Search

The cell division cycle-associated protein (CDCA) family is important in regulating cell division. High CDCA expression is significantly linked to tumor development. This review summarizes clinical and basic studies on CDCAs conducted in recent decades. Furthermore, it systematically introduces the molecular expression and function, key mechanisms, cell cycle regulation, and roles of CDCAs in tumor development, cell proliferation, drug resistance, invasion, and metastasis. Additionally, it presents the latest research on tumor diagnosis, prognosis, and treatment targeting CDCAs. These findings are pivotal for further in-depth studies on the role of CDCAs in promoting tumor development and provide theoretical support for their application as new anti-tumor targets., Competing Interests: Declaration of competing interest The authors do not have any possible conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: We aimed to investigate the associations of individual and area-level socioeconomic status (SES) with incident cardiovascular diseases (CVD) alone, cancer alone, and comorbid CVD and cancer, and the mediation role of cardiovascular health score in these associations., Study Design: This was a population-based prospective cohort study., Methods: We used data from the UK Biobank, a population-based prospective cohort study. Latent class analysis was used to create an individual-level SES index based on three indicators (household income, education level, and employment status), and the Townsend Index was defined as the area-level socioeconomic status. We used the American Heart Association's (AHA) Life's Simple 7 (smoking, body weight, physical activity, diet, blood pressure, blood glucose, and total cholesterol) to calculate the cardiovascular health score. We used Cox proportional hazard regression models to estimate the hazard ratio (HR) and 95% confidence interval (CI) adjusted for demographic, environmental, and genetic factors., Results: Compared with high SES, the HRs in participants with low individual and area-level SES were 1.33 (95% confidence interval [CI] 1.29 to 1.38) and 1.24 (95% CI 1.20 to 1.29) for incident CVD, 0.96 (95% CI 0.93 to 0.99) and 0.95 (95%CI 0.92 to 0.98) for incident cancer, 1.32 (95%CI 1.24 to 1.40) and 1.15 (95%CI 1.08 to 1.22) for incident comorbid CVD and cancer, respectively. Additionally, the mediation proportion of CVD score for individual and area-level SES was 47.93% and 48.87% for incident CVD, 44.83% and 59.93% for incident comorbid CVD and cancer. The interactions between individual-level SES and CVD scores were significant on incident CVD, and comorbid CVD and cancer, and the protective associations were stronger in participants with high individual-level SES., Conclusions: Life's Simple 7 significantly mediated the associations between SES and comorbid CVD and cancer, while almost half of the associations remained unclear., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cancer has emerged as a formidable global health challenge, with treatment methods like chemotherapy and radiation often exacerbating the situation due to their associated side effects. Opting for natural sources like plants as a safer and environmentally friendly alternative seems promising. Historically, plants have served as valuable sources for treating diverse health conditions, attributable to their rich composition of therapeutic phytochemicals. Within this array of phytochemicals, alkaloids, especially those found in the Solanaceae plant family, are notably prominent. Alkaloids from Solanaceae plant family called Solanum alkaloids demonstrate noteworthy anti-tumour characteristics and exert a potent inhibitory influence on cancer cell proliferation. They trigger programmed cell death in cancerous cells through various molecular pathways, whether administered alone or combined with other medications. S olanum alkaloids act upon cancer cells via multiple mechanisms, including apoptosis induction, suppression of cell growth and migration, as well as inhibition of angiogenesis. This review provides insights into the anti-cancer attributes of Solanum alkaloids found in various Solanum plant species, along with a brief overview of their other medicinal properties., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Manoharan et al.)

Cancer heterogeneity analysis is essential for precision medicine. Most of the existing heterogeneity analyses only consider a single type of data and ignore the possible sparsity of important features. In cancer clinical practice, it has been suggested that two types of data, pathological imaging and omics data, are commonly collected and can produce hierarchical heterogeneous structures, in which the refined sub-subgroup structure determined by omics features can be nested in the rough subgroup structure determined by the imaging features. Moreover, sparsity pursuit has extraordinary significance and is more challenging for heterogeneity analysis, because the important features may not be the same in different subgroups, which is ignored by the existing heterogeneity analyses. Fortunately, rich information from previous literature (for example, those deposited in PubMed) can be used to assist feature selection in the present study. Advancing from the existing analyses, in this study, we propose a novel sparse hierarchical heterogeneity analysis framework, which can integrate two types of features and incorporate prior knowledge to improve feature selection. The proposed approach has satisfactory statistical properties and competitive numerical performance. A TCGA real data analysis demonstrates the practical value of our approach in analyzing data heterogeneity and sparsity., (© 2024 John Wiley & Sons Ltd.)

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Accurate identification of driver mutations is crucial in genetic studies of human cancers. While numerous cancer driver missense mutations have been identified, research into potential cancer drivers for synonymous mutations has shown limited success to date. Here, we developed a novel machine learning framework, epSMic, for predicting cancer driver synonymous mutations. epSMic employs an iterative feature representation scheme that facilitates the learning of discriminative features from various sequential models in a supervised iterative mode. We constructed the benchmark datasets and encoded the embedding sequence, physicochemical property, and basic information such as conservation and splicing feature. The evaluation results on benchmark test datasets demonstrate that epSMic outperforms existing methods, making it a valuable tool for researchers in identifying functional synonymous mutations in cancer. We hope epSMic can enable researchers to concentrate on synonymous mutations that have a functional impact on cancer.

Introduction: Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a common cause of nephrotic syndrome in nondiabetic adults who are also within the common age group for malignancy. How to treat patients with PLA2R-associated MN and malignancy effectively and safely still requires careful consideration. The aim of our study was to examine the outcomes and safety of rituximab (RTX) in these patients., Methods: Retrospective analysis of clinical data was performed on 15 patients with PLA2R-associated MN and malignancy. Patients were followed every 1-3 months for a minimum of 24 months. Clinical data were collected, including CD19+ B cells, anti-PLA2R antibodies, 24-hour urinary protein, serum albumin, and serum creatinine. The percentage of patients who achieved clinical remission and immunological remission was also measured., Results: Among these 15 patients, 14 patients with solid tumors received treatment for malignant diseases with complete resection. One patient received chemotherapy for chronic myeloid leukemia, and achieved complete remission 36 months before the diagnosis of MN. There were 6 (40.00 %) patients who achieved complete remission and 14 (93.33 %) patients who achieved complete or partial remission at the last visit after RTX treatment. At the last visit, patients were clinically improved, as evidenced by significant improvements in anti-PLA2R antibody titer [2.00 (2.00, 2.00) vs 35.25 (11.18, 91.58) RU/ml, P = 0.002], 24-hour urine protein [0.39 (0.11, 2.28) vs 9.22 (4.47, 14.73) g/d, P = 0.001], and serum albumin [38.15 (34.80, 43.20) vs 23.70 (18.70, 25.70) g/L, P = 0.001]. During the follow-up, the renal function of those patients remained stable. Recurrence of malignant tumors or the occurrence of new tumor events were not observed., Conclusion: In this single-center retrospective study with a small sample size, RTX therapy might be an effective and safe treatment in patients with PLA2R-associated MN and malignancy., 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 Elsevier B.V. All rights reserved.)

Ferroptosis, an iron-dependent cell death mechanism driven by an accumulation of lipid peroxides on cellular membranes, has emerged as a promising strategy to treat various diseases, including cancer. Ferroptosis inducers not only exhibit cytotoxic effects on multiple cancer cells, including drug-resistant cancer variants, but also hold potential as adjuncts to enhance the efficacy of other anti-cancer therapies, such as immunotherapy. In addition to synthetic inducers, natural compounds, such as artemisinin, can be considered ferroptosis inducers. Artemisinin, extracted from Artemisia annua L. , is a poorly water-soluble antimalarial drug. For clinical applications, researchers have synthesized various water-soluble artemisinin derivatives such as dihydroartemisinin, artesunate, and artemether. Artemisinin and artemisinin derivatives (ARTEs) upregulate intracellular free iron levels and promote the accumulation of intracellular lipid peroxides to induce cancer cell ferroptosis, alleviating cancer development and resulting in strong anti-cancer effects in vitro and in vivo . In this review, we introduce the mechanisms of ferroptosis, summarize the research on ARTEs-induced ferroptosis in cancer cells, and discuss the clinical research progress and current challenges of ARTEs in anti-cancer treatment. This review deepens the current understanding of the relationship between ARTEs and ferroptosis and provides a theoretical basis for the clinical anti-cancer application of ARTEs in the future.

Avoiding the low specificity of phototheranostic reagents at the tumor site is a major challenge in cancer phototherapy. Meanwhile, angiogenesis in the tumor is not only the premise of tumor occurrence but also the basis of tumor growth, invasion, and metastasis, making it an ideal strategy for tumor therapy. Herein, biomimetic cancer cell membrane-coated nanodrugs (mBPP NPs) have been prepared by integrating (i) homotypic cancer cell membranes for evading immune cell phagocytosis to increase drug accumulation, (ii) protocatechuic acid for tumor vascular targeting along with chemotherapy effect, and (iii) near-infrared phototherapeutic agent diketopyrrolopyrrole derivative for photodynamic/photothermal synergetic therapy. The mBPP NPs exhibit high biocompatibility, superb phototoxicity, excellent antiangiogenic ability, and double-trigging cancer cell apoptosis in vitro. More significantly, mBPP NPs could specifically bind to tumor cells and vasculature after intravenous injection, inducing fluorescence and photothermal imaging-guided tumor ablation without recurrence and side effects in vivo. The biomimetic mBPP NPs could cause drug accumulation at the tumor site, inhibit tumor neovascularization, and improve phototherapy efficiency, providing a novel avenue for cancer treatment.

Immunotherapy has become a mainstay of cancer therapy. Since chimeric antigen receptor (CAR) T immunotherapy achieves unprecedented success in curing hematological malignancies, the possibility of it revolutionizing the paradigm of solid tumors has aroused increasing attention. However, the restricted accessibility to tumor parenchyma, the immunosuppressive tumor microenvironment, and antigen heterogeneity of solid tumors make it difficult to replicate its success. Therefore, dynamic evaluation of CAR T cells' tumor accessibility, intratumoral viability, and anti-tumor cytotoxicity is necessary to facilitate its translation to solid tumors. Besides, real-timely imaging above events in vivo can help evaluate therapeutic responses and optimize CAR T immunotherapy for solid tumors. Nuclear imaging, including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging, is frequently applied for evaluating adoptive cell therapies owing to its excellent sensitivity, high tissue penetration, and great translation potential. In addition, quantitative analysis can be performed in dynamic and noninvasive patterns. This review focuses on recent advances in PET/SPECT technologies and imaging probes in monitoring CAR T cells' migration, viability, and cytotoxicity to solid tumors post-administration. Prospects of what should be done in the next stage to promote CAR T therapy's application in solid tumors are also discussed., (© 2023 Wiley-VCH GmbH.)

The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase-2, PFKFB3) is a glycolysis regulatory enzyme and plays a key role in oncogenesis of several cancers. However, the systematic study of crosstalk between PFKFB3 and Tumor microenvironment (TME) in pan-cancer has less been examined. In this study, we conducted a comprehensive analysis of the relationship between PFKFB3 expression, patient prognostic, Tumor mutational burden (TMB), Microsatellite instability (MSI), DNA mismatch repair (MMR), and especially TME, including immune infiltration, immune regulator, and immune checkpoint, across 33 types of tumors using datasets of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). We found that PFKFB3 expression was significantly correlated with patient prognostic and TME factors in various tumors. Moreover, we confirmed that PFKFB3 was an independent prognostic factor for kidney renal papillary cell carcinoma (KIRP), and established a risk prognostic model based on the expression of PFKFB3 as a clinical risk factor, which has a good predictive ability. Our study indicated that PFKFB3 is a potent regulatory factor for TME and has the potential to be a valuable prognostic biomarker in human tumor therapy.

In cancer research, supervised heterogeneity analysis has important implications. Such analysis has been traditionally based on clinical/demographic/molecular variables. Recently, histopathological imaging features, which are generated as a byproduct of biopsy, have been shown as effective for modeling cancer outcomes, and a handful of supervised heterogeneity analysis has been conducted based on such features. There are two types of histopathological imaging features, which are extracted based on specific biological knowledge and using automated imaging processing software, respectively. Using both types of histopathological imaging features, our goal is to conduct the first supervised cancer heterogeneity analysis that satisfies a hierarchical structure. That is, the first type of imaging features defines a rough structure, and the second type defines a nested and more refined structure. A penalization approach is developed, which has been motivated by but differs significantly from penalized fusion and sparse group penalization. It has satisfactory statistical and numerical properties. In the analysis of lung adenocarcinoma data, it identifies a heterogeneity structure significantly different from the alternatives and has satisfactory prediction and stability performance., (© 2021 The International Biometric Society.)

Gold nanoparticles (Au NPs) used as photosensitizers for photothermal therapy (PTT) have attracted extensive attention. However, limited tissue penetration of light seriously hinders the practical application, causing Au NPs to be combined with multiple theranostic agents to improve the treatment effect. Herein, we fabricate one potent gold nanostars (GNS) that can unify the dual nanozyme activities and photothermal property, achieving effective synergistic cascade catalytic and photothermal therapy. Notably, GNS is prepared by a green and facile one-step synthesis method using biodegradable poly(γ-glutamic acid) as a medium. The single GNS exhibits inherent dual nanozyme activities, glucose oxidase- and peroxidase-like activities, which not only convert glucose of tumor tissue into hydrogen peroxide (H 2 O 2 ) but also catalyze H 2 O 2 to produce the amount of toxic hydroxyl radicals (•OH), leading to an amplified cascade catalytic therapy. Moreover, the cascade catalytic activity of GNS is enhanced 1.4-fold in the photothermal effect. Finally, the GNS can achieve photoacoustic imaging-guided efficient synergistic cascade catalytic and photothermal therapy with a high antitumor rate of 97.0%. This simple but multifunctional GNS could provide a new strategy facilitating the practical treatment application of single Au NPs.

The pursuit of mesoporous Fe-based nanoagents addresses the field of developing alternative Fe-bearing nanoagents for synergistic cancer therapy with the expectation that the use of an essential element may avoid the issues raised by the exogenous administration of other metal element-based nanoagents. Herein, we highlight the interface-engineered mesoporous FeB ( mFeB ) where the core mFeB is interfacially oxidized into an FeOOH nanosheet loaded with the chemotherapeutic drug doxorubicin (DOX) and further encapsuled within the double-sulfide-bonded SiO 2 outer layer, denoted as mFeB@DOX-ss-SiO 2 , which can realize programmed drug release for synergistic cancer theranostics. When only in a tumor microenvironment, the nanoagent can be activated to release DOX from the mFeB and FeOOH nanosheets as well as expose the easily oxidized mFeB to spontaneously transform to FeOOH nanosheets with Fenton activity to facilitate chemodynamic therapy (CDT). In addition, the high photothermal conversion efficiency of mFeB@DOX-ss-SiO 2 would promote CDT. Also, owing to the inherent nature of ferromagnetism and red fluorescence of DOX, mFeB@DOX-ss-SiO 2 can realize T2-weighted magnetic resonance imaging and fluorescence imaging. In vivo mouse model experiments demonstrate that mFeB@DOX-ss-SiO 2 with good biocompatibility realizing CDT/photothermal therapy/chemotherapy achieved complete tumor suppression. This study opens up a new way to explore theranostic nanoagents.

MiRNA-targeted therapy holds great promise for precision cancer therapy. It is important to investigate the effect of changes in miRNA expression on apoptosis in order to evaluate miRNA-targeted therapy and achieve personalized therapy. In this study, we designed a dual-color fluorescent nanosensor consisting of grapheme oxide modified with a molecular beacon and peptide. The nanosensor can simultaneously detect and image miRNA-221 and apoptotic protein caspase-3 in living cells. Intracellular experiments showed that the nanosensor could be successfully applied for in situ monitoring of the effect of miRNA-221 expression changes on apoptosis by dual-color imaging. The current strategy could provide new avenues for investigating the feasibility of miRNA-targeted therapy, screening new anti-cancer drugs targeting miRNA and developing personalized treatment plans.

Nucleic-acid-based immune adjuvants have been extensively investigated for the design of cancer vaccines. However, nucleic acids often require the assistance of a carrier system to improve cellular uptake. Yet, such systems are prone to carrier-associated adaptive immunity, leading to difficulties in a multidose treatment regimen. Here, we demonstrate that a spherical nucleic acid (SNA)-based self-adjuvanting system consisting of phosphodiester oligonucleotides and vitamin E can function as a potent anticancer vaccine without a carrier. The two functional modules work synergistically, serving as each other's delivery vector to enhance toll-like receptor 9 activation. The vaccine rapidly enters cells carrying OVA model antigens, which enables efficient activation of adaptive immunity in vitro and in vivo . In OVA-expressing tumor allograft models, both prophylactic and therapeutic vaccinations significantly retard tumor growth and prolong animal survival. Furthermore, the vaccinations were also able to reduce lung metastasis in a B16F10-OVA model.

Purpose: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy., Patients and Methods: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective., Results: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased., Conclusions: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing., (©2022 The Authors; Published by the American Association for Cancer Research.)

In high-throughput cancer studies, gene-environment interactions associated with outcomes have important implications. Some commonly adopted identification methods do not respect the "main effect, interaction" hierarchical structure. In addition, they can be challenged by data contamination and/or long-tailed distributions, which are not uncommon. In this article, robust methods based on γ $\gamma$ -divergence and density power divergence are proposed to accommodate contaminated data/long-tailed distributions. A hierarchical sparse group penalty is adopted for regularized estimation and selection and can identify important gene-environment interactions and respect the "main effect, interaction" hierarchical structure. The proposed methods are implemented using an effective group coordinate descent algorithm. Simulation shows that when contamination occurs, the proposed methods can significantly outperform the existing alternatives with more accurate identification. The proposed approach is applied to the analysis of The Cancer Genome Atlas (TCGA) triple-negative breast cancer data and Gene Environment Association Studies (GENEVA) Type 2 Diabetes data., (© 2021 Wiley-VCH GmbH.)

Background: Attributed to the immunosuppression caused by malignancy itself and its treatments, cancer patients are vulnerable to developing nosocomial infections. This study aimed to develop a nomogram to predict the in-hospital death risk of these patients., Methods: This retrospective study was conducted at a medical center in Northwestern China. The univariate and multivariate logistic regression analyses were adopted to identify predictive factors for in-hospital mortality of nosocomial infections in cancer patients. A nomogram was developed to predict the in-hospital mortality of each patient, with receiver operating characteristic curves and calibration curves being generated to assess its predictive ability. Furthermore, decision curve analysis (DCA) was also performed to estimate the clinical utility of the nomogram., Results: A total of 1,008 nosocomial infection episodes were recognized from 14,695 cancer patients. Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (15.5%) was the most predominant causative pathogen. Besides, multidrug-resistant strains were discovered in 25.5% of cases. The multivariate analysis indicated that Eastern Cooperative Oncology Group Performance Status 3-4, mechanical ventilation, septic shock, hypoproteinemia, and length of antimicrobial treatment < 7 days were correlated with higher in-hospital mortality. Patients who received curative surgery were correlated with favorable survival outcomes. Ultimately, a nomogram was constructed to predict the in-hospital mortality of nosocomial infections in cancer patients. The area under the curve values of the nomogram were 0.811 and 0.795 in the training and validation cohorts. The calibration curve showed high consistency between the actual and predicted in-hospital mortality. DCA indicated that the nomogram was of good clinical utility and more credible net clinical benefits in predicting in-hospital mortality., Conclusions: Nosocomial infections stay conjoint in cancer patients, with gram-negative bacteria being the most frequent causative pathogens. We developed and verified a nomogram that could effectively predict the in-hospital death risk of nosocomial infections among these patients. Precise management of high-risk patients, early recognition of septic shock, rapid and adequate antimicrobial treatment, and dynamic monitoring of serum albumin levels may improve the prognosis of these individuals., (© 2022. The Author(s).)

The cGAS-STING pathway discovered ten years ago is an important component of the innate immune system. Activation of cGAS-STING triggers downstream signalling, such as TBK1-IRF3, NF-κB and autophagy, which in turn leads to antipathogen responses, durable antitumour immunity or autoimmune diseases. 2',3'-Cyclic GMP-AMP dinucleotides (2',3'-cGAMP), the key second messengers produced by cGAS, play a pivotal role in cGAS-STING signalling by binding and activating STING. Thus, 2',3'-cGAMP has immunotherapeutic potential, which in turn has stimulated research on the design and synthesis of 2',3'-cGAMP analogues for clinical applications over the past ten years. This review presents the discovery, metabolism, and function of 2',3'-cGAMP in the cGAS-STING innate immune signalling axis. The enzymatic and chemical syntheses of 2',3'-cGAMP analogues as STING-targeting therapeutics are also summarized., (© 2021 Wiley-VCH GmbH.)

Hydrogen peroxide (H 2 O 2 ) plays a vital role in organism due to its strong oxidizability, especially in resisting the invasion of pathogens. Cancer cells have abnormal concentrations of hydrogen peroxide due to their disordered reproduction. In complex biological systems, however, conventional fluorescent probes based solely on their fluorescent response to abnormal H 2 O 2 overexpression in cancer cells are not enough to distinguish cancer cells from other unhealthy or immune cells. Therefore, it is necessary to develop other methods to allow the probe to selectively enter the cancer cells and perform fluorescence imaging of the hydrogen peroxide in the cancer cells. Herein, we developed a biotin-guided, two-photon fluorescent probe (BT-HP) for sensitive detection of H 2 O 2 in cancer cells. Through the study on the properties of the probe, it was found that the probe can selectively enter cancer cells. The depth penetration imaging of H 2 O 2 in cancer cells and tumor tissues by two-photon microscope proves the potential of the probe BT-HP as a tumor targeting H 2 O 2 biosensor. The probe was further applied to detect hydrogen peroxide in cancer cells during the ferroptosis process., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly(ethylene glycol) (PEG) and MEL. Termed pacMEL, the conjugate consists of a high-density PEG arrangement, which provides MEL with steric inhibition against protein access, while the high molecular weight of pacMEL substantially enhances plasma pharmacokinetics with a ∼10-fold increase in the area under the curve (AUC ∞ ) compared to free MEL. pacMEL also significantly reduces hepatic damage and unwanted innate immune response and all but eliminated hemolytic activities of MEL. Importantly, pacMEL passively accumulates at subcutaneously inoculated tumor sites and exhibits stronger tumor-suppressive activity than molecular MEL. Collectively, pacMEL makes MEL a safer and more appealing drug candidate.

This study demonstrates the development of topotecan (TCN) loaded thermosensitive nanocargos (TCN-TS-NC) for intramuscular (IM) administration with enhanced antitumor activity. In this regards, TCN loaded temperature dependent solid lipid nanoparticles (SLNs) were prepared with micro-emulsion method, which were then incorporated into temperature sensitive poloxamer solution to develop TCN-TS-NC. The particle size, entrapment efficiency (%EE), zeta potential and transmission electron microscopy (TEM) analysis of the TCN-TS-NC were performed. Moreover, the inject-ability, release pattern, apoptosis, cellular uptake, pharmacokinetics and antitumor studies of the TCN-TS-NC were attained and compared with TCN solution and TCN-Emulgel (poloxamer solution containing TCN). At room temperature, the TCN loaded SLNs were solid and poloxamer solution remains liquid, however, TCN loaded SLNs melted to liquid and Emulgel converted into gel from, at body temperature, resulting controlled release of the incorporated drug. The TCN-TS-NC showed enhanced cellular uptake and better apoptosis. Similarly, it reduces C max and sustained its level for a significantly longer time in rats, as compared to the TCN-Emulgel and TCN solution. Moreover, a significantly improved antitumor activity was observed in TCN-TS-NC treated tumor bearing athymic nude mice when compared with the control, TCN solution and TCN-Emulgel applied mice. Thus, the TCN-TS-NC system showed control release of the drug with no initial fast effect. Furthermore, it enhanced the antitumor activity of TCN with comparatively no toxicity. It is therefore concluded that TCN-TS-NC could be a potentially more suitable drug delivery system for the delivery of TCN., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Targeting ferroptosis, which provokes lipid peroxidation in cancer cells, presents potentially new avenues for anticancer therapy. Recent studies have begun to explore how immune cells in the tumor microenvironment (TME) respond and adapt to lethal lipid peroxides (LPOs). A better understanding of this process in the TME is likely to uncover another side of ferroptosis in cancer immunity and promote the development of ferroptosis-targeted therapy. This Opinion article overviews the main metabolic processes in ferroptosis, summarizes the emerging roles of ferroptosis not only in immune cells in the TME but also in the crosstalk between tumor cells and immune cells, and presents a perspective on the targeting of ferroptosis in cancer immunotherapy., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

As evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten-/- mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

rHDL is a synthesized drug delivery nanoplatform exhibiting excellent biocompatibility, which possesses most of the advantages of HDL. rHDL shows almost no toxicity and can be degraded to non-toxic substances in vivo. The severe limitation of the application of various antitumor agents is mainly due to their low bioavailability, high toxicity, poor stability, etc. Favorably, antitumor drug-loaded rHDL nanoparticles (NPs), which are known as an important drug delivery system (DDS), help to change the situation a lot. This DDS shows an outstanding active-targeting ability towards tumor cells and improves the therapeutic effect during antitumor treatment while overcoming the shortcomings mentioned above. In the following text, we will mainly focus on the various applications of rHDL in tumor targeted therapy by describing the properties, preparation, receptor active-targeting ability and antitumor effects of antineoplastic drug-loaded rHDL NPs.

Background: E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046., Methods: This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment., Results: No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t 1/2 ) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses., Conclusions: In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting., Trial Registration Number: NCT02540291., Competing Interests: Competing interests: DSH has received research grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda; DSH received travel, accommodations, and expenses from LOXO and MiRNA; DSH held a consulting or advisory role for the following: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer (advisory boards and Speakers’ Bureaux), Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics. DSH discloses the following other ownership interests: Molecular Match (Advisor), OncoResponse (founder), and Presagia (Advisor). AN has received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and the Immune Deficiency Foundation (spouse); AN has served on an advisory board for CytomX Therapeutics and Novartis; AN has received travel and accommodation expenses paid for by ARMO BioSciences. GIS has received research funding from EL, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology. GIS has served on advisory boards for Pfizer, EL, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, and Daiichi Sankyo. The Dana-Farber Cancer Institute has received funding from Pfizer and Array BioPharma for the conduct of investigator-initiated clinical trials of palbociclib led by GIS. GIS holds Patent 9872874, entitled, “Dosage regimen for sapacitabine and seliciclib,” and also has a pending patent related to his work on CDK4/6 inhibition entitled, ‘‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition.’’ FMB has no conflicts of interest to disclose. AP is a consultant/advisory board member for Puretech, Driver, Foundation Medicine, and Eisai; AP has institutional research funding from Array, Plexxikon, Guardant, BMS, MacroGenics, Genentech, Novartis, OncoMed, and Tolero; AP has received travel support from Eisai. AM has received honoraria and consulting fees from Eisai. XB is an employee of H3 Biomedicine, a subsidiary of Eisai. LR, TAB, MR, SD, PS, LX, IT, ViB-P, and CEO are employees of Eisai or Eisai Ltd. ML, ÖA, and AYS were employees of Eisai at the time the study was conducted., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

SIRT3 is a major mitochondrial deacetylase, which regulates various metabolic pathways by deacetylation; however, the effect of SIRT3 on proline metabolism is not reported. Pyrroline-5-carboxylate reductase 1 (PYCR1) participates in proline synthesis process by catalyzing the reduction of P5C to proline with concomitant generation of NAD + and NADP + . PYCR1 is highly expressed in various cancers, and it can promote the growth of tumor cells. Here, through immunoprecipitation and mass spectrometry, we found that PYCR1 is in SIRT3's interacting network. PYCR1 directly binds to SIRT3 both in vivo and in vitro. CBP is the acetyltransferase for PYCR1, whereas SIRT3 deacetylates PYCR1. We further identified that K228 is the major acetylation site for PYCR1. Acetylation of PYCR1 at K228 reduced its enzymatic activity by impairing the formation of the decamer of PYCR1. As a result, acetylation of PYCR1 at K228 inhibits cell proliferation, while deacetylation of PYCR1 mediated by SIRT3 increases PYCR1's activity. Our findings on the regulation of PYCR1 linked proline metabolism with SIRT3, CBP and cell growth, thus providing a potential approach for cancer therapy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The traditional view holds that apoptosis is non-immunogenic and does not induce an inflammatory response. However, recent studies have suggested that certain chemotherapeutic drugs that induce tumor cell apoptosis can induce immunogenic cell death (ICD) in cancer cells. This process is characterized by not only up-regulation of a series of signaling molecules in cancer cells, including expose of calreticulin (CRT), secretion of adenosine triphosphate (ATP) and release of high mobility group box 1 (HMGB1). In this review, we summarize recent progress in identifying and classifying ICD inducers; concepts and molecular mechanisms of ICD; and the impact and potential applications of ICD in clinical studies. We also discuss the contributions of ICD inducers in combination with other anticancer drugs in clinical applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors., Experimental Design: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort., Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively)., Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients., (©2015 American Association for Cancer Research.)

Crucial parts of the genome including genes encoding microRNAs and noncoding RNAs went unnoticed for years, and even now, despite extensive annotation and assembly of the human genome, RNA-sequencing continues to yield millions of unmappable and thus uncharacterized reads. Here, we examined > 300 billion reads from 536 normal donors and 1,873 patients encompassing 21 cancer types, identified ~300 million such uncharacterized reads, and using a distinctive approach de novo assembled 2,550 novel human transcripts, which mainly represent long noncoding RNAs. Of these, 230 exhibited relatively specific expression or non-expression in certain cancer types, making them potential markers for those cancers, whereas 183 exhibited tissue specificity. Moreover, we used lentiviral-mediated expression of three selected transcripts that had higher expression in normal than in cancer patients and found that each inhibited the growth of HepG2 cells. Our analysis provides a comprehensive and unbiased resource of unmapped human transcripts and reveals their associations with specific cancers, providing potentially important new genes for therapeutic targeting., (This article is a U.S. Government work and is in the public domain in the USA Published under the terms of the CC BY 4.0 license.)

Background: Platelets play a fundamental role in maintaining hemostasis and have been shown to participate in hematogenous dissemination of tumor cells. Abundant platelets were detected in the tumor microenvironment outside of the blood vessel, thus, platelet -tumor cell interaction outside of the bloodstream may play a role in regulating primary tumor growth and metastasis initiation. However, it is unclear that platelet depletion affects tumor vessel structure and dynamics., Methods: Using thrombocytopenia induction in two different tumor-bearing mouse models, tumor tissues were performed by Westernblotting and immunohistochemical staining. Vascular permeability was evaluated by determination of intratumoral Evans blue and Miles vascular permeability assay. Furthermore, microdialysis was used to examining the intratumoral extracellular angiogenic growth factors (VEGF, TGF-β) by ELISA., Results: Platelet depletion showed no change in tumor growth and reduced lung metastasis. Platelet depletion led to reduced tumor hypoxia and Met receptor activation and was associated with a decreased release of MMP-2, 9, PAI-1, VEGF, and TGF-β. Tumor vessels in platelet-depleted mice showed impaired vessel density and maturation., Conclusions: Our findings demonstrate that platelets within the primary tumor microenvironment play a critical role in the induction of vascular permeability and initiation of tumor metastasis.

Isoflavones, rich in soybean, are currently receiving much attention because of their potential role in preventing and treating cancer and other human chronic diseases. The present review provides an overview of the recent results in this research field. Data from epidemiological reports and laboratories have shown that isoflavones have multi-biological and pharmacological effects in animals and humans. These include estrogenic and antiestrogenic effects, cell signalling conduction, as well as cell growth and death. Based on these properties, soy protein and isoflavones have been associated with reduced incidences of breast and prostate cancers, cardiovascular diseases or osteoporosis, and exhibit some other favorable effects. The mechanism through which isoflavones may exert the above-mentioned functions are not only based on the estrogenic properties of isoflavones, but also on their role as protein tyrosine kinase inhibitors, as regulators of gene transcription, modulators of transcription factors, antioxidants, as well as by altering some enzyme activities. However, to draw a clear conclusion regarding the clinical use of isoflavones further investigation would be required, although only a few effects of short- or long-term use of soy proteins are known in humans.