a model of mammary carcinoma., Procedures: Female BALB/c mice with established EMT6 tumors received 10 µg, IP of either IgG control antibodies, ICOS agonist monotherapy, or ICOS/PD-1 combination therapy on days 0, 3, 5, 7, 9, 10, or 14. Imaging was performed at 24 and 48 h post IV dose of 89 Zr IAB42M1-14. In addition to 89 Zr-IAB42M1-14 uptake in tumor and tumor-draining lymph node (TDLN), 3D radiomic features were extracted from PET/CT images to identify treatment effects. Imaging mass cytometry (IMC) and immunohistochemistry (IHC) was performed at end of study., Results: 89 Zr-IAB42M1-14 uptake in the tumor was observed by day 11 and was preceded by an increase in the TDLN as early as day 4. The spatial distribution of 89 Zr-IAB42M1-14 was more uniform in the drug treated vs. control tumors, which had spatially distinct tracer uptake in the periphery relative to the core of the tumor. IMC analysis showed an increased percentage of cytotoxic T cells in the ICOS monotherapy and ICOS/PD-1 combination group compared to IgG controls. Additionally, temporal radiomics analysis demonstrated early predictiveness of imaging features., Conclusion: To our knowledge, this is the first detailed description of the use of a novel immune-PET imaging technique to assess the kinetics of CD8 + T-cell infiltration into tumor and lymphoid tissues following ICOS agonist and PD-1 blocking antibody therapy. By demonstrating the capacity for increased spatial and temporal resolution of CD8 + T-cell infiltration across tumors and lymphoid tissues, these observations underscore the widespread potential clinical utility of non-invasive PET imaging for T-cell-based immunotherapy in cancer., (© 2022. The Author(s).)

Mitochondrial DNA (mtDNA) somatic mutations play important roles in the initiation and progression of cancer. Although next-generation sequencing (NGS) of paired tumor and control samples has become a common practice to identify tumor-specific mtDNA mutations, the unique nature of mtDNA and NGS-associated sequencing bias could cause false-positive/-negative somatic mutation calling. Additionally, there are clinical scenarios where matched control tissues are unavailable for comparison. Therefore, a novel approach for accurately identifying somatic mtDNA variants is greatly needed, particularly in the absence of matched controls. In this study, the ground truth mtDNA variants orthogonally validated by triple-paired tumor, adjacent nontumor, and blood samples were used to develop mitoSomatic, a random forest-based machine learning tool. We demonstrated that mitoSomatic achieved area under the curve (AUC) values over 0.99 for identifying somatic mtDNA variants without paired control in three tumor types. In addition, mitoSomatic was also applicable in nontumor tissues such as adjacent nontumor and blood samples, suggesting the flexibility of mitoSomatic's classification capability. Furthermore, analysis of triple-paired samples identified a small group of variants with uncertain somatic/germline origin, whereas application of mitoSomatic significantly facilitated the prediction of their possible source. Finally, a control-free evaluation of the public pan-cancer NGS dataset with mitoSomatic revealed a substantial number of variants that were probably misclassified by conventional tumor-control comparison, further emphasizing the usefulness of mitoSomatic in application. Taken together, our study demonstrates that mitoSomatic is valuable for accurately identifying somatic mtDNA variants in mtDNA NGS data without paired controls, applicable for both tumor and nontumor tissues., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we identified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small molecule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophagosomes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of inhibiting cancer proliferation through methuosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cancer is complicated to treat because of its high propensity for recurrence and metastasis, and various side effects of conventional cancer treatments. With the development of nanotechnology, biology, material science and pharmacy, nanoparticles emerge as a promising method to load anti-cancer drugs to deal with the downsides of conventional treatments. Among the various class of nanoparticles, endogenous stimuli-responsive nanoparticles exert significant anti-cancer effects by releasing drugs due to the stimulations from pH gradient, redox as well as other enzymes of cancer microenvironment. Extraordinary progress has been achieved as the latest endogenous stimuli-responsive nanoparticles exhibit better therapeutic effects, lower toxicity, and superior biocompatibility, indicating brighter prospects for cancer therapy. However, these stimuli-responsive nanoparticles are still not ready for large-scale clinical application, due to reasons such as the lack of clinical trials and high cost of manufacturing. Here, we consolidate the advancements and limitations of various endogenous stimuli-responsive nanoparticles, as well as critically discuss the prospects of this kind of nanoparticles in tumor treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The mortality and recurrence of patients with cancer is of high prevalence. Long non-coding RNA (lncRNA) forkhead box P4 antisense RNA 1 (FOXP4-AS1) is a promising lncRNA. There is increasing evidence that lncRNA FOXP4-AS1 is abnormally expressed in various tumors and is associated with cancer prognosis. This study was designed to identify the prognostic value of lncRNA FOXP4-AS1 in human malignancies., Methods: We searched electronic databases up to April 29, 2022, including PubMed, Cochrane Library, Embase, MEDLINE, and Web of Science. Eligible studies that evaluated the clinicopathological and prognostic role of lncRNA FOXP4-AS1 in patients with malignant tumors were included. The pooled odds ratios (ORs) and the hazard ratios (HRs) were calculated to assess the role of lncRNA FOXP4-AS1 using Stata/SE 16.1 software., Results: A total of 6 studies on cancer patients were included in the present meta-analysis. The combined results revealed that high expression of lncRNA FOXP4-AS1 was significantly associated with unfavorable overall survival (OS) (HR = 1.99, 95% confidence interval [CI]: 1.65-2.39, P < .00001), and poor disease-free survival (DFS) (HR = 1.81, 95% CI: 1.54-2.13, P < .00001) in a variety of cancers. In additional, the increase in lncRNA FOXP4-AS1 expression was also correlated with tumor size ((larger vs smaller) (OR = 3.16, 95% CI: 2.12-4.71, P < .00001), alpha-fetoprotein (≥400 vs <400) (OR = 3.81, 95%CI: 2.38-6.11, P = .83), lymph node metastasis (positive vs negative) (OR = 2.93, 95%CI: 1.51-5.68, P = .001), and age (younger vs older) (OR = 2.06, 95% CI: 1.41-3.00, P = .00002) in patients with cancer. Furthermore, analysis results using The Cancer Genome Atlas (TCGA) dataset showed that the expression level of lncRNA FOXP4-AS1 was higher in most tumor tissues than in the corresponding normal tissues, which predicted a worse prognosis., Conclusions: In this meta-analysis, we demonstrate that high lncRNA FOXP4-AS1 expression may become a potential marker to predict cancer prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: This study aimed to compare the treatment preference among oncologists, patients with lung cancer, and their family members in China., Methods: A face-to-face discrete choice experiment survey was conducted among oncologists, patients, and their family members. Participants completed 13 choice sets describing 6 key attributes, namely, overall survival time, risk of severe adverse effect, severity of pain, appetite, physical functioning status, and monthly cost. Mixed logit model and latent class analysis were used to estimate attribute level preference weights and the relative importance (RI) for attributes. The willingness to pay (WTP) and maximum acceptable risk (MAR) were also estimated. The RI, WTP, and MAR of oncologists, patients, and family members were compared., Results: A total of 121 oncologists and 161 dyads of patients and family members completed the survey. Overall survival time, physical functioning status, and pain were the 3 most important attributes across all 3 groups. Oncologists and family members had higher RI on overall survival time than patients (48% and 51% vs 38%). Patients had higher RI on physical functioning status and pain (23% and 14%) than oncologists (13% and 12%) and family members (16% and 11%). For extending survival, patients had the least WTP, and family members had the highest MAR. The latent class analysis identified 2 classes in the patient group and 3 classes in oncologist and family member groups., Conclusions: There were differences in preferences for survival, risk, quality of life, and costs associated with cancer treatments among patients, oncologists, and family members. This finding highlights the need of involving patients in treatment decision making in China., (Copyright © 2022. Published by Elsevier Inc.)

Pyroptosis is a form of programmed cell death mediated by gasdermin and is a product of continuous cell expansion until the cytomembrane ruptures, resulting in the release of cellular contents that can activate strong inflammatory and immune responses. Pyroptosis, an innate immune response, can be triggered by the activation of inflammasomes by various influencing factors. Activation of these inflammasomes can induce the maturation of caspase-1 or caspase-4/5/11, both of which cleave gasdermin D to release its N-terminal domain, which can bind membrane lipids and perforate the cell membrane. Here, we review the latest advancements in research on the mechanisms of pyroptosis, newly discovered influencing factors, antitumoral properties, and applications in various diseases. Moreover, this review also provides updates on potential targeted therapies for inflammation and cancers, methods for clinical prevention, and finally challenges and future directions in the field., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)

Single-cell omics is the profiling of individual cells through sequencing and other technologies including high-throughput analysis for single-cell resolution, cell classification, and identification as well as time series analyses. Unlike multicellular studies, single-cell omics overcomes the problem of cellular heterogeneity. It provides new methods and perspectives for in-depth analyses of the behavior and mechanism of individual cells in the cell population and their relationship with the body, and plays an important role in basic research and precision medicine. Single-cell sequencing technologies mainly include single-cell transcriptome sequencing, single-cell assay for transposase accessible chromatin with high-throughput sequencing, single-cell immune profiling (single-cell T-cell receptor [TCR]/B-cell receptor [BCR] sequencing), and single-cell transcriptomics. Single-cell TCR/BCR sequencing can be used to obtain a large amount of single-cell gene expression and immunomics data at one time, and combined with transcriptome sequencing and TCR/BCR diversity data, can resolve immune cell heterogeneity. This paper summarizes the progress in applying single-cell TCR/BCR sequencing technology to the tumor immune microenvironment, autoimmune diseases, infectious diseases, immunotherapy, and chronic inflammatory diseases, and discusses its shortcomings and prospects for future application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Shen, Luo, Han, Xie, Pang, Liao, Guo, Li, Li and Chen.)

TGF-β signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-β/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-β receptor TβRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-β/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TβRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-β/SMAD signaling, and reduces TβRII stability and the number of TβRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy., (© 2022 The Authors.)

The self-delivery of sonosensitizers and immunomodulators to tumor areas, which is highly recommended for enhancing sonodynamic immunotherapy, remains a challenge. Herein, a self-delivering nanodrug (HB-NLG8189, drug loading: ≈100 wt%) is developed by the small-molecule self-assembly of "HB" (a new clinical photosensitizer) and NLG8189 (indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor) for sonodynamic-augmented immunotherapy; this preparation method ensures the absence of excipient-related toxicity and immunogenicity. To evade immune recognition and prolong the circulation time, the HB-NLG8189 nanodrugs are camouflaged using macrophage cell membranes (MPCMs). The constructed HB-NLG8189@MPCM nanodrugs show an ability to preferentially accumulate within tumors. Upon ultrasound triggering, the HB-NLG8189@MPCM is able to generate reactive oxygen species efficiently for robust sonodynamic therapy; it induces immunogenic cell death, initiates an antitumor immune response to activate tumor-specific effector T cells, and promotes the secretion of inflammatory cytokines. The concomitant delivery of NLG8189 reverses the immunosuppressive tumor microenvironment by restraining IDO-1 activation and the intratumoral infiltration of regulatory T cells. Sonodynamic-augmented immunotherapy with HB-NLG8189@MPCM significantly inhibits the growth of both primary and distant tumors with little systemic toxicity. The biomimetic self-delivery nanodrug provides a promising paradigm for improving sonodynamic immunotherapy., (© 2022 Wiley-VCH GmbH.)

Microbes with complex functions have been found to be a potential component in tumor microenvironments. Due to their low biomass and other obstacles, intratumor microbiota is poorly understood. Mucosal sites and normal adjacent tissues are important sources of intratumor microbiota, while hematogenous spread also leads to the invasion of microbes. Intratumor microbiota affects the progression of tumors through several mechanisms, such as DNA damage, activation of oncogenic pathways, induction of immunosuppression, and metabolization of drugs. Notably, in different types of tumors, the composition and abundance of intratumor microbiota are highly heterogeneous and may play different roles in the progression of tumors. Because of the concern in this field, several techniques such as omics and immunological methods have been used to study intratumor microbiota. Here, recent progress in this field is reviewed, including the potential sources of intratumor microbiota, their functions and related mechanisms, and their heterogeneity. Techniques that can be used to study intratumor microbiota are also discussed. Moreover, research is summarized into the development of strategies that can be used in antitumor treatment and prospects for possible future research in this field., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Photothermal therapy is a promising tumor ablation technique that converts light into heat energy to kill cancer cells. Prussian blue (PB), a biocompatible photothermal reagent, has been widely explored for cancer treatment. However, the translational potential of PB is severely hampered by its low photothermal conversion efficiency (PCE) and poor stability. To tackle these issues, we adopted the biomineralization modality where PB was integrated with calcium phosphate (CaP) through the binding between calcium ions and PB. The mineralized PB (CaP&PB) demonstrated significantly improved PCE (40.2%), resulting from a calcium-induced bandgap-narrowing effect, and exhibited superior suspension stability. Using a 4T1 orthotopic breast cancer BALB/c mouse model, we observed that mineralized PB showed a significant temperature increase within the tumor, which led to better tumoricidal activity compared with CaP and PB when identical NIR treatment was applied. These achievements demonstrated the success of introducing calcium phosphate into Prussian blue by biomineralization to improve the PCE and stability of photothermal reagents, suggesting an alternative translational strategy for enhanced cancer photothermal therapy.

Inorganic nanomaterials showed great potential as drug carriers for chemotherapeutics molecules due to their biocompatible physical and chemical properties. A manganese-based inorganic nanomaterial manganese phosphate (MnP) had become a new drug carrier in cancer therapy. However, the approach for manganese phosphate preparation and drug integration is still confined in complex methods. Inspired by mimetic mineralization, we proposed a "one-step" method for the preparation of manganese phosphate-doxorubicin (DOX) nanomedicines (MnP-DOX) by manganese ion and DOX complexation. The structural characterization results revealed that the prepared MnP-DOX nanocomplexes were homogeneous with controlled sizes and shapes. More importantly, the MnP-DOX nanocomposites could significantly induce cancer inhibition in vitro and in vivo . The results indicated that the drug molecules were integrated into MnP nanocarriers by mimetic mineralization, which not only prevented the premature release of the drug but also reduced excessive modification. Moreover, the designed MnP-DOX complex showed high loading efficacy and pH-dependent degradation leading to drug release, achieving high efficiency for cancer chemotherapy in vitro and in vivo via a facile process . These achievements presented an approach to construct the manganese phosphate-based chemotherapy nanomedicines by mimetic mineralization for cancer therapy.

Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. They are consisted of a heterogeneous population of immature myeloid cells including polymorphonuclear MDSC (PMN-MDSC) and monocytes MDSC (M-MDSC) that are found in both the systemic circulation and in the tumor microenvironment (TME). While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy. We aimed in this study to develop a drug encapsulated liposome formulation L-ATRA with sustained release properties and examined the immuno-modulation effects. We showed that the actively loaded L-ATRA achieved stable encapsulation and enabled controlled drug release and accumulation in the tumor tissues. In vivo administration of L-ATRA promoted the remodeling of the systemic immune homeostasis as well as the tumor microenvironment. They were found to promote MDSCs maturation into DCs and facilitate immune responses against cancer cells. When used as a single agent treatment, L-ATRA deterred tumor growth, but only in immune-competent mice. In mice with impaired immune functions, L-ATRA at the same dose was not effective. When combined with checkpoint inhibitory agents, L-ATRA resulted in greater anti-cancer activities. Thus, L-ATRA may present a new IO strategy targeting the MDSCs that needs be further explored for improving the immunotherapy efficacy in cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Xie, Shi, Liu, Long and Xu.)

The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

RNA polymerase III (Pol III) transcribes hundreds of non-coding RNA genes (ncRNAs), which involve in a variety of cellular processes. However, the expression, functions, regulatory networks and evolution of these Pol III-transcribed ncRNAs are still largely unknown. In this study, we developed a novel resource, Pol3Base (http://rna.sysu.edu.cn/pol3base/), to decode the interactome, expression, evolution, epitranscriptome and disease variations of Pol III-transcribed ncRNAs. The current release of Pol3Base includes thousands of regulatory relationships between ∼79 000 ncRNAs and transcription factors by mining 56 ChIP-seq datasets. By integrating CLIP-seq datasets, we deciphered the interactions of these ncRNAs with >240 RNA binding proteins. Moreover, Pol3Base contains ∼9700 RNA modifications located within thousands of Pol III-transcribed ncRNAs. Importantly, we characterized expression profiles of ncRNAs in >70 tissues and 28 different tumor types. In addition, by comparing these ncRNAs from human and mouse, we revealed about 4000 evolutionary conserved ncRNAs. We also identified ∼11 403 tRNA-derived small RNAs (tsRNAs) in 32 different tumor types. Finally, by analyzing somatic mutation data, we investigated the mutation map of these ncRNAs to help uncover their potential roles in diverse diseases. This resource will help expand our understanding of potential functions and regulatory networks of Pol III-transcribed ncRNAs., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

T cells are one of the most important effector cells in cancer immunotherapy. Various T cell-dependent bispecific antibody (TDB) drugs that engage T cells for targeted cancer cell lysis are being developed. Here, we describe supra-molecular T-cell redirecting antibody fragment-anchored liposomes (TRAFsomes) and report their immune modulation and anti-cancer effects. We found that TRAFsomes containing different copies of anti-CD3 fragments displayed different T cell modulation profiles, showing that optimization of surface density is needed to define the therapeutic window for potentiating cancer cell-specific immune reactions while minimizing nonspecific side effects. Moreover, small molecular immunomodulators may also be incorporated by liposomal encapsulation to drive CD8 + T cell biased immune responses. In vivo studies using human peripheral blood mononuclear cell reconstituted mouse models showed that TRAFsomes remained bounded to human T cells and persisted for more than 48 hours after injection. However, only TRAFsomes containing a few anti-CD3 (n = 9) demonstrated significant T cell-mediated anti-cancer activities to reverse tumor growth. Those with more anti-CD3s (n = 70) caused tumor growth and depletion of human T cells at the end of treatments. These data suggested that TRAFsomes can be as potent as traditional TDBs and the liposomal structure offers great potential for immunomodulation and improvement of the therapeutic index. Abbreviation : Chimeric antigen receptor T cells (CAR-T cells), Cytokine release syndrome (CRS) Cytotoxic T cell (CTL) Effector: target ratios (E:T ratios), Heavy chain (HC) Immune-related adverse events (irAE), Large unilamellar vesicle (LUV), Peripheral blood mononuclear cells (PBMCs, Single-chain variable fragment (scFv), T cell-dependent bispecific antibody (TDB), T cell redirecting antibody fragment-anchored liposomes (TRAFsomes), Methoxy poly-(ethylene glycol) (mPEG).

Background: ArfGAP with GTPase domain, Ankyrin repeat and PH domain 2 Antisense 1 (AGAP2-AS1) is a promising long noncoding RNA that may possess prognostic value for different types of tumors. The objective of this meta-analysis is to evaluate the prognostic value of long noncoding RNA AGAP2-AS1 in cancer patients., Methods: A systematic literature search of the PubMed, Cochrane Library, EMBASE, Medline, Web of Science, CNKI, Weipu, and Wanfang electronic databases were carried out in this meta-analysis. Synthetic hazard ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were obtained to determine the prognostic and clinicopathological significance of AGAP2-AS1 expression in tumors., Results: The final meta-analysis included 10 studies that contained 948 patients. The pooled results provided evidence that AGAP2-AS1 overexpression predicted reduced overall survival (OS) (HR = 1.77, 95% CI: 1.49-2.09, P < .00001), disease-free survival (HR = 1.84, 95% CI: 1.40-2.41, P < .0001), and progression-free survival (HR = 1.84, 95% CI: 1.01-3.33, P = .04) and for various cancers. Additionally, the AGAP2-AS1 overexpression was concerned with lymph node metastasis (positive vs negative, OR = 2.95, 95% CI: 1.96-4.45, P < .00001), advanced tumor node metastasis stage (III/IV vs I/II, OR = 3.73, 95% CI: 2.71-5.13, P < .00001), and tumor size (larger vs smaller, OR = 2.28, 95% CI: 1.24-4.18, P = .008). Besides, data from gene expression profiling interactive analysis dataset verified the results in our meta-analysis. The results showed that the expression level of AGAP2-AS1 was higher in most tumor tissues than in the corresponding normal tissues and was linked to poor OS and disease-free survival., Conclusions: Our results indicated that AGAP2-AS1 overexpression was closely correlated with shorter OS in multiple cancer types, suggesting that AGAP2-AS1 might function as a promising predictor for clinical outcomes in cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti-tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor-infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti-tumor immune response to certain groups of patients. Herein, the recent research progress on tumor-infiltrating B cells and T cells, including CD8 + T cells, CD4 + T cells, and exhausted T cells and their role in anti-tumor immunity, is summarized. Moreover, several anti-tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Disruption of DNA methylation (DNAm) is one of the key signatures of cancer, however, detailed mechanisms that alter the DNA methylome in cancer remain to be elucidated., Methods: Here we present a novel integrative analysis framework, called MeLncTRN (Methylation mediated LncRNA Transcriptional Regulatory Network), that integrates genome-wide transcriptome, DNA methylome and copy number variation profiles, to systematically identify the epigenetically-driven lncRNA-gene regulation circuits across 18 cancer types., Finding: We show that a significant fraction of the aberrant DNAm and gene expression landscape in cancer is associated with long noncoding RNAs (lncRNAs). We reveal distinct types of regulation between lncRNA modulators and target genes that are operative in either only specific cancers or across cancers. Functional studies identified a common theme of cancer hallmarks that lncRNA modulators may participate in. The coupled lncRNA gene interactions via DNAm also serve as markers for classifications of cancer subtypes with different prognoses., Interpretation: Our study reveals a vital layer of DNAm and associated expression regulation for many cancer-related genes and we also provide a valuable database resource for interrogating epigenetically mediated lncRNA-gene interactions in cancer., Funding: National Natural Science Foundation of China [91959106, 31871255]., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Abstract: A newly discovered long non-coding RNA (lncRNA) is associated with the progression of a variety of tumors. The purpose of this meta-analysis is to explore further the relationship between clinicopathological features and the prognostic value of LINC00675 in caners.We searched the various database, including PubMed, Web of Science, Cochrane Library, Embase together with Wanfang, and China National Knowledge Infrastructure for articles on LINC00675 and clinicopathological characteristics and prognosis of patients with cancers before February 20, 2020. According to the inclusion and exclusion criteria, the studies that meet the criteria were systematically collected through search keywords. The Newcastle Ottawa document quality assessment system was used to evaluate the quality of documents. The required data from literature were extracted, and the hazard ratio (HR), odds ratio (OR), and 95confidence interval (CI) were calculated using stata12.0 software and RevMan5.3 software.A total of 5 studies covering 462 patients were included in this meta-analysis to evaluate the prognostic value of LINC00675 in cancers. Our results showed that high LINC00675 expression was significantly correlated with poor overall survival (OS) (HR = 1.60, 95% CI: 1.23-2.08, P = .0005). Additionally, upregulated expression of LINC00675 was significantly associated with tumor node metastasis stage (OR = 1.74, 95% CI: 1.18-2.58, P = .006) and distant metastasis (OR = 2.22, 95% CI: 1.21-4.08, P = .01).Our study suggests that LINC00675 could be used as a biomarker to evaluate the prognosis of cancer patients. More studies to further confirm that the clinical value of LINC00675 in cancers will be required., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Neoantigen-based immunotherapy has yielded promising results in clinical trials. However, it is limited to tumor-specific mutations, and is often tailored to individual patients. Identifying suitable tumor-specific antigens is still a major challenge. Previous proteogenomics studies have identified peptides encoded by predicted non-coding sequences in human genome. To investigate whether tumors express specific peptides encoded by non-coding genes, we analyzed published proteomics data from five cancer types including 933 tumor samples and 275 matched normal samples and compared these to data from 31 different healthy human tissues. Our results reveal that many predicted non-coding genes such as DGCR9 and RHOXF1P3 encode peptides that are overexpressed in tumors compared to normal controls. Furthermore, from the non-coding genes-encoded peptides specifically detected in cancers, we predict a large number of "dark antigens" (neoantigens from non-coding genomic regions), which may provide an alternative source of neoantigens beyond standard tumor specific mutations.

Purpose: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers., Experimental Design: We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy., Results: Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden., Conclusions: Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels., (©2020 American Association for Cancer Research.)

There exists an emergency clinical demand to overcome TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) resistance, which is a major obstacle attributed to insufficient level or mutation of TRAIL receptors. Here, we developed an iron oxide cluster-based nanoplatform for both sensitization and MR image-guided evaluation to improve TRAIL/Apo2L efficacy in colorectal cancer, which has an inadequate response to TRAIL/Apo2L or chemotherapy. Specifically, NanoTRAIL (TRAIL/Apo2L-iron oxide nanoparticles) generated ROS (reactive oxygen species)-triggered JNK (c-Jun N-terminal kinase) activation and induced subsequent autophagy-assisted DR5 upregulation, resulting in a significant enhanced antitumor efficacy of TRAIL/Apo2L, which confirmed in both TRAIL-resistant HT-29, intermediately resistant SW-480 and sensitive HCT-116 cells. Furthermore, in a subcutaneous colorectal cancer mouse model, the in vivo tumor retention of NanoTRAIL can be demonstrated by MR T 2 weighted contrast imaging, and NanoTRAIL significantly suppressed tumor growth and prolonged the survival time without observable adverse effects compared with control and TRAIL/Apo2L monotherapy. Importantly, in the study of colorectal cancer patient-derived xenograft models, we found that the NanoTRAIL treatment could significantly improve the survival outcome with consistent ROS-dependent autophagy-assisted DR5 upregulation and tumor apoptosis. Our results describe a transformative design that can be applied clinically to sensitize Apo2L/TRAIL-resistant patients using FDA-approved iron oxide nanoparticles., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Programmed death ligand 1 (PD-L1), a type I transmembrane protein, binds to its receptor PD-1 to suppress the activation of T cells, thereby maintaining immunological homeostasis. In contrast, tumor cells highly express PD-L1, which binds to receptor PD-1 expressed on activated T cells, leading to immune escape. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the binding of PD-1/PD-L1 to reinvigorate the exhausted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid-bilayer nanovesicles secreted by various cell types that mediate intercellular signal communication. Numerous studies have shown that tumor cells are able to promote tumor epithelial-mesenchymal transition, angiogenesis, and immune escape by releasing exosomes. Recent studies imply that tumor-derived exosomes could carry PD-L1 in the same membrane topology as the cell surface, thereby resisting immune checkpoint therapy. In this review, we mainly discuss the role of exosomes in the regulation of tumor progression and the potential resistance mechanism to immunotherapy via exosomal PD-L1. In addition, we propose that exosomal PD-L1 may have the potential to be a target to overcome resistance to anti-PD-1/PD-L1 antibody therapy.

X-linked inhibitor of apoptosis protein (XIAP) is aberrantly expressed in solid tumors. Considering conflicting data, we conducted this meta-analysis to investigate its prognostic role. Electronic databases were searched to collect studies about associations between XIAP expressions and survival outcomes. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) were utilized as effect size estimates. A total of 3,794 patients from 21 published studies were included. The results revealed that high XIAP expressions correlated with age (OR = 2.02; 95% CI, 1.07-3.84), lymph node metastasis (OR = 1.69; 95% CI, 1.02-2.77), histological grade (OR = 2.04; 95% CI, 1.01-4.11), and tumor stage (OR = 2.18; 95% CI, 1.20-3.96). The combined HR revealed that high XIAP expressions associated with poor overall survival (OS) (HR = 1.60; 95% CI, 1.22-2.10). Our study suggested high XIAP expressions may be indicative of poor prognosis in solid tumors., (© 2019 Wiley Periodicals, Inc.)

Importance: Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit., Objective: To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life., Data Sources: For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016., Study Selection: Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies., Data Extraction and Synthesis: We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions., Main Outcome and Measure: The association between PFS duration and HRQoL., Results: Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were -0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, -0.27 to 0.52); for physical HRQoL (n = 20 trials) it was -0.20 (95% CI, -0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, -0.05 to 1.60)., Conclusions and Relevance: We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Objective: To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO)., Methods: We performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy., Results: We identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4))., Conclusion: Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use., Competing Interests: Competing interests: TB has received consulting fees from UCB, Genentech/Roche, Novartis, Bristol-Myers Squibb and Sobi. JDL has received consulting fees from Takeda, Pfizer, Lilly, Gilead, Johnson & Johnson, Samsung Bioepis, AbbVie, UCB and Merck; and research funding from Takeda. RM has received consulting fees from Takeda. KGS has received consulting fees from Abbot, Amgen, Ardea/AstraZeneca, BMS, Crealta, Lilly, Merck, Pfizer and Genentech/Roche; and research funding from Amgen, Ardea/AstraZeneca, Crealta, Lilly, Merck and Takeda. JRC has received consulting fees from Genentech/Roche, UCB, Janssen, CORRONA, Amgen, Pfizer, BMS, Crescendo and AbbVie; and research funding from Genentech/Roche, UCB, Janssen, CORRONA, Amgen, Pfizer, BMS, Crescendo and AbbVie., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The esophagus is a pivotal organ originating from anterior foregut that links the mouth and stomach. Moreover, its development involves precise regulation of multiple signal molecules and signal transduction pathways. After abnormal regulation of these molecules in the basal cells of the esophagus occurs, multiple diseases, including esophageal atresia with or without tracheoesophageal fistula, Barrett esophagus, gastroesophageal reflux, and eosinophilic esophagitis, will take place as a result. Furthermore, expression changes of signal molecules or signal pathways in basal cells and the microenvironment around basal cells both can initiate the switch of malignant transformation. In this review, we highlight the molecular events underlying the transition of normal development to multiple esophageal diseases. Additionally, the animal models of esophageal development and related diseases, challenges, and strategies are extensively discussed., (© 2017 Wiley Periodicals, Inc.)

Malignancies can compromise innate immunity, but the mechanisms of this are largely unknown. Here we found that, via tumor-derived exosomes (TEXs), cancers were able to transfer activated epidermal growth factor receptor (EGFR) to host macrophages and thereby suppress innate antiviral immunity. Screening of the human kinome identified the kinase MEKK2 in macrophages as an effector of TEX-delivered EGFR that negatively regulated the antiviral immune response. In the context of experimental tumor implantation, MEKK2-deficient mice were more resistant to viral infection than were wild-type mice. Injection of TEXs into mice reduced innate immunity, increased viral load and increased morbidity in an EGFR- and MEKK2-dependent manner. MEKK2 phosphorylated IRF3, a transcription factor crucial for the production of type I interferons; this triggered poly-ubiquitination of IRF3 and blocked its dimerization, translocation to the nucleus and transcriptional activity after viral infection. These findings identify a mechanism by which cancer cells can dampen host innate immunity and potentially cause patients with cancer to become immunocompromised.

The transforming growth factor (TGF)-β signaling events are well known to control diverse processes and numerous responses, such as cell proliferation, differentiation, apoptosis, and migration. TGF-β signaling plays context-dependent roles in cancer: in pre-malignant cells TGF-β primarily functions as a tumor suppressor, while in the later stages of cancer TGF-β signaling promotes invasion and metastasis. Recent studies have also suggested that the cross-talk between TGF-β signaling and other signaling pathways, such as Hippo, Wnt, EGFR/RAS, and PI3K/AKT pathways, may substantially contribute to our current understanding of TGF-β signaling and cancer. As a result of the wide-ranging effects of TGF-β, blockade of TGF-β and its downstream signaling components provides multiple therapeutic opportunities. Therefore, the outlook for anti-TGF-β signaling therapy for numerous diseases appears bright and will provide valuable information and thinking on the drug molecular design. In this review, we focus on recent insights into the regulation of TGF-β signaling in cancer metastasis which may contribute to the development of novel cancer-targeting therapies., (© The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

cAMP-response element binding protein (CREB) is a nuclear transcription factor activated by multiple extracellular signals including growth factors and hormones. These extracellular cues activate CREB through phosphorylation at Ser133 by various protein serine/threonine kinases. Once phosphorylated, it promotes its association with transcription coactivators CREB-binding protein (CBP) and its paralog p300 to activate CREB-dependent gene transcription. Tumor tissues of different origins have been shown to present overexpression and/or overactivation of CREB, indicating CREB as a potential cancer drug target. We previously identified 666-15 as a potent inhibitor of CREB with efficacious anti-cancer activity both in vitro and in vivo. Herein, we investigated the specificity of 666-15 and evaluated its potential in vivo toxicity. We found that 666-15 was fairly selective in inhibiting CREB. 666-15 was also found to be readily bioavailable to achieve pharmacologically relevant concentrations for CREB inhibition. Furthermore, the mice treated with 666-15 showed no evidence of changes in body weight, complete blood count, blood chemistry profile, cardiac contractility and tissue histologies from liver, kidney and heart. For the first time, these results demonstrate that pharmacological inhibition of CREB is well-tolerated in vivo and indicate that such inhibitors should be promising cancer therapeutics.

Introduction: There is an increasing number of new oncology drugs being studied, approved and put into clinical practice based on improvement in progression-free survival, when no overall survival benefits exist. In oncology, the association between progression-free survival and health-related quality of life is currently unknown, despite its importance for patients with cancer, and the unverified assumption that longer progression-free survival indicates improved health-related quality of life. Thus far, only 1 study has investigated this association, providing insufficient evidence and inconclusive results. The objective of this study protocol is to provide increased transparency in supporting a systematic summary of the evidence bearing on this association in oncology., Methods and Analysis: Using the OVID platform in MEDLINE, Embase and Cochrane databases, we will conduct a systematic review of randomised controlled human trials addressing oncology issues published starting in 2000. A team of reviewers will, in pairs, independently screen and abstract data using standardised, pilot-tested forms. We will employ numerical integration to calculate mean incremental area under the curve between treatment groups in studies for health-related quality of life, along with total related error estimates, and a 95% CI around incremental area. To describe the progression-free survival to health-related quality of life association, we will construct a scatterplot for incremental health-related quality of life versus incremental progression-free survival. To estimate the association, we will use a weighted simple regression approach, comparing mean incremental health-related quality of life with either median incremental progression-free survival time or the progression-free survival HR, in the absence of overall survival benefit., Discussion: Identifying direction and magnitude of association between progression-free survival and health-related quality of life is critically important in interpreting results of oncology trials. Systematic evidence produced from our study will contribute to improvement of patient care and practice of evidence-based medicine in oncology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)