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AbstractAs the integration of novel agents in the frontline therapy has primarily impacted upfront therapy of advanced stage classic Hodgkin lymphoma (cHL), this review will outline current management of advanced stage cHL at first line and at progression and relapse, focusing on the biology, clinical features, and therapeutic approaches. Due to S1826, HD21, and ECHELON-1, the first-line treatment of advanced cHL has dramatically changed, with novel agents part of standard frontline therapy. BV-AVD, BrECADD, and Nivo-AVD are now standard first-line regimens for patients with stage III-IV cHL, with improved outcomes compared to historical data in cHL. The addition of BV and PD-1 inhibitors to relapsed/refractory (r/r) cHL chemotherapy regimens improved outcomes in this population. Now, there is a paradigm shift with PD-1 moving into frontline therapy, so new studies to evaluate the role of these novel agents in salvage will be required to determine the optimal salvage approach in r/r cHL. [ABSTRACT FROM AUTHOR]

This article describes how the transcriptional alterations of the innate immune system divide dysplasias into aggressive forms that, despite the treatment, relapse quickly and more easily, and others where the progression is slow and more treatable. It elaborates on how the immune system can change the extracellular matrix, favoring neoplastic progression, and how infections can enhance disease progression by increasing epithelial damage due to the loss of surface immunoglobulin and amplifying the inflammatory response. We investigated whether these dysregulated genes were linked to disease progression, delay, or recovery. These transcriptional alterations were observed using the RNA-based next-generation sequencing (NGS) panel Oncomine Immune Response Research Assay (OIRRA) to measure the expression of genes associated with lymphocyte regulation, cytokine signaling, lymphocyte markers, and checkpoint pathways. During the analysis, it became apparent that certain alterations divide dysplasia into two categories: progressive or not. In the future, these biological alterations are the first step to provide new treatment modalities with different classes of drugs currently in use in a systemic or local approach, including classical chemotherapy drugs such as cisplatin and fluorouracile, older drugs like fenretinide, and new checkpoint inhibitor drugs such as nivolumab and pembrolizumab, as well as newer options like T cell therapy (CAR-T). Following these observed alterations, it is possible to differentiate which dysplasias progress or not or relapse quickly. This information could, in the future, be the basis for determining a close follow-up, minimizing surgical interventions, planning a correct and personalized treatment protocol for each patient and, after specific clinical trials, tailoring new drug treatments. [ABSTRACT FROM AUTHOR]

Cancer research calls for new approaches that account for the regulatory complexities of biology. We present, in this study, the differential transcriptional regulome (DIFFREG) approach for the identification and prioritization of key transcriptional regulators and apply it to the case of renal cell carcinoma (RCC) biology. Of note, RCC has a poor prognosis and the biomarker and drug discovery studies to date have tended to focus on gene expression independent from mutations and/or post-translational modifications. DIFFREG focuses on the differential regulation between transcription factors (TFs) and their target genes rather than differential gene expression and integrates transcriptome profiling with the human transcriptional regulatory network to analyze differential gene regulation between healthy and RCC cases. In this study, RNA-seq tissue samples (n = 1020) from the Cancer Genome Atlas (TCGA), including healthy and tumor subjects, were integrated with a comprehensive human TF-gene interactome dataset (1122603 interactions between 1289 TFs and 25177 genes). Comparative analysis of DIFFREG profiles, consisting of perturbed TF-gene interactions, from three common subtypes (clear cell RCC, papillary RCC and chromophobe RCC) revealed subtype-specific alterations, supporting the hypothesis that these signatures in the transcriptional regulome profiles may be considered potential biomarkers that may play an important role in elucidating the molecular mechanisms of RCC development and translating knowledge about the genetic basis of RCC into the clinic. In addition, these indicators may help oncologists make the best decisions for diagnosis and prognosis management. [ABSTRACT FROM AUTHOR]

Three-dimensional cancer-on-a-chip tissue models aim to replicate the key hallmarks of the tumour microenvironment and allow for the study of dynamic interactions that occur during tumour progression. Recently, complex cancer-on-a-chip models incorporating multiple cell types and biomimetic extracellular matrices have been developed. These models have generated new research directions in engineering and medicine by allowing for the real-time observation of cancer-host cell interactions in a physiologically relevant microenvironment. However, these cancer-on-a-chip models have yet to overcome limitations including the complexity of device manufacturing, the selection of optimal materials for preclinical drug screening studies, long-term microfluidic cell culture as well as associated challenges, and the technical robustness or difficulty in the use of these microfluidic platforms. In this review, an overview of the tumour microenvironment, its unique characteristics, and the recent advances of cancer-on-a-chip models that recapitulate native features of the tumour microenvironment are presented. The current challenges that cancer-on-a-chip models face and the future directions of research that are expected to be seen are also discussed. Highlights: • Recent advanced cancer-on-a-chip models for studying the tumour microenvironment are reviewed. • Models examining interactions between tumours and multiple components of the tumour microenvironment are discussed. • Advanced cancer-on-a-chip models can provide a controlled environment for studying complex aspects of cancer biology. [ABSTRACT FROM AUTHOR]

RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary brain cancer with an incidence rate of 3.21 per 100,000 people. Even with standard-of-care treatment, the median survival time is 15 months. Therefore, new, more effective therapies are sought. In recent years, interest in combination therapies has grown because of the ineffectiveness of many monotherapies. In particular, combination therapies present the possibility of synergistic drug-drug interactions, which allow for promising clinical implementation. This investigation aims to create novel compound combinations of Aurora kinase, EZH2, and BET inhibitors to determine whether pharmacotherapies such as these can effectively treat GBM in vitro as an immunotherapy by interacting synergistically with one another. With five different combinations within two separate cell lines (LN229 and GBM22) of an Aurora kinase inhibitor drug (alisertib), EZH2 inhibitor drug (tazemetostat), and BET inhibitor drug (UM-002), the combination therapy of alisertib and UM-002 tested in vitro in LN229 cells displayed the most positive and synergistic results. Compared to the other combinations tested, the inhibition percentages were at least 34% greater for the alisertib and UM-002 combination, indicating promising drug-drug interactions between Aurora kinase and BET inhibitors which cause the GBM cell survival to decrease significantly. This illustrates the possibility of highly effective immunotherapy for this malignant disease with poor prognosis and survival. [ABSTRACT FROM AUTHOR]

Identifying specific biomarkers associated with pancreatic ductal adenocarcinoma (PDAC) patients' survival at an early stage is essential. After analyzing 1,206 pancreatic cancer patients' genomic data provided by cBioPortal database, an open web-based platform for cancer genomics, fourteen genes were found to be significantly amplified in the deceased patient group compared to the living patient group. Among those fourteen genes, it was found that CFAP418-AS1 amplified patients (n= 9) are significantly associated with decreased median overall survival month (9.14 months) when compared with the median overall survival month (24.9 months) of CFAP418-AS1 non-amplified patients (n= 457). To determine how CFAP418-AS1 amplification decreased patients' survival rates, an in vitro assay was performed to overexpress CFAP418-AS1 in ASPC1 pancreatic cancer cell line. In addition, Prestoblue assay indicated that overexpression of CFAP418-AS1 increased cell proliferation. Therefore, CFAP418-AS1 may function as an oncogene and decrease survival rates of pancreatic cancer patients by increasing cancer cell proliferation. Further investigation of the mechanisms affecting CFAP418-AS1 dysregulation will provide insights into the molecular differences underpinning pancreatic cancer's survival rate. [ABSTRACT FROM AUTHOR]

Cancers are worldwide health concerns, whether they are sporadic or hereditary. The fundamental mechanism that causes somatic or oncogenic mutations and ultimately aids cancer development is still unknown. However, mammalian cells with protein-only somatic inheritance may also contribute to cancerous malignancies. Emerging data from a recent study show that prion-like proteins and prions (PrPC) are crucial entities that have a functional role in developing neurological disorders and cancer. Furthermore, excessive PrPC expression profiling has also been detected in non-neuronal tissues, such as the lymphoid cells, kidney, GIT, lung, muscle, and mammary glands. PrPC expression is strongly linked with the proliferation and metastasis of pancreatic, prostate, colorectal, and breast malignancies. Similarly, experimental investigation presented that the PrPC expression, including the prion protein-coding gene (PRNP) and p53 ag are directly associated with tumorigenicity and metastasis (tumor suppressor gene). The ERK2 (extracellular signal-regulated kinase) pathway also confers a robust metastatic capability for PrPC-induced epithelial to mesenchymal transition. Additionally, prions could alter the epigenetic regulation of genes and overactive the mitogen-activated protein kinase (MAPK) signaling pathway, which promotes the development of cancer in humans. Protein overexpression or suppression caused by a prion and prion-like proteins has also been linked to oncogenesis and metastasis. Meanwhile, additional studies have discovered resistance to therapeutic targets, highlighting the significance of protein expression levels as potential diagnostic indicators and therapeutic targets. [ABSTRACT FROM AUTHOR]

Cell-penetrating peptides (CPPs) are short peptides, which can carry various types of molecules into cells. Therefore, CPPs have been predominantly used in preclinical and basic cancer research for more than 30 years. However, low cellular uptake of CPPs caused severe side effects for breast cancer treatment. CPPs are rich in positively charged amino acids such as arginine and lysine and can translocate over membranes and gain access to the cell interior. Therefore, we hypothesized that the addition of positive charge peptides on cell-penetrating peptides would enhance the cellular uptake of CPPs. In this study, we constructed three types of CPPs: BR2 (+7 charge), R9 (+9 charge), BR2-R9 (+16 charge). To localize the CPPs inside the cancer cells, we added Fluorescein isothiocyanate (FITC), which is a bright green fluorophore, on the C-terminal of each peptide. BR2-R9 showed much higher cellular uptake compared to BR2 and R9 on both human breast cancer cell lines (MCF-7 and MDA-MB-231). This result indicates that BR2-R9, which contains the most positive amino acids, can be applied for efficient drug delivery in cancer treatment. This study successfully develops a novel CPP for enhancing the cellular uptake in cancer cells and provides new insights into clinical applications of cancer treatment. [ABSTRACT FROM AUTHOR]

Patient-derived tumour organoids (PDOs) have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly. Here, we summarise recent advancements in PDOs from the perspective of cancer biology and clinical applications, focusing on the current challenges and opportunities of reconstructing and standardising more sophisticated PDO models. Patient-derived tumour organoids (PDOs), three-dimensional (3D) self-assembled organotypic structures, have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly. [Display omitted] [ABSTRACT FROM AUTHOR]

Metastatic pancreatic adenocarcinoma (PDAC) is a rapidly lethal disease, with less than half of patients surviving 12 months, and 5-year survival approximately 3%. These outcomes are in large part due to a lack of effective medical and surgical therapies for metastatic PDAC. Herein, we present the case of a patient with oligometastatic liver recurrence of BRCA2-mutated PDAC following a curative-intent resection. Through a combination of systemic chemotherapy, metastasectomy, radiotherapy, and subsequent targeted therapy with olaparib, the patient is asymptomatic four years following metastatic diagnosis with stable low-volume disease. This patient's excellent outcome is attributable to the multi-disciplinary care received, all aspects of which were informed by new evidence surrounding metastasectomy for metastatic PDAC, the unique biology and medical treatment of BRCA-mutated PDAC, and the role of radiotherapy in controlling locoregional recurrence. We provide a review of this evidence, while highlighting the importance of evaluating disease biology through somatic and germline genetic testing as well as monitoring response to systemic chemotherapy. [ABSTRACT FROM AUTHOR]

The amino acid sequence enriched with proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) is a signal‐transducing agent providing unique features to its substrate nuclear proteins (PEST‐NPs). The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST‐NPs that are responsible for their activation/inhibition, intracellular localization, and stability/degradation. PEST‐NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene‐based therapeutics are getting the attention of researchers because of their cell specificity. PEST‐NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST‐NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to/from their active site to promote/inhibit tumors. Thus, the role of PEST‐NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST‐NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST‐mediated PTMs on activation, localization, stability, and protein–protein interactions of PEST‐NPs. We also recommend researchers to adopt a pragmatic approach in gene‐based cancer therapy. [ABSTRACT FROM AUTHOR]

Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy. [ABSTRACT FROM AUTHOR]

Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein. [ABSTRACT FROM AUTHOR]

Understanding molecular, cellular, genetic and functional heterogeneity of tumors at the single-cell level has become a major challenge for cancer research. The microfluidic technique has emerged as an important tool that offers advantages in analyzing single-cells with the capability to integrate time-consuming and labor-intensive experimental procedures such as single-cell capture into a single microdevice at ease and in a high-throughput fashion. Single-cell manipulation and analysis can be implemented within a multi-functional microfluidic device for various applications in cancer research. Here, we present recent advances of microfluidic devices for single-cell analysis pertaining to cancer biology, diagnostics, and therapeutics. We first concisely introduce various microfluidic platforms used for single-cell analysis, followed with different microfluidic techniques for single-cell manipulation. Then, we highlight their various applications in cancer research, with an emphasis on cancer biology, diagnosis, and therapy. Current limitations and prospective trends of microfluidic single-cell analysis are discussed at the end. • Reviewed recent advances microfluidic single cell analysis in cancer research. • Introduced various microfluidic platforms for single cancer cell analysis. • Summarized different microfluidic techniques for single cancer cell manipulation. • Highlighted applications of microfluidics in cancer biology, diagnosis and therapy. • Discussed current limitation and future prospects. [ABSTRACT FROM AUTHOR]

We describe an advanced, inquiry driven undergraduate course in Cancer Biology that combines faculty lectures typical of undergraduate courses with literature‐driven discussions typical of graduate courses. As a capstone course, one goal of this course is to integrate knowledge from previous coursework in physiology, cell and molecular biology, genetics, and chemistry, so that students acquire a state‐of‐the‐art understanding of cancer and cancer treatment. A related goal is for students to learn, from the primary literature, how science is performed and how new scientific knowledge is used to improve cancer treatment. We report on the development of this course and the methods used to accomplish the course goals. We present the results of a 5‐year survey that provides a detailed picture of the demographics of the class and demonstrates that the course results in improved understanding of both cancer biology and how science is performed. Student responses to our survey strongly support the use of original literature as a teaching tool. We suggest that incorporation of primary literature into advanced undergraduate science courses is an effective approach for improving scientific literacy. © 2019 International Union of Biochemistry and Molecular Biology, 47(4):408–416, 2019. [ABSTRACT FROM AUTHOR]

Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8+ effector memory cells, in SNUC) and "other cells": keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic β-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities. [ABSTRACT FROM AUTHOR]

In this paper, we describe a system dynamics model that views cancer as a dysfunction of the cellular system rather than as an ailment of cells. Our experiments with the model replicate the propagation of the ailment and the impacts of the treatments. It presents a concept that deviates from the pervasive view of cancer as a cell malfunction that has led to treatments aiming to destroy the rogue cells. It points to more holistic treatment options aiming at reforming cell interaction so the system can contain the growth of cancer cells. Further research is needed to explore the details for such options.