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T-cell receptor therapy (TCR-T) has demonstrated efficacy, durability, and safety advantages in certain solid tumors (such as human papillomavirus-related tumors, synovial sarcoma, and melanoma). This study aimed to provide careful considerations for developing TCR-T for solid tumors. Therefore, in this review, we have summarized the current clinical application, advantage of TCR-T modalities and explored efficacy/safety-related parameters, particularly avidity, pharmacokinetics/pharmacodynamics, and indications, for solid tumors. Furthermore, we have investigated critical factors related to avidity, including antigen selection, T-cell receptor acquisition, optimization, and co-receptor engagement. Moreover, we have re-examined the expression of tumor antigens for a potentially higher coverage rate of solid tumors based on the current RNA-seq datasets. Finally, we have discussed the current limitations and future directions of TCR-Ts., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC 50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC 50 of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent., Competing Interests: Declaration of competing interest The authors declare the following competing financial interest(s): S.L.Z., Y.Y.L., J.X., H.H. are or were Wuhan Yuxiang Pharmaceutial Technology Co., Ltd. employees or consultants at the time that the work was conducted. H. X. F. is shareholder of Wuhan Yuxiang Pharmaceutial Technology Co., Ltd., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Vaccine technology is effective in preventing and treating diseases, including cancers and viruses. The efficiency of vaccines can be improved by increasing the dosage and frequency of injections, but it would bring an extra burden to people. Therefore, it is necessary to develop vaccine-boosting techniques with negligible side effects. Herein, we reported a cupping-inspired noninvasive suction therapy that could enhance the efficacy of cancer/SARS-CoV-2 nanovaccines. Negative pressure caused mechanical immunogenic cell death and released endogenous adjuvants. This created a subcutaneous niche that would recruit and activate antigen-presenting cells. Based on this universal central mechanism, suction therapy was successfully applied in a variety of nanovaccine models, which include prophylactic/therapeutic tumor nanovaccine, photothermal therapy induced in situ tumor nanovaccine, and SARS-CoV-2 nanovaccine. As a well-established physical therapy method, suction therapy may usher in an era of noninvasive and high-safety auxiliary strategies when combined with vaccines.

Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option., (© 2023. The Author(s).)

Background: Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear., Methods: Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models., Results: In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8 + T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo . Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8 + T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment., Conclusions: Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Albeit remarkable achievements in anti-cancer endeavors, the prevention and treatment of cancer remain unresolved challenges. Hence, there is an urgent need to explore new and efficacious natural compounds with potential anti-cancer therapeutic agents. One such group of compounds is alisols, tetracyclic triterpene alcohols extracted from alisma orientale. Alisols play a significant role in cancer therapy as they can suppress cancer cell proliferation and migration by regulating signaling pathways such as mTOR, Bax/Bcl-2, CHOP, caspase, NF-kB and IRE1. Pharmacokinetic studies showed that alisols can be absorbed entirely, rapidly, and evenly distributed in vivo. Moreover, alisols are low in toxicity and relatively safe to take. Remarkably, each alisol can be converted into many compounds with different pathways to their anti-cancer effects in the body. Thus, alisols are regarded as promising anti-cancer agents with minimal side effects and low drug resistance. This review will examine and discuss alisols' anti-cancer molecular mechanism, pharmacokinetics and metabolism. Based on a comprehensive analysis of nearly 20 years of research, we evaluate the therapeutic potential of alisols for various types of cancer and offer insights and strategies for developing new cancer 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Lymphoid-tyrosine phosphatase (LYP) is mainly expressed in the immune system and plays an important role in the T-cell receptor (TCR) signaling pathway and tumor immunity. Herein, we identify benzofuran-2-carboxylic acid as a potent pTyr mimic and design a new series of new LYP inhibitors. The most active compound, D34 and D14, reversibly inhibits LYP (K i  = 0.93 μM and 1.34 μM) and possess a certain degree of selectivity toward other phosphatases. Meanwhile, D34 and D14 regulate the TCR signaling by specifically inhibiting LYP. In particular, D34 and D14 significantly suppress tumor growth in an MC38 syngeneic mouse model by boosting antitumor immunity, including activation of T-cell and inhibition of M2 macrophage polarization. Moreover, treatment of D34 or D14 upregulate PD-1/PD-L1 expression, which can be leveraged with PD-1/PD-L1 inhibition to augment immunotherapy. In summary, our study demonstrates the feasibility of targeting LYP for cancer immunotherapy and provides new lead compounds for further drug development., 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 Masson SAS. All rights reserved.)

Duplex sequencing technology has been widely used in the detection of low-frequency mutations in circulating tumor deoxyribonucleic acid (DNA), but how to determine the sequencing depth and other experimental parameters to ensure the stable detection of low-frequency mutations is still an urgent problem to be solved. The mutation detection rules of duplex sequencing constrain not only the number of mutated templates but also the number of mutation-supportive reads corresponding to each forward and reverse strand of the mutated templates. To tackle this problem, we proposed a Depth Estimation model for stable detection of Low-Frequency MUTations in duplex sequencing (DELFMUT), which models the identity correspondence and quantitative relationships between templates and reads using the zero-truncated negative binomial distribution without considering the sequences composed of bases. The results of DELFMUT were verified by real duplex sequencing data. In the case of known mutation frequency and mutation detection rule, DELFMUT can recommend the combinations of DNA input and sequencing depth to guarantee the stable detection of mutations, and it has a great application value in guiding the experimental parameter setting of duplex sequencing technology., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The development of quantitative analytical methods to assess the heterogeneous distribution and penetration of nanodrugs in solid tumors is of great importance for anticancer nanomedicine. Herein, Expectation-Maximization (EM) iterate algorithm and threshold segmentation methods were used to visualize and quantify the spatial distribution patterns, penetration depth and diffusion features of two-sized hafnium oxide nanoparticles (s-HfO 2 NPs in 2 nm and l-HfO 2 NPs in 50 nm sizes) in mouse models of breast cancer using synchrotron radiation micro-computed tomography (SR-μCT) imaging technique. The three-dimensional (3D) SR-μCT images were reconstructed based on the EM iterate algorithm thus clearly displayed the size-related penetration and distribution within the tumors after intra-tumoral injection of HfO 2 NPs and X-ray irradiation treatment. The obtained 3D animations clearly show that a considerable amount of s-HfO 2 and l-HfO 2 NPs diffused into tumor tissues at 2 h post-injection and displayed the obvious increase in the tumor penetration and distribution area within the tumors at day 7 after combination with low-dose X-ray irradiation treatment. A thresholding segmentation for 3D SR-μCT image was developed to assess the penetration depth and quantity of HfO 2 NPs along the injection sites in tumors. The developed 3D-imaging techniques revealed that the s-HfO 2 NPs presented more homogeneous distribution pattern, diffused more quickly and penetrated more deeply within tumor tissues than the l-HfO 2 NPs did. Whereas, the low-dose X-ray irradiation treatment greatly enhanced the wide distribution and deep penetration of both s-HfO 2 and l-HfO 2 NPs. This developed method may provide quantitative distribution and penetration information for the X-ray sensitive high-Z metal nanodrugs in the cancer imaging and therapy., 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.)

MicroRNAs (miRNAs) are a family of non-coding RNA molecules with vital roles in regulating gene expression. Although researchers have recognized the importance of miRNAs in the development of human diseases, it is very resource-consuming to use experimental methods for identifying which dysregulated miRNA is associated with a specific disease. To reduce the cost of human effort, a growing body of studies has leveraged computational methods for predicting the potential miRNA-disease associations. However, the extant computational methods usually ignore the crucial mediating role of genes and suffer from the data sparsity problem. To address this limitation, we introduce the multi-task learning technique and develop a new model called MTLMDA (Multi-Task Learning model for predicting potential MicroRNA-Disease Associations). Different from existing models that only learn from the miRNA-disease network, our MTLMDA model exploits both miRNA-disease and gene-disease networks for improving the identification of miRNA-disease associations. To evaluate model performance, we compare our model with competitive baselines on a real-world dataset of experimentally supported miRNA-disease associations. Empirical results show that our model performs best using various performance metrics. We also examine the effectiveness of model components via ablation study and further showcase the predictive power of our model for six types of common cancers. The data and source code are available from https://github.com/qwslle/MTLMDA., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy., (© 2023 Wiley-VCH GmbH.)

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients., (© 2023. Higher Education Press.)

Background: Older adults are a growing segment of oncology population in China and beyong. However, older cancer patients were vastly underrepresented in clinical trial. To facilitate that all patients with cancer have equal access to the cutting edging treatment and receive evidence-based medication in mainland China, it's of particular importance to fully grasp the proportion of upper age restriction in cancer clinical trials, as well as associated factors., Methods: Based on clinical trials registered on the China Food and Drug Administration Registration and Information Disclosure Platform, we sought to characterize the overall proportion and trajectory of upper age-restriction among registered cancer drug trials in mainland China from 2009 to 2021, and potential influencing factors were determined by multivariate logistic regression., Results: According to the 3485 trials, upper age restriction proportion of cancer drug trials for patients over 65 years and 75 years was 18.8% (95% CI = 17.5%-20.1%) and 56.5% (95% CI = 51.3%-54.6%), respectively. Phase IV trials, international multicenter trials, or trials initiated by global companies seldom excluded patients over 65 years compared with phase I trials, domestic trials and trials initiated by Chinese enterprise, similar for 75 years and above. Both of 65 and 75 years old age limit sponsored by domestic enterprises showed slowly downward trend, while no such trend was observed for that of foreign companies. Solution to upper age eligibility of cancer drug trials was also provided., Conclusions: Although there is a certain downward trend, use of eligibility criteria that explicitly exclude older cancer patients in mainland China was remarkably high, especially for trials initiated by domestic enterprise, domestic trials and early-phase trials. Action is urgently needed to promote treatment equity in the older patients while obtaining adequate evidence in clinical trials., (© 2023. The Author(s).)

Background: Previous studies have revealed the significant roles of SHC SH2 domain-binding protein 1 (SHCBP1) in occurrence and progression of cancers, but there is no pan-cancer analysis of SHCBP1., Methods: In this study, we explored the potential carcinogenic role of SHCBP1 across 33 tumors from the TCGA and GTEx databases. We investigated SHCBP1 expression, prognosis, genetic alterations, tumor mutational burden (TMB) score, microsatellite instability (MSI) and tumor microenvironment from TIMER2, GEPIA2, UALCAN and cBioPortal databases. Moreover, the cellular functions and potential mechanisms were evaluated by GO and KEGG analysis. Besides, the mRNA expression of SHCBP1 was examined using qRT-PCR assay in gastrointestinal cancers., Results: SHCBP1 was significantly upregulated in various cancers, and apparent relationship existed between SHCBP1 and survival prognosis in patients. The TMB, MSI, and tumor microenvironment analysis indicated that SHCBP1 was closely related to immune checkpoints, immune targets, as well as CD4+ naive T cell, CD8+ T cell, and neutrophil. Moreover, the cellular functions of SHCBP1 were mainly in regulating cell cycle motor protein activity. In addition, we validated that SHCBP1 mRNA expression was over-expressed in gastrointestinal cancers., Conclusions: This study was the first to systematically determine the prognostic value of SHCBP1, providing a forward-looking perspective on immunotherapy and cellular processes in pan-cancer.

Obesity usually induces systemic metabolic disturbances, including in the tumor microenvironment (TME). This is because adaptive metabolism related to obesity in the TME with a low level of prolyl hydroxylase-3 (PHD3) depletes the major fatty acid fuels of CD8 + T cells and leads to the poor infiltration and unsatisfactory function of CD8 + T cells. Herein, we discovered that obesity could aggravate the immunosuppressive TME and weaken CD8 + T cell-mediated tumor cell killing. We have thus developed gene therapy to relieve the obesity-related TME to promote cancer immunotherapy. An efficient gene carrier was prepared by modifying polyethylenimine with p -methylbenzenesulfonyl (abbreviated as PEI-Tos) together with hyaluronic acid (HA) shielding, achieving excellent gene transfection in tumors after intravenous administration. H A/ P EI-Tos/ p D NA ( HPD ) containing the plasmid encoding PHD3 ( p PHD3) can effectively upregulate the expression of PHD3 in tumor tissues, revising the immunosuppressive TME and significantly increasing the infiltration of CD8 + T cells, thereby improving the responsiveness of immune checkpoint antibody-mediated immunotherapy. Efficient therapeutic efficacy was achieved using HPD together with αPD-1 in colorectal tumor and melanoma-bearing obese mice. This work provides an effective strategy to improve immunotherapy of tumors in obese mice, which may provide a useful reference for the immunotherapy of obesity-related cancer in the clinic.

Radiotherapy (RT), as one of the main methods in the clinical treatment of various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) of cancer cells. However, the antitumor immune responses produced by RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against cancer metastases. Herein, a biomimetic mineralization method for facile synthesis of MnO 2 nanoparticles with high anti-programmed death ligand 1 (αPDL1) encapsulation efficiency (αPDL1@MnO 2 ) is proposed to reinforce RT-induced systemic antitumor immune responses. This therapeutic nanoplatforms-mediated RT can significantly improve the killing of tumor cells and effectively evoke ICD by overcoming hypoxia-induced radio-resistance and reprogramming the immunosuppressive tumor microenvironment (TME). Furthermore, the released Mn 2+ ions from αPDL1@MnO 2 under acidic tumor pH can activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and facilitate the dendritic cells (DCs) maturation. Meanwhile, αPDL1 released from αPDL1@MnO 2 nanoparticles would further promote the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and trigger systemic antitumor responses, resulting in a strong abscopal effect to effectively inhibit tumor metastases. Overall, the biomineralized MnO 2 -based nanoplatforms offer a simple strategy for TME modulation and immune activation, which are promising for enhanced RT immunotherapy.

Natural killer (NK) cell therapy is emerging as a cancer treatment. NK cells are innate cytotoxic lymphocytes that act as first-line responders to kill target cells without prior encounters. NK cells recognize cancer cells, virus-infected cells, and other types of stressed cell through a reservoir of germline-encoded receptors. NK cells are safe for allogeneic applications. Therefore, they are the ideal off-the-shelf cell, which overcome the low efficiency issue caused by the patient-by-patient nature of autologous cell therapy. Unlike T cells, NK cells cannot form a strong immune memory; therefore, they suffer from short in vivo persistence. However, different from T cells, NK cells have a reservoir of innate immune receptors targeting a variety of malignant cells. In addition, they can utilize antibody guidance in target recognition. With suitable engineering, NK cells can function as universal anticancer drugs that are not restricted to HLA and cancer types, which will benefit the large cohort of patients with rare cancer types and patients with no convenient drug targets for precision and personalized medicine. Here, we summarize and discuss the designs of current anticancer NK cell therapies., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule-guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown., Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs., Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV sig . A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV sig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV sig in cell lines and organoids., Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients., (© 2022. The Author(s).)

The main challenge in cancer genomics is to distinguish the driver genes from passenger or neutral genes. Cancer genomes exhibit extensive mutational heterogeneity that no two genomes contain exactly the same somatic mutations. Such mutual exclusivity (ME) of mutations has been observed in cancer data and is associated with functional pathways. Analysis of ME patterns may provide useful clues to driver genes or pathways and may suggest novel understandings of cancer progression. In this article, we consider a probabilistic, generative model of ME, and propose a powerful and greedy algorithm to select the mutual exclusivity gene sets. The greedy method includes a pre-selection procedure and a stepwise forward algorithm which can significantly reduce computation time. Power calculations suggest that the new method is efficient and powerful for one ME set or multiple ME sets with overlapping genes. We illustrate this approach by analysis of the whole-exome sequencing data of cancer types from TCGA., (© The Author 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Platinum-based photosensitizers are promising anticancer agents in photodynamic therapy. The cytotoxic effects primarily arise from the production of singlet oxygen and platination of DNA. However, their efficacy is limited by drug resistance and hypoxic tumor microenvironment. A naphthalimide-modified cyclometalated platinum(II) complex PtPAN [PA = N -(2-(diethylamino)ethyl)picolinamide, N = N -(2'-ethylhexyl)-4-ethynyl-1,8-naphthalimide] is designed to conquer these problems. PtPAN generates ROS efficiently under both normoxia and hypoxia. It does not interact with DNA and shows low cytotoxicity in the dark, while it kills tumor cells via ROS under near-infrared light irradiation; moreover, it inhibits tumor growth in mice at a low light dose with negligible side effects. PtPAN is the first reported platinum-based photosensitizer that is unreactive to DNA in the dark but highly cytotoxic upon near-infrared (NIR) irradiation for oxygen-independent photodynamic therapy. Owing to its two-photon excitation property (λ = 825 nm), PtPAN may be suitable for the treatment of deep solid tumors.

A home-brew, tri-color MECOM breakapart FISH probe with a full MECOM coverage labeled with a separate dye is compared in parallel with a 2-color commercial MECOM breakapart probe in 17 cases of hematologic malignancies. Cases with a typical positive signal pattern (or "balanced" signal pattern) (n = 2) and a negative result (n = 3) using the commercial probe achieved the same results using the new probe (100% concordance), whereas 9 of 12 (75%) remaining cases with an atypical signal pattern (or "unbalanced" signal pattern) using the commercial probe showed a "balanced" signal pattern using the new probe. Three cases with undetermined MECOM rearrangement status by the commercial probe were further clarified with no MECOM rearrangement in 2 cases and presence of a subclone with simultaneous gain and rearrangement of MECOM in 1 case. More importantly, the new probe is capable of determining the presence, location and integrity of MECOM after rearrangement. In conclusion, atypical signal patterns obtained using a commercial FISH probe for MECOM can be solved through re-design and optimization of a new BAP probe, especially in those cases with a true MECOM rearrangement. The potential of the new probe for use in the clinical laboratory will be further investigated. (Word count: 196)., Competing Interests: Declaration of Competing Interest None of the authors declared conflicts of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We observed a synergistic antiproliferation effect with combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor. Inspired by this result, a new series of benzimidazole - hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities compared to SAHA but also possessed potent antiproliferation activities against tumor cells. Importantly, compounds 9k and 9l showed good in vivo antitumor efficacies in both HEL xenograft model and murine melanoma model. We also found that 9k and 9l promote the antigen presentation and activate T cells, thereby triggering antitumor immunity. Moreover, these inhibitors reshaped the tumor immune microenvironment by inhibiting the recruitment of Treg cells and promoting the polarization of tumor-infiltrating macrophages to M2 type with antitumor activity. Our study validated the effectiveness of incorporating a DNA-binding fragment in HDAC inhibitors as novel multitargeting antitumor agents.

Several C2 domain-containing proteins play key roles in tumorigenesis, signal transduction, and mediating protein-protein interactions. Tandem C2 domains nuclear protein (TC2N) is a tandem C2 domain-containing protein that is differentially expressed in several types of cancers and is closely associated with tumorigenesis and tumor progression. Notably, TC2N has been identified as an oncogene in lung and gastric cancer but as a tumor suppressor gene in breast cancer. Recently, a large number of tumor-associated antigens (TAAs), such as heat shock proteins, alpha-fetoprotein, and carcinoembryonic antigen, have been identified in a variety of malignant tumors. Differences in the expression levels of TAAs between cancer cells and normal cells have led to these antigens being investigated as diagnostic and prognostic biomarkers and as novel targets in cancer treatment. In this review, we summarize the clinical characteristics of TC2N-positive cancers and potential mechanisms of action of TC2N in the occurrence and development of specific cancers. This article provides an exploration of TC2N as a potential target for the diagnosis and treatment of different types of cancers., 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 © 2021 Li, Fang, Chang, Qiu, Ren, Cao, Bian, Wang, Guo, Lv, Sun, Wang and Li.)

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis., (© 2021. The Author(s).)

Aim: To establish a highly sensitive time-resolved fluorescence immunoassay of heparin-binding protein (HBP-TRFIA) and evaluate its application value for bacterial or fungal infections in tumor patients., Methods: Two types of HBP monoclonal specific antibodies against different epitopes of the antigen molecule were used as coating antibodies and Eu 3+ -labeled antibodies, respectively. The double-antibody sandwich method was used in establishing HBP-TRFIA, and the methodology was evaluated. The established HBP-TRFIA was used in detecting HBP concentration in the plasma samples of healthy individuals, patients with bacterial or fungal infections, and infected or uninfected patients with various types of tumors., Results: The linear range of HBP-TRFIA was (0.11-530 ng/mL). Plasma HBP concentrations detected through HBP-TRFIA were consistent with the results of fluorescence quantitative immunochromatography (ρ = 0.964). The plasma HBP concentrations of infected tumor patients were significantly higher than those of uninfected tumor patients (P < 0.01)., Conclusion: This study successfully established a highly sensitive HBP-TRFIA, which was highly comparable to commercially available fluorescent quantitative immunochromatographic kits and was able to facilitate the timely diagnosis of bacterial or fungal infections in patients with tumor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immunotherapy holds great promise for patients undergoing tumor treatment. However, the clinical effect of immunotherapy is limited because of tumor immunogenicity and its immunosuppressive microenvironment. Herein, the metal-organic framework (MIL-100) loaded with chemotherapeutic agent mitoxantrone (MTO) was combined with photothermal-chemotherapy for enhancing immunogenic cell death. M IL-100 loaded with M TO and h yaluronic acid as nanoparticles ( MMH NPs) yielded an NP with two therapeutic properties (photothermal and chemotherapy) with dual imaging modes (photoacoustic and thermal). When MMH NPs were coinjected with an anti-OX40 antibody in colorectal cancer, the highest antitumor efficacy and a robust immune effect were achieved. This work provides a novel combined therapeutic strategy, which will hold great promise in future tumor therapy.

Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles, and efficacy. We also highlight the current challenges, potential solutions, and future directions of bsAb development for cancer treatment., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting "undruggable" proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently., (© 2021. Higher Education Press.)

Purpose: Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors., Patients and Methods: This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days., Results: In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response., Conclusions: ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted., (©2021 American Association for Cancer Research.)

Introduction: Limited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours., Methods and Analysis: This is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon's two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events., Ethics and Dissemination: Ethics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations., Trial Registration Numbers: NCT04423185; ChiCTR2000039310., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses., Results: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells., Conclusions: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

Reversible NIR luminescent probes with negligible photocytotoxicity are required for long-term tracking of cycling hypoxia in vivo. However, almost all of the reported organic fluorescent hypoxia probes reported until now were irreversible. Here we report a reversible arylazo-conjugated fluorescent probe (HDSF) for cycling hypoxia imaging. HDSF displays an off-on fluorescence switch at 705 nm in normoxia-hypoxia cycles. Mass spectroscopic and theoretical studies confirm that the reversible sensing behavior is attributed to the two electron-withdrawing trifluoromethyl groups, which stabilizes the reduction intermediate phenylhydrazine and blocks the further reductive decomposition. Cycling hypoxia monitoring in cells and zebrafish embryos is realized by HDSF using confocal imaging. Moreover, hypoxic solid tumors are visualized and the ischemia-reperfusion process in mice is monitored in real-time. This work provides an effective strategy to construct organic fluorescent probes for cycling hypoxia imaging and paves the way for the study of cycling hypoxia biology.

Background: Tumor mutational burden (TMB) is a promising biomarker for stratifying patient subpopulation who would benefit from immune checkpoint blockade (ICB) therapies. Although great efforts have been made for standardizing TMB measurement, mutation calling and TMB quantification can be challenging in samples with low tumor content including liquid biopsies. The effect of varying tumor content on TMB estimation by different assay methods has never been systematically investigated., Method: We established a series of reference standard DNA samples derived from 11 pairs of tumor-normal matched human cell lines across different cancer types. Each tumor cell line was mixed with its matched normal at 0% (control), 1%, 2%, 5%, and 10% mass-to-mass ratio to mimic the clinical samples with low tumor content. TMB of these reference standards was evaluated by both ∼1000× whole-exome sequencing (wesTMB) and targeted panel sequencing (psTMB) at four different vendors. Both regression and classification analyses of TMB were performed for theoretical investigation and clinical practice purposes., Results: Linear regression model was established that demonstrated in silico psTMB determined by regions of interest (ROI) as a great representative of wesTMB based on TCGA dataset. It was also true in our reference standard samples as the predicted psTMB interval based on the observed wesTMB captured the intended 90% of the in silico psTMB values. Although ∼1000× deep WES was applied, reference standard samples with less than 5% of tumor proportions are below the assay limit of detection (LoD) of wesTMB quantification. However, predicted wesTMB based on observed psTMB accurately classify (>0.97 AUC) for TMB high and low patient stratification even in samples with 2% of tumor content, which is more clinically relevant, as TMB determination should be a qualitative assay for TMB high and low patient classification. One targeted panel sequencing vendor using an optimized blood psTMB pipeline can further classify TMB status accurately (>0.82 AUC) in samples with only 1% of tumor content., Conclusions: We developed a linear model to establish the quantitative correlation between wesTMB and psTMB. A set of DNA reference standards was produced in aid to standardize TMB measurements in samples with low tumor content across different targeted sequencing panels. This study is a significant contribution aiming to harmonize TMB estimation and extend its future application in clinical samples with low tumor content including liquid biopsy., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Mutual exclusivity analyses provide an effective tool to identify driver genes from passenger genes for cancer studies. Various algorithms have been developed for the detection of mutual exclusivity, but controlling false positive and improving accuracy remain challenging. We propose a forward selection algorithm for identification of mutually exclusive gene sets (FSME) in this paper. The method includes an initial search of seed pair of mutually exclusive (ME) genes and subsequently including more genes into the current ME set. Simulations demonstrated that, compared to recently published approaches (i.e., CoMEt, WExT, and MEGSA), FSME could provide higher precision or recall rate to identify ME gene sets, and had superior control of false positive rates. With application to TCGA real data sets for AML, BRCA, and GBM, we confirmed that FSME can be utilized to discover cancer driver genes.

Background: Independent decision-making is one of the basic rights of patients. However, in clinical practice, most older cancer patients' treatment decisions are made by family members., Objective: This study attempted to analyze the treatment decision-making process and formation mechanism for older cancer patients within the special cultural context of Chinese medical practice., Method: A qualitative study was conducted. With the sample saturation principle, data collected by in-depth interviews with 17 family members and 12 patients were subjected to thematic analysis., Ethical Considerations: The study was approved by the ethics committees of Sun Yat-sen University. All participants provided verbal informed consent after being told their rights of confidentiality, anonymity, and voluntary participation. They had the right to refuse to answer questions and could withdraw at any time., Results: Three themes emerged: (1) complex process; (2) transformation of family decision-making power; and (3) individual compromise. Family members inevitably had different opinions during the long process of treatment decision-making for older cancer patients. The direction of this process could be regarded as an extension of the family power relationship. The patient usually compromised the decision to survive, which was made by family members., Conclusion: This study describes the treatment decision-making process of older cancer patients in the context of Chinese culture. The reasons underlying this process are related to the views on life and death and family values. An individual is a part of the family, which is often seen as the minimal interpersonal unit in Chinese society. It is significant that while emphasizing patient autonomy in the decision-making process, health professionals should also pay attention to the important roles of culture and family.

Objective: To explore the latest progress of oncology drug clinical trials in China under COVID-19, as well as to provide decision-making evidence for related stakeholders. Research progress of oncology drug trials and approved cancer drugs in China in 2020 were systematically summarized and compared with 2019. Methods: Information Disclosure Platform for Drug Clinical Studies and China Food and Drug Administration Query System for Domestic and Imported Drug were searched for registered clinical trials and approved oncology drugs, respectively. The trial scope, stage, drug type, effect and mechanism of domestic and global pharmaceutical enterprises were compared between 2019 and 2020. Results: A total of 722 cancer drug trials registered in China in 2020, with an annual growth rate of 52.3%, accounting for 28.3% of all registered trials. Among them, 603 (83.5%) trials were initiated by domestic pharmaceutical enterprises, and 105 (14.5%) were international multicenter trials, phase I trials accounted for 44.5%. For all those trials, there were 458 cancer drug varieties, with an annual growth rate of 36.7%, and 361 (85.8%) were developed by domestic enterprises. Most of the investigational products were therapeutic innovative drugs (77.1%), major in tumor treatment (92.8%). In terms of mechanism, targeted drugs were the most popular, accounting for 76.6%, and programmed cell death-1 (PD-1) and epithelial growth factor receptor (EGFR) were the most common targets. In addition, there were 19 anticancer drugs from 17 companies approved in China in 2019, with 10 drugs from domestic companies. Lung cancer and breast cancer are the most common indications for both registered trials and marketed drugs. No statistically significant differences were found between 2020 and 2019 in terms of the distribution of trial sponsor, scope and stage, as well as the distribution of drug type, effect and mechanism ( P >0.05). Conclusions: During the Covid-19 epidemic period, clinical trials of oncology drugs in China progress smoothly and maintain a high growth rate. Series of innovative products obtained by domestic enterprises in 2020 is the main driving force of development of oncology drug clinical trials in China.

Background: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity., Methods: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression., Results: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population., Conclusions: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer., Trial Registration Number: NCT02955251., Competing Interests: Competing interests: JJL: Data and Safety Monitoring Board for TTC Oncology; consultancy/advisory role for 7 Hills, Abbvie, Actym, Akrevia, Algios, Alphamab Oncology, Array, Astellas, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Ideaya, Incyte, Janssen, Kanaph, Mavu (now part of AbbVie), Merck, Mersana, Novartis, Onc.AI, Pyxis, PTx, RefleXion, Regeneron, Silicon, Springbank, Tempest, Tesaro, and Vividion; research support (all to institution for clinical trials unless noted) from AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, and Xencor; patents (both provisional) with the University of Chicago: Serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); travel support from Akrevia, Bayer, Bristol-Myers Squibb, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis, Pyxis, and RefleXion. FB: consulting/advisory role for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. KC: no conflicts to disclose. AWT: Independent Data Monitoring Committee for Mirati and Genentech/Roche; consulting/advisory role (fees paid to NEXT Oncology) for AbbVie, AbGenomics, Adagene, ADC Therapeutics, Agenus, Aro Biotherapeutics, Ascentage Pharma, BioInvent, AxImmune, Bayer, BioInvent, Birdie, Cello Health, Eleven Bio, Ellipses, Elucida, EMD Serono, Five Prime, Forbius (Formation Biologics), Gilde Healthcare Partners, HBM Partners, Immunome, Immunomet, Jazz, Karma Oncology, Mekanistic, Menarini, Mersana, Nanobiotix, NBE Therapeutics, Nuvalent, Pelican, PSI Pharma Support America, Oncology International, OSI, Partner Therapeutics, Pfizer, Pieris, Pierre Fabre, Ridgeway, Ryvu Therapeutics, Scitemex, Seattle Genetics, Symphogen, Syneos, TFS Trial Form Support International, and Zymeworks. KK: consultancy/advisory role for AstraZeneca, Bristol-Myers Squibb, EMD Serono, Eli Lilly Oncology, Genentech/Roche, Inviata, Merck, Novartis, Regeneron, and Symphogen; research funding from Astellas, AbbVie, Bristol-Myers Squibb, EMD Serono, Five Prime Therapeutics, Genentech, Regeneron, Tizona, and Transgene. AH: honoraria from Amgen, Eisai, and Servier; consulting/advisory role for AstraZeneca, Incyte, and Debiopharm; travel support from Amgen, Servier, Lilly, AstraZeneca, and MedImmune; research funding from Incyte. CLT: consultancy/advisory role for MSD, Bristol-Myers Squibb, Merck Serono, Roche, AstraZeneca, GlaxoSmithKline, Rakuten, Seattle Genetics, and Nanobiotix. VS: one-time educational honoraria from Medscape; consultancy/advisory role for Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, Incyte, QED Pharma, MedImmune, and Novartis; travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, and Incyte; research funding from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals. FT: stock or other ownership in Salarius Pharmaceuticals; consultancy/advisory role for Tempus Lab; patents, royalties, or other intellectual property for clinical trial software. SK: honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; consultancy/advisory role for AstraZeneca, Boehringer, Merck Sharp & Dohme, and Pfizer; travel support from AstraZeneca, Boehringer, Bristol-Myers Squibb, and Roche. PAC: honoraria from Novartis, Roche/Genentech, Blueprint Medicines, Amgen, and Merck Serono; research funding from Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, and Merck Sharp & Dohme. MK: consultancy/advisory role for AbbVie, Ipsen, Pfizer, Roche, and Jackson Laboratory for Genomic Medicine; research funding from AbbVie, Bristol-Myers Squibb, and Specialized Therapeutics. HLK: personal fees from Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Deciphera, Inhibrx, Inventiva, Kyowa, Merck, and Paredox Therapeutics; non-financial support from AstraZeneca, Boehringer Ingelheim, Inventiva, Merck, and Paredox Therapeutics; research funding to institution from Aduro, AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Lilly, Merck, Polaris, Verastem, Blueprint, Tesaro, and Inhibrx. FF: no conflicts to disclose. KA: no conflicts to disclose. HF, MP, SY, DTC, WRH, JSH, and MAM: employment with AbbVie and may hold stock or other options. LF: research funding from AbbVie, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Janssen, Merck, and Roche/Genentech. No honoraria or payments were made for authorship., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

As an important post-transcription modification, histone deacetylation plays significant roles in chromatin remodeling and gene expression. The aberrant modification of histone deacetylation leads to various diseases. As a critical member of histone deacetylase (HDAC), HDAC6 serves as a key modulator in many physiological processes. Abnormal expression of HDAC6 gives rise to cancer, neurodegeneration and other diseases. Here, we have reviewed recent advances in physiological, protein structure and development of HDAC6 selective inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The PROTAC (PROteolysis TArgeting Chimera) technology is a target protein degradation strategy, based on the ubiquitin-proteasome system, which has been gradually developed into a potential means of targeted cancer therapy in recent years. This strategy has already shown significant advantages over traditional small-molecule inhibitors in terms of pharmacodynamics, selectivity, and drug resistance. Several small molecule PROTACs have been in Phase I clinical trial. Herein, we have introduced the mechanism, characteristics, and advantages of PROTAC strategy. And we have summarized the recent advances in the development of small-molecule PROTACs for cancer treatment. We hope this review will be helpful in optimizing the design of the ideal small- molecule PROTACs and advancing targeted anticancer research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction : Cyclin-dependent kinase 7 (CDK7) is a part of the CDK-activating kinase family (CAK) which has a key role in the cell cycle and transcriptional regulation. Several lines of evidence suggest that CDK7 is a promising therapeutic target for cancer. CDK7 selective inhibitors such as SY-5609 and CT7001 are in clinical development. Areas covered : We explore the biology of CDK7 and its role in cancer and follow this with an evaluation of the preclinical and clinical progress of CDK7 inhibitors, and their potential in the clinic. We searched PubMed and ClinicalTrials to identify relevant data from the database inception to 14 October 2020. Expert opinion : CDK7 inhibitors are next generation therapeutics for cancer. However, there are still challenges which include selectively, side effects, and drug resistance. Nevertheless, with ongoing clinical development of these inhibitors and greater analysis of their target, CDK7 inhibitors will become a promising approach for treatment of cancer in the near future.

Chimeric antigen receptor (CAR) therapy has been proved effective in a stream of clinical trials, especially in hematologic malignancies. However, current CAR therapy is highly personalized as cells used are derived from patients themselves, which can be costly, time-consuming, and sometimes fails to achieve optimal therapeutic results due to poor quality/quantity of patient-derived cells. On the contrary, universal CAR therapy, which is based on healthy individuals' cells, circumvents several limitations of current autologous CAR therapy. To achieve the universality of CAR therapy, the allogeneic cell transplantation related issues, such as graft- versus -host disease (GVHD) and host- versus -graft activities (HVGA), must be addressed. In this review, we focus on current progress regarding GVHD and HVGA in the universal CAR therapy, followed by a universal CAR design that may be applied to allogeneic cells and a summary of key clinical trials in this field. This review may provide valuable insights into the future design of universal CAR products., 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 © 2020 Zhang, Li, Fang, Wang and Zeng.)

Few prospective cohort studies have investigated associations between environmental tobacco smoke (ETS) and other cancer sites, in addition to lung cancer. We assessed these associations in a population-based prospective cohort study started from 2008 to 2011 with average of 9.1 years of follow-up, in Minhang district, Shanghai, China. The study included a total of 23,415 participants (8388 men, 15,027 women) and 205,515 person-years. Epidemiological data were collected by a standardized questionnaire including ETS exposure. Newly diagnosed patients with primary cancers and deaths were identified by record linkage system with the Shanghai Cancer Registry and Shanghai Vital Statistics. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models, adjusting for potential confounders. During the study period, a total of 1462 patients with diagnoses of primary cancers were identified. Among all participants and non-smokers, ETS was associated with an increased risk of all smoking-related cancers (all: adjusted HR: 1.23, 95% CI: 1.05-1.43 and non-smokers: 1.24, 1.02-1.49), lung cancer (1.29, 0.98-1.71 and 1.27, 0.91-1.77), and stomach cancer (1.86, 1.21-2.85 and 1.75, 1.05-2.91), respectively. Furthermore, associations for lung and stomach cancers were the strongest among non-smoking females. The joint effects of both ETS and active smoking were strongest for all cancers, all smoking-related cancers, lung cancer, and stomach cancer. No clear interactions were observed. These results suggest that ETS exposure may increase the risk of smoking-related cancers in a Chinese population. Further studies on the relationship between ETS exposure and specific cancer sites are warranted to replicate our findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Peripherally inserted central catheters (PICCs) and implantable port catheters (IPCs) are 2 most common central venous access for cancer patients receiving chemotherapy. However, no specific evidence exists to guide practitioners on safety and less cost., Objective: To compare the differences of complications and costs of PICC and IPC in the treatment of cancer patients with chemotherapy and to provide a basis for better clinical decision making., Methods: All the cohort studies were searched in the Cochrane Library, JBI, PubMed, Elsevier, Web of Science, CINAHL, CBM, and CNKI from inception to July 2018. Two reviewers screened and selected trials, evaluated quality, and extracted data. Meta-analysis and description of the outcomes were performed by using the RevMan 5.3 software., Results: A total of 761 articles were retrieved, with 15 articles meeting eligibility criteria. Outcome analysis showed no difference in 1-puncture success rate. Peripherally inserted central catheter use was associated with higher complication rates than IPC, including occlusion, infection, malposition, catheter-related thrombosis, extravasation, phlebitis, and accidental removal rate. The life span of IPC was longer than that of PICC, and the costs of IPC were lower., Conclusions: Implantable port catheter has advantages over PICC in reducing cancer patients' complications and less cost in terms of long-term cancer chemotherapy., Implications for Practice: In terms of safety, the results provide evidence for practitioners to choose which type of central venous catheters is better for cancer chemotherapy patients. In terms of costs, practitioners need to make decisions about which type of central venous catheters has less cost.

Ru(ii) complexes have been recognized as excellent anticancer candidates. However, the poor cell uptake of these complexes has been the major obstacle in improving their anticancer efficacy. Along with the development of the knowledge on the anticancer nature of the Ru(ii) complexes, several strategies have been designed to increase the cellular accumulation of these complexes. Among them, the light-triggered drug uptake approach is most promising. In this study, a bioactive Ru(ii)-polypyridyl complex Ru-1 is constructed via incorporating a modified phenanthroline ligand into the enlarged conjugate structure. The modulation of the ligand makes Ru-1 powerful in generating singlet oxygen and effective in photodynamic therapeutic activity. Moreover, the cell uptake is improved during this photodynamic process and induces further chemotherapeutic effect, which act synergistically to enhance its anticancer activity. The photoinduced synergistic cytotoxicity of Ru-1 towards cancer cells offers an effective way to sensitize the antitumor activity of Ru(ii) complexes.