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Simple Summary: Prostate cancer (PCa) is among the most common cancers. While PCa is frequently diagnosed in elderly men as a slow-growing, low-risk disease, in about 10–15% of cases, it can become a life-threatening danger. Unfortunately, biomarkers able to discriminate indolent prostatic tumors from aggressive forms are lacking, and watchful waiting remains one of the best options. However, available data support the hypothesis that distinctive biological characteristics of PCa stroma can contribute to cancer progression in a clinically relevant way. According to the current view, tissue alterations induced by tumor growth affect both metabolism of resident normal cells and composition of the extracellular matrix and are able also to recruit cells from circulation. Here, we seek to respond to the challenge of identifying stroma-associated biomarkers that may be relevant to assist prognostic decisions in PCa patients. Prostate cancer (PCa), the most commonly diagnosed cancer in men worldwide, is particularly challenging for oncologists when a precise prognosis needs to be established. Indeed, the entire clinical management in PCa has important drawbacks, generating an intense debate concerning the possibility to individuate molecular biomarkers able to avoid overtreatment in patients with pathological indolent cancers. To date, the paradigmatic change in the view of cancer pathogenesis prompts to look for prognostic biomarkers not only in cancer epithelial cells but also in the tumor microenvironment. PCa ecology has been defined with increasing details in the last few years, and a number of promising key markers associated with the reactive stroma are now available. Here, we provide an updated description of the most biologically significant and cited prognosis-oriented microenvironment biomarkers derived from the main reactive processes during PCa pathogenesis: tissue adaptations, inflammatory response and metabolic reprogramming. Proposed biomarkers include factors involved in stromal cell differentiation, cancer-normal cell crosstalk, angiogenesis, extracellular matrix remodeling and energy metabolism. [ABSTRACT FROM AUTHOR]

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat shock proteins (HSPs) are extensively distributed throughout cells. They play a crucial role as molecular chaperones and regulate various cellular processes, such as metabolism, growth, differentiation, cell signaling, and programmed cell death. However, in cancers, HSPs are frequently overexpressed and associated with tumor advancement and metastasis, as well as in acquiring drug resistance against chemotherapeutic agents, leading to poor prognosis. Thus, the expression of HSPs can be modulated to imitate the cellular response against cancer cells by targeting the tumor microenvironment through different mechanisms. For instance, HSPs bind to antigens (peptides) associated with tumors, forming a complex that is easily recognized as an antigen-presenting cell (APC), leading to specific antitumor responses. This review summarizes and discusses recent advances, perspectives, and involvement of HSPs, including small and large HSPs, as well as the molecular mechanisms underlying tumor progression and metastasis. This study may offer new insights into the development of safer and more effective anticancer therapeutics. Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized. [ABSTRACT FROM AUTHOR]

Tumors not only consist of cancerous cells, but they also harbor several normallike cell types and non-cellular components. cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. Autophagy is an intracellular degradation and quality control mechanism, and recent studies provided evidence that autophagy played a critical role in CAF formation, metabolic reprograming and tumor-stroma crosstalk. Therefore, shedding light on the autophagy and its role in CAF biology might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the exploitation of more efficient cancer diagnosis and treatment. Here, we provide an overview about the involvement of autophagy in CAF-related pathways, including transdifferentiation and activation of CAFs, and further discuss the implications of targeting tumor stroma as a treatment option. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are antigen presenting cells that link innate and adaptive immunity. DCs have been historically considered as the most effective and potent cell population to capture, process and present antigens to activate naïve T cells and originate favorable immune responses in many diseases, such as cancer. However, in the last decades, it has been observed that DCs not only promote beneficial responses, but also drive the initiation and progression of some pathologies, including inflammatory bowel disease (IBD). In line with those notions, different therapeutic approaches have been tested to enhance or impair the concentration and role of the different DC subsets. The blockade of inhibitory pathways to promote DCs or DC-based vaccines have been successfully assessed in cancer, whereas the targeting of DCs to inhibit their functionality has proved to be favorable in IBD. In this review, we (a) described the general role of DCs, (b) explained the DC subsets and their role in immunogenicity, (c) analyzed the role of DCs in cancer and therapeutic approaches to promote immunogenic DCs and (d) analyzed the role of DCs in IBD and therapeutic approaches to reduced DCinduced inflammation. Therefore, we aimed to highlight the “yin-yang” role of DCs to improve the understand of this type of cells in disease progression. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have opened up new possibilities in clinical oncology. Monoclonal antibodies have shown their high clinical efficiency. They block CTLA-4, PD-1, and PD-L1 receptors and activate the immune response. Many patients have stable and even complete responses. However, some patients have primary or acquired resistance. Therefore, the treatment results in this category of patients are not predictable. Mechanisms of resistance to immune checkpoint inhibitors have not been definitively studied. Many theories try to explain the mechanisms of this phenomenon. Our study aimed to structure and combine the data into groups depending on the etiological factor that reduces the immune response. In addition, based on understanding the mechanisms of resistance and the results of recent clinical studies, we aimed to identify the main ways to overcome it. Therefore, mechanisms that lead to resistance may be associated with tumor properties, tumor microenvironment, or patient characteristics. Tumor properties that reduce the immune response include a) low tumor mutation burden and loss of tumor neoantigens, b) changes in the processing or presentation of neoantigens, and c) changes in signaling pathways of tumor development and epigenetic modifications in genes. The tumor microenvironment is represented by stromal and immune cells, extracellular matrix, cytokines, and blood vessels. Each structure can enhance or reduce the immune response and contribute to the acquired resistance to immune checkpoint inhibitors. The effectiveness of the treatment depends not only on the cells in the tumor microenvironment but also on the metabolic background. In addition, the basic characteristics of the patient ( gender, gut microbiota, HLA-I genotype) can modify the immune response. Based on knowledge about the mechanisms of resistance to immune checkpoint inhibitors, several therapeutic strategies aimed at activating antitumor activity have been evaluated. All of them are based on combining immune checkpoint inhibitors with other drugs. One of the most common options is a combination of PD-1/PD-L1 and CTLA-4 inhibitors. Alternative immune checkpoints are TIM-3, LAG-3, TIGIT and VISTA. Combining immunotherapy with chemotherapy, targeted therapy, neoangiogenesis inhibitors, epigenetic modifiers, PARP or TGF-β inhibitors enhances antitumor response by preventing depletion of effector T cells, enhancing T cell infiltration in the tumor, changes on the tumor microenvironment, and decreasing the accumulation of immunosuppressive cells. This review explores the biological mechanisms of resistance and potential ways of solving this problem. [ABSTRACT FROM AUTHOR]

In the current era of screening colonoscopy and increasing incidence of early rectal cancer, interventional endoscopy moves toward resections in deeper planes than the submucosal layer. Several reports support the use of endoscopic intermuscular dissection (EID) instead of endoscopic submucosal dissection (ESD) for the removal of deeply invasive rectal submucosal cancers. The resection plane into the intermuscular space, the space between the longitudinal (external) and circular (internal) muscle layer, allows radical removal of rectal invasive submucosal cancers. Furthermore, the technique offers the potential for dissection of scarred and severe fibrotic lesions in the rectum by cutting deeper and performing a partial myectomy avoiding the narrow submucosal space. We present 23 cases of EIDs both for deeply invasive rectal cancers and benign rectal lesions. This is the first report in the literature of EID resections for malignant and benign disease, including cases of severely fibrotic rectal lesions. [ABSTRACT FROM AUTHOR]

Background: Oral mucositis (OM) is a severe and common adverse effect of cancer treatment. The oral microbiome appears to play a role on the onset and severity of OM. Therefore, this systematic review aims to characterize the oral dysbiosis associated with OM. Methods: The PRISMA checklist was followed and PubMed, Web of Science, and Scopus were screened for clinical studies characterizing the oral microbiome alterations in patients with OM. Results: From a total of 2500 articles retrieved, we included nine articles in this systematic review. Certain types of bacteria, as Fusobacterium, were recognized as predictors of the onset of OM. In addition, it was reported that patients with severe OM presented a reduction in alpha‐diversity, an increase in beta‐diversity. The abundance of some taxa significantly changed with OM severity, with Bacillota phylum and genera Leptotrichia, Actinomyces, and Prevotella decreasing and Treponema increasing with disease progression. Additionally, during cancer treatment, changes in the oral microbiome have been observed in OM patients, with an increase in Candida and nosocomial pathogens, including Staphylococcus species. Conclusion: Our review indicates that cancer treatment can significantly alter the oral microbiome, with more pronounced changes observed in patients with severe OM in all relevant oral phyla, but more pronounced in Bacillota phylum. [ABSTRACT FROM AUTHOR]

(1) Background: Colon polyps are common protrusions in the colon's lumen, with potential risks of developing colorectal cancer. Early detection and intervention of these polyps are vital for reducing colorectal cancer incidence and mortality rates. This research aims to evaluate and compare the performance of three machine learning image classification models' performance in detecting and classifying colon polyps. (2) Methods: The performance of three machine learning image classification models, Google Teachable Machine (GTM), Roboflow3 (RF3), and You Only Look Once version 8 (YOLOv8n), in the detection and classification of colon polyps was evaluated using the testing split for each model. The external validity of the test was analyzed using 90 images that were not used to test, train, or validate the model. The study used a dataset of colonoscopy images of normal colon, polyps, and resected polyps. The study assessed the models' ability to correctly classify the images into their respective classes using precision, recall, and F1 score generated from confusion matrix analysis and performance graphs. (3) Results: All three models successfully distinguished between normal colon, polyps, and resected polyps in colonoscopy images. GTM achieved the highest accuracies: 0.99, with consistent precision, recall, and F1 scores of 1.00 for the 'normal' class, 0.97–1.00 for 'polyps', and 0.97–1.00 for 'resected polyps'. While GTM exclusively classified images into these three categories, both YOLOv8n and RF3 were able to detect and specify the location of normal colonic tissue, polyps, and resected polyps, with YOLOv8n and RF3 achieving overall accuracies of 0.84 and 0.87, respectively. (4) Conclusions: Machine learning, particularly models like GTM, shows promising results in ensuring comprehensive detection of polyps during colonoscopies. [ABSTRACT FROM AUTHOR]

The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision‐making of cancer treatment. [ABSTRACT FROM AUTHOR]

The protein disulfide isomerase A3 (PDIA3) is directly or indirectly involved in various physiopathological processes and participates in cancer initiation, progression and chemosensitivity. However, little is known about its involvement in glioblastoma. To obtain specific information, we performed cellular experiments in the T98G and U−87 MG glioblastoma cell lines to evaluate the role of PDIA3. The loss of PDIA3 functions, either through inhibition or silencing, reduced glioblastoma cells spreading by triggering cytotoxic phenomena. PDIA3 inhibition led to a redistribution of PDIA3, resulting in the formation of protein aggregates visualized through immunofluorescence staining. Concurrently, cell cycle progression underwent arrest at the G1/S checkpoint. After PDIA3 inhibition, ROS-independent DNA damage and the activation of the repair system occurred, as evidenced by the phosphorylation of H2A.X and the overexpression of the Ku70 protein. We also demonstrated through a clonogenic assay that PDIA3 inhibition could increase the chemosensitivity of T98G and U-87 MG cells to the approved glioblastoma drug temozolomide (TMZ). Overall, PDIA3 inhibition induced cytotoxic effects in the analyzed glioblastoma cell lines. Although further in vivo studies are needed, the results suggested PDIA3 as a novel therapeutic target that could also be included in already approved therapies. [ABSTRACT FROM AUTHOR]

Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions. [ABSTRACT FROM AUTHOR]

Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types. [ABSTRACT FROM AUTHOR]

Summary: Microbiota plays an essential role in human development and body homeostasis. Individual and environmental variables influence the diversity of microbiota, which performs crucial biochemical activities in the human body and influences health status and disease in later years. Many diseases in adulthood may be prevented or treated if the relationship between the microbiome, nutrition, especially the immune system, and growth and development could be fully understood. For a healthy gut microbiota, the diet‐related changes in the core microbiota must be long‐lasting, achieving permanence in microbiota change. This process is possible by maintaining a sustainable diet and adhering to this diet for a long time. Therefore, this study reviewed the relationship between nutrition, microbiota, and various life‐threatening diseases. [ABSTRACT FROM AUTHOR]

The properties of the variable domain of heavy-chain (VHH) antibodies are particularly relevant in cancer therapy. To isolate tumor cell-specific VHH antibodies, VHH phage libraries were constructed from multiple tumor cells. After enriching the libraries against particular tumor cell lines, a next-generation sequencer was used to screen the pooled phages of each library for potential antibody candidates. Based on high amplification folds, 50 sequences from each library were used to construct phylogenetic trees. Several clusters with identical CDR3 were observed. Groups X, Y, and Z were assigned as common sequences among the different trees. These identical groups over the trees were considered to be cross-reactive antibodies. To obtain monoclonal antibodies, we assembled 200 sequences (top 50 sequences from each library) and rebuilt a combined molecular phylogenetic tree. Groups were categorized as A–G. For each group, we constructed a phagemid and determined its binding specificity with tumor cells. The phage-binding results were consistent with the phylogenetic tree-generated groups, which indicated particular tumor-specific clusters; identical groups showed cross-reactivity. The strategy used in the current study is effective for screening and isolating monoclonal antibodies. Specific antibodies can be identified, even when the target markers of cancer cells are unknown. [ABSTRACT FROM AUTHOR]

One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer. [ABSTRACT FROM AUTHOR]

Basophils bind IgE via FceRI-abg2, which they uniquely share only with mast cells. In doing so, they can rapidly release mediators that are hallmark of allergic disease. This fundamental similarity, along with some morphological features shared by the two cell types, has long brought into question the biological significance that basophils mediate beyond that of mast cells. Unlike mast cells, which mature and reside in tissues, basophils are released into circulation from the bone marrow (constituting 1% of leukocytes), only to infiltrate tissues under specific inflammatory conditions. Evidence is emerging that basophils mediate non-redundant roles in allergic disease and, unsuspectingly, are implicated in a variety of other pathologies [e.g., myocardial infarction, autoimmunity, chronic obstructive pulmonary disease, fibrosis, cancer, etc.]. Recent findings strengthen the notion that these cells mediate protection from parasitic infections, whereas related studies implicate basophils promoting wound healing. Central to these functions is the substantial evidence that human and mouse basophils are increasingly implicated as important sources of IL-4 and IL-13. Nonetheless, much remains unclear regarding the role of basophils in pathology vs. homeostasis. In this review, we discuss the dichotomous (protective and/or harmful) roles of basophils in a wide spectrum of non-allergic disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammation is the biological response of the body to damaging and toxic stimuli, and is a positive event that evolves with the resolution of critical events (acute inflammation). However, when the process becomes chronic it acquires pathological characteristics, and is associated with detrimental diseases such as cancer. It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, metastasis, angiogenesis, and immune escape. The enzymes' expression in PGE2 synthesis positively correlates with tumor progression and aggressiveness. This review describes the interplay between the PGE2 cascade and epidermal growth factor receptor that fuel cancer progression, and new therapeutic strategies that target these signaling pathways, to outline the importance of the modulation of the inflammatory process in cancer fighting. It is recognized that prostaglandin E2 (PGE2) is one key lipid mediator involved in chronic inflammation, and it is directly implicated in tumor development by regulating cancer cell growth and migration, apoptosis, epithelial–mesenchymal transition, angiogenesis, and immune escape. In addition, the expression of the enzymes involved in PGE2 synthesis, cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES1), positively correlates with tumor progression and aggressiveness, clearly indicating the crucial role of the entire pathway in cancer. Moreover, several lines of evidence suggest that the COX2/mPGES1/PGE2 inflammatory axis is involved in the modulation of epidermal growth factor receptor (EGFR) signaling to reinforce the oncogenic drive of EGFR activation. Similarly, EGFR activation promotes the induction of COX2/mPGES1 expression and PGE2 production. In this review, we describe the interplay between COX2/mPGES1/PGE2 and EGFR in cancer, and new therapeutic strategies that target this signaling pathway, to outline the importance of the modulation of the inflammatory process in cancer fighting. [ABSTRACT FROM AUTHOR]

Rapidly proliferating cancer cells exhibit a high energy demand. However, their utilization of the glycolytic pathway is inefficient, leading to a compensatory effect wherein cancer cells consume ten to twenty times more glucose than normal cells. In cases where glucose availability is limited due to a poorly perfused hypoxic microenvironment, cancer cells resort to alternative energy sources, including fructose. Certain tumors have been found to rely heavily on fructose, and fructose utilization contributes to pro-tumoral signaling and increased cancer risk. Over the past 70 years, dietary fructose intake has steadily increased, resulting in a rise in obesity and metabolic syndrome, both of which elevate cancer risk. In this paper, we present compelling evidence that highlights the role of fructose and the glucose transporter GLUT5 in promoting specific types of tumors. We summarize the existing evidence and pathways through which fructose contributes to cancer metabolism, particularly in cases where glucose availability is restricted. Furthermore, we propose a hypothesis that elucidates the regulation of the lipogenic phenotype by dietary fructose intake and cellular energy status. It is important to note that the effects of fructose are contextdependent, with its tumor-promoting effects varying based on the energy status of the cell. We comprehensively analyze why targeting fructose uptake and fructolysis should be important for the management of some tumors and cancer prevention. [ABSTRACT FROM AUTHOR]

Simple Summary: In the tumor microenvironment, cancer-associated fibroblasts (CAFs) have multiple tumor-promoting functions in drug resistance, regulation of the niche of cancer stem cells and formation of the immunosuppressive network. Multiple mechanisms are involved, including production of growth factors, cytokines, and chemokines, as well as extracellular matrix remodeling. While cancer treatment generally targets cancer cells, elucidation of the tumor microenvironment has allowed for successful targeting of cells other than cancer cells involved in the construction of the tumor microenvironment. Cancer cells are prone to develop drug resistance, whereas resistance to treatments targeting the tumor microenvironment may be less likely to develop. Therefore, various treatment strategies against CAFs have attracted attention as possible novel cancer treatments. Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A better understanding of the mechanism underlying lung cancer metastasis is therefore urgently needed. The tumor microenvironment involves different types of stromal cells and functions as key components in the progression of NSCLC. Through epithelial–mesenchymal transition (EMT), in which epithelial cells lose their polarity and acquire mesenchymal potential, cancer cells acquire metastatic abilities, as well as cancer stem-cell-like potential. We previously reported that cancer-associated fibroblasts (CAFs) interact with lung cancer cells to allow for the acquisition of malignancy and treatment resistance by paracrine loops via EMT signals in the tumor microenvironment. Furthermore, CAFs regulate the cytotoxic activity of immune cells via various cytokines and chemokines, creating a microenvironment of immune tolerance. Regulation of CAFs can therefore affect immune responses. Recent research has shown several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, so molecular markers of CAFs should be elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. CAF-targeted cancer treatments may suppress EMT and regulate the niche of cancer stem cells and the immunosuppressive network and thus may prove useful for NSCLC treatment through multiple mechanisms. [ABSTRACT FROM AUTHOR]

Colorectal cancer is an important health problem with a significant impact on the individual and society. Malignancy (including colorectal cancer) is usually slightly symptomatic in its initial stages. This causes cancer to be discovered in some patients accidentally (either through screening tests in predisposed individuals or during routine investigations for other diseases), while in other patients the colorectal cancer is discovered in late stages, when the symptoms are much more intense due to complications. Unfortunately, such advanced cases of the disease have high rates of morbidity and mortality even with treatment. Current treatment methods are usually complex, interdisciplinary, causing significant suffering (physical, mental) to the individual, while the cost of treatment per patient seems to be extremely high. Until finding therapeutic methods that are effective and accessible to most patients with advanced colorectal cancer, several methods of prophylaxis and early diagnosis should be considered, to reduce as much as possible the devastating impact of this disease. The purpose of this review is to present literature data regarding the current methods of diagnosis and treatment of patients presenting to the doctor with colorectal cancer in advanced stages of complications. [ABSTRACT FROM AUTHOR]

Simple Summary: The biological relevance of peptides that originate from non-canonical translational initiation sites have been increasingly recognized over the years. Peptides encoded by open reading frames upstream of canonical protein coding sequences are frequently translated and act as translational regulators, contribute to the immunopeptidome as cellular antigens, and are implicated in various cellular functions through peptide–protein interactions or as part of protein complexes. In this review, we first give an overview of the most relevant technical advances in non-canonical peptide detection. In the second part of the review, we focus on the functional implications of uPeptides and delineate how this largely unexplored compartment of the human peptidome affects tumor biology and may offer new opportunities for targeted and immunological cancer therapy. Recent technological advances have facilitated the detection of numerous non-canonical human peptides derived from regulatory regions of mRNAs, long non-coding RNAs, and other cryptic transcripts. In this review, we first give an overview of the classification of these novel peptides and summarize recent improvements in their annotation and detection by ribosome profiling, mass spectrometry, and individual experimental analysis. A large fraction of the novel peptides originates from translation at upstream open reading frames (uORFs) that are located within the transcript leader sequence of regular mRNA. In humans, uORF-encoded peptides (uPeptides) have been detected in both healthy and malignantly transformed cells and emerge as important regulators in cellular and immunological pathways. In the second part of the review, we focus on various functional implications of uPeptides. As uPeptides frequently act at the transition of translational regulation and individual peptide function, we describe the mechanistic modes of translational regulation through ribosome stalling, the involvement in cellular programs through protein interaction and complex formation, and their role within the human leukocyte antigen (HLA)-associated immunopeptidome as HLA uLigands. We delineate how malignant transformation may lead to the formation of novel uORFs, uPeptides, or HLA uLigands and explain their potential implication in tumor biology. Ultimately, we speculate on a potential use of uPeptides as peptide drugs and discuss how uPeptides and HLA uLigands may facilitate translational inhibition of oncogenic protein messages and immunotherapeutic approaches in cancer therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of anti-angiogenic drugs in pediatric patients is only partially assessed. We aimed to evaluate the safety of these drugs in children with solid tumors. This systematic review and meta-analysis reported that one out of two pediatric patients using anti-angiogenic drugs in monotherapy experienced a serious adverse event despite proportions varying per single drug. Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations. [ABSTRACT FROM AUTHOR]

Periostin (POSTN), a member of the matricellular protein family, is a secreted adhesion-related protein produced in the periosteum and periodontal ligaments. Matricellular proteins are a nonstructural family of extracellular matrix (ECM) proteins that regulate a wide range of biological processes in both normal and pathological conditions. Recent studies have demonstrated the key roles of these ECM proteins in the tumor microenvironment. Furthermore, periostin is an essential regulator of bone and tooth formation and maintenance, as well as cardiac development. Also, periostin interacts with multiple cell-surface receptors, especially integrins, and triggers signals that promote tumor growth. According to recent studies, these signals are implicated in cancer cell survival, epithelial-mesenchymal transition (EMT), invasion, and metastasis. In this review, we will summarize the most current data regarding periostin, its structure and isoforms, expressions, functions, and regulation in normal and cancerous tissues. Emphasis is placed on its association with cancer progression, and also future potential for periostin-targeted therapeutic approaches will be explored. [ABSTRACT FROM AUTHOR]

Purpose of the Review: The reintroduction of immune checkpoint inhibitors (ICIs) after disease progression (rechallenge) or immune-related adverse events (irAEs) recovering (resumption) raises questions in terms of efficacy and safety. Recent Findings: Here, we reviewed literature data about ICIs rechallenge/resumption in cancer patients along with their clinical characteristics to explore those factors associated with better outcomes. Summary: Heterogenous results were pointed out across rechallenge studies with an overall response rate between 0 and 54%, and a progression free survival ranged from 1.5 to 12.9 months and an overall survival between 6.5 and 23.8 months. Better outcomes have been recorded in patients with good ECOG PS, longer duration of initial ICI, discontinuation reason of initial ICI other than progression, and those who received ICI sequence other than the switch between anti-PD1 and anti-PDL1. Studies about ICI resumption highlighted that certain types of irAEs were more likely to relapse at retreatment. These results suggest that ICI rechallenge/resumption can be an interesting strategy for selected patients. [ABSTRACT FROM AUTHOR]

Background: Despite the recent advances in chemotherapy, the outcomes and the success of these treatments still remain insufficient. Novel combination treatments and treatment strategies need to be developed in order to achieve more effective treatment. This study was designed to investigate the combined effect of ethacrynic acid and cinnamic acid on cancer cell lines. Methods: The anti-proliferative effect of ethacrynic acid and cinnamic acid was investigated by MTT cell viability assay in three different cancer cell lines. Combination indexes were calculated using CompuSyn software. Apoptosis was assessed by flow cytometric Annexin V-FITC/PI double-staining. The effect of the inhibitors on cell cycle distribution was measured by propidium iodide staining. Results: The combination treatment of ethacrynic acid and cinnamic acid decreased cell proliferation significantly, by 63%, 75% and 70% for K562, HepG2 and TFK-1 cells, respectively. A 5.5-fold increase in the apoptotic cell population was observed after combination treatment of K562 cells. The population of apoptotic cells increased by 9.3 and 0.4% in HepG2 and TFK-1 cells, respectively. Furthermore, cell cycle analysis shows significant cell cycle arrest in S and G2/M phase for K562 cells and non-significant accumulation in G0/G1 phase for TFK-1 and HepG2 cells. Conclusions: Although there is a need for further investigation, our results suggest that the inhibitors used in this study cause a decrease in cellular proliferation, induce apoptosis and cause cell cycle arrest. [ABSTRACT FROM AUTHOR]

BACKGROUND Results of preceding studies on the relationship between blood pressure (BP) and cancers have been confounded due to individuals taking antihypertensive medications or shared risk factors. We assessed whether medication-naïve high BP is a risk factor for incident cancers. METHODS This retrospective observational study included 1,388,331 individuals without a prior history of cancer and not taking antihypertensive medications enrolled in the JMDC Claims Database between 2005 and 2018. The primary outcome was 16 cancers. RESULTS The median [interquartile range] age was 45 [40–52] years and 56.2% were men. Mean systolic BP (SBP) and diastolic BP (DBP) were 117.7 ± 15.8 and 72.8 ± 11.6 mm Hg. Multivariate Cox regression analysis demonstrated that SBP per 1-SD was associated with a higher incidence of thyroid (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.03–1.16), esophageal (HR: 1.15, 95% CI: 1.07–1.24), colorectal (HR: 1.04, 95% CI: 1.01–1.07), liver (HR: 1.11, 95% CI: 1.03–1.20), and kidney (HR: 1.22, 95% CI: 1.14–1.31) cancers, but with a lower incidence of stomach cancer (HR: 0.94, 95% CI: 0.91–0.98). These associations remained significant after adjustment for multiple testing. DBP was associated with higher incidences of thyroid, esophageal, colorectal, kidney, and corpus uteri cancers, but with a lower incidence of stomach cancer. The associations between SBP and incidences of thyroid, esophageal, colorectal, liver, and kidney cancers were confirmed in the Korean National Health Insurance Service database. CONCLUSIONS Medication-naïve BP was associated with higher incidences of thyroid, esophageal, colorectal, liver, and kidney cancers. Uncovering the underlying mechanisms for our results may help identify novel therapeutic approach for hypertension and cancer. [ABSTRACT FROM AUTHOR]

Histone lysine methylation plays a key role in gene activation and repression. The trimethylation of histone H3 on lysine-27 (H3K27me3) is a critical epigenetic event that is controlled by Jumonji domain-containing protein-3 (JMJD3). JMJD3 is a histone demethylase that specifically removes methyl groups. Previous studies have suggested that JMJD3 has a dual role in cancer cells. JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung. In contrast, JMJD3 can suppress the propagation of tumor cells, and enhance their apoptosis in colorectal, breast, and pancreatic cancers. In this review, we summarized the recent advances of JMJD3 function in cancer cells. [ABSTRACT FROM AUTHOR]

Tumours develop within complex tissue environments consisting of aberrant oncogenic cancer cells, diverse innate and adaptive immune cells, along with structural stromal cells, extracellular matrix and vascular networks, and many other cellular and non-cellular soluble constituents. Understanding the heterogeneity and the complex interplay between these cells remains a key barrier in treating tumours and cancers. The immune status of the pre-tumour and tumour milieu can dictate if the tumour microenvironment (TME) supports either a pro-malignancy or an anti-malignancy phenotype. Identification of the factors and cell types that regulate the dysfunction of the TME is crucial in order to understand and modulate the immune status of tumours. Among these cell types, tumour-associated fibroblasts are emerging as a major component of the TME that is often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of tumour-associated fibroblasts in regulating tumour immunity and cancer therapy could provide new insight into targeting the TME in various human cancers. In this review, we summarize recent studies investigating the role of immune and key stromal cells in regulating the immune status of the TME and discuss the therapeutic potential of targeting stromal cells, especially tumour-associated fibroblasts, within the TME as an adjuvant therapy to sensitize immunosuppressive tumours and prevent cancer progression, chemo-resistance and metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: The need for predictive and prognostic biomarkers in colorectal carcinoma (CRC) brought us to an era where the use of artificial intelligence (AI) models is increasing. We investigated the expression of Claudin-7, a tight junction component, which plays a crucial role in maintaining the integrity of normal epithelial mucosa, and its potential prognostic role in advanced CRCs by drawing a parallel between statistical and AI algorithms. Claudin-7 immunohistochemical expression was evaluated in the tumor core and invasion front of CRCs and correlated with clinicopathological parameters and survival using statistical and AI algorithms. The Kaplan–Meier univariate survival analysis showed that the immunohistochemical overexpression of Claudin-7 in the tumor invasive front may represent a poor prognostic factor in advanced stages of CRCs. On the contrary, AI models could not predict the same outcome, probably because of the small number of patients included in our cohort. Aim: The need for predictive and prognostic biomarkers in colorectal carcinoma (CRC) brought us to an era where the use of artificial intelligence (AI) models is increasing. We investigated the expression of Claudin-7, a tight junction component, which plays a crucial role in maintaining the integrity of normal epithelial mucosa, and its potential prognostic role in advanced CRCs, by drawing a parallel between statistical and AI algorithms. Methods: Claudin-7 immunohistochemical expression was evaluated in the tumor core and invasion front of CRCs from 84 patients and correlated with clinicopathological parameters and survival. The results were compared with those obtained by using various AI algorithms. Results: the Kaplan–Meier univariate survival analysis showed a significant correlation between survival and Claudin-7 intensity in the invasive front (p = 0.00), a higher expression being associated with a worse prognosis, while Claudin-7 intensity in the tumor core had no impact on survival. In contrast, AI models could not predict the same outcome on survival. Conclusion: The study showed through statistical means that the immunohistochemical overexpression of Claudin-7 in the tumor invasive front may represent a poor prognostic factor in advanced stages of CRCs, contrary to AI models which could not predict the same outcome, probably because of the small number of patients included in our cohort. [ABSTRACT FROM AUTHOR]

Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment, as an important constituent of neoplastic tissue, has been a promising target for cancer therapy. Triple-negative breast cancer accounts for around 10–20% of invasive breast cancers. This study describes a new cancer-associated fibroblast subtype characterized by high ERα36 levels that secretes HGF, which can impact triple-negative breast cancer. The data enlighten the importance of the stromal effect on the disease course and underlines the significance of further research on the tumor microenvironment and its role in the progression of cancer. Background: Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor microenvironment (TME). Estrogen receptor alpha 36 (ERα36), the alternatively spliced variant of ERα, is described as an unfavorable factor when expressed in cancer cells. ERα can be expressed also in CAFs; however, the role of ERα36 in CAFs is unknown. Methods: Four CAF cultures were isolated from chemotherapy-naïve BC patients and characterized for ERα36 expression and the NanoString gene expression panel using isolated RNA. Conditioned media from CAF cultures were used to assess the influence of CAFs on triple-negative breast cancer (TNBC) cells using a matrigel 3D culture assay. Results: We found that ERα36high CAFs significantly induced the branching of TNBC cells in vitro (p < 0.001). They also produced a set of pro-tumorigenic cytokines compared to ERα36low CAFs, among which hepatocyte growth factor (HGF) was the main inducer of TNBC cell invasive phenotype in vitro (p < 0.001). Tumor stroma rich in ERα36high CAFs was correlated with high Ki67 expression (p = 0.041) and tumor-associated macrophages markers (CD68 and CD163, p = 0.041 for both). HGF was found to be an unfavorable prognostic factor in TCGA database analysis (p = 0.03 for DFS and p = 0.04 for OS). Conclusions: Breast cancer-associated fibroblasts represent distinct subtypes based on ERα36 expression. We propose that ERα36high CAFs could account for an unfavorable prognosis for TNBC patients. [ABSTRACT FROM AUTHOR]

Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a prevalent disease globally, and conventional treatment options have been associated with substantial morbidity for patients. The unique acoustic properties and biological effects of focused ultrasound have been investigated for use as an alternative treatment option for various forms of cancer with lower associated morbidity than standard treatments. The objective of our review was to assess the current state and various applications of focused ultrasound for the treatment of genitourinary cancers, including prostate, kidney, bladder, penile, and testicular malignancies. Current research demonstrates that focused ultrasound-based focal therapy shows promise for the treatment of localized prostate and kidney cancer, and the effect of ultrasound on cell membranes may increase the efficacy of chemotherapeutics and radiotherapy. Focused ultrasound-based treatment modalities should continue to be investigated as an alternative or complementary treatment option for cancer patients. Traditional cancer treatments have been associated with substantial morbidity for patients. Focused ultrasound offers a novel modality for the treatment of various forms of cancer which may offer effective oncological control and low morbidity. We performed a review of PubMed articles assessing the current applications of focused ultrasound in the treatment of genitourinary cancers, including prostate, kidney, bladder, penile, and testicular cancer. Current research indicates that high-intensity focused ultrasound (HIFU) focal therapy offers effective short-term oncologic control of localized prostate and kidney cancer with lower associated morbidity than radical surgery. In addition, studies in mice have demonstrated that focused ultrasound treatment increases the accuracy of chemotherapeutic drug delivery, the efficacy of drug uptake, and cytotoxic effects within targeted cancer cells. Ultrasound-based therapy shows promise for the treatment of genitourinary cancers. Further research should continue to investigate focused ultrasound as an alternative cancer treatment option or as a complement to increase the efficacy of conventional treatments such as chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Patient awareness plays an important role in integrating palliative care into the patient care process. Lack of awareness can create a negative attitude towards palliative care and affect patients' decisions during the treatment process. The present study was conducted to determine the level of knowledge about palliative care in Iranian patients with cancer. Methods: The descriptive study was conducted with a convenience sample of 103 cancer patients admitted to an oncology center in Yazd, Iran, A three-part questionnaire including demographic information, sources of palliative care information and the Palliative Care Knowledge Scale (PaCKS) was used to collect data. All statistical analyses were performed using software SPSS 21. Results: The mean age of patients was 36.2 ± 13.5 years. Of the total, 38.8% of patients received information about palliative care through the media and 36.9% from the treatment team. On a scale of 0 to 13, the mean PaCKS score was 6.7 ± 3.7. A 'good' level of knowledge was reported by 29.1% of participants; however 84.5% stated that they should leave other doctors at the time of receiving palliative care, 71.8% considered palliative care for patients in the last six months of life, 84.5% considered palliative care for patients with cancer, and 70.9% stated that palliative care encourages people to discontinue treatments aimed at treating their disease. Conclusion: Our study found most cancer patients have a moderate to weak level of knowledge and considerable misinformation about palliative care, which highlights the importance of providing palliative care education. The development of training programs in this area could play an effective role in improving patients' knowledge of palliative care. [ABSTRACT FROM AUTHOR]

The ERp57/PDIA3 protein is a pleiotropic member of the PDIs family and, although predominantly located in the endoplasmic reticulum (ER), has indeed been found in other cellular compartments, such as the nucleus or the cell membrane. ERp57/PDIA3 is an important research target considering it can be found in various subcellular locations. This protein is involved in many different physiological and pathological processes, and our review describes new data on its functions and summarizes some ligands identified as PDIA3-specific inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Patients with terminal cancer undergoing multidisciplinary palliative care often have oral health problems, but these details are still unclear. This cross-sectional study aimed to elucidate the oral health of patients with terminal-stage cancer who are inpatient recipients of acute-phase palliative care, and to unveil the factors affecting their oral health. Methods: Participants were 121 patients with terminal-stage cancer (68 males, 53 females, mean age: 73.6 ± 11.1 years) and oral health complaints. They received palliative care at Tokyo Medical and Dental University Medical Hospital between April 2017 and August 2019. Their demographic and medical details were extracted, retrospectively, from their medical records, and their oral health status, such as the number of natural teeth, removable denture usage, Oral Health Assessment Tool (OHAT), and Dysphagia Severity Scale, were evaluated. All outcomes were assessed by a dentist from the palliative care team. Results: The problems with soft tissue, saliva, and oral cleanliness were observed. The absence of posterior occlusal support was common, and the use of removable dentures was often inadequate. In contrast, swallowing function was relatively well-conserved and 46.3% of the participants were capable of nutrition intake solely by mouth. Multiple regression analysis revealed a significant association between total OHAT score and age, consciousness level, prognostic level, and method of nutritional intake. Conclusion: The results revealed that the oral health of terminal cancer patients under palliative care declined despite receiving routine oral care from nurses, and suggest the importance of including dental professionals in multidisciplinary palliative care. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) RNA methylation is a reversible posttranscriptional modification in eukaryotes involving three types of functional proteins: "writers", "erasers", and "readers". m6A regulates the metabolism of messenger RNAs and noncoding RNAs through RNA structure, splicing, stability, export, and translation, thereby participating in various physiological and pathological processes. Here, we summarize the current state of m6A methylation researches, focusing on how these modifications modulate the fate decisions of innate and adaptive immune cells and regulate immune responses in immune‐associated diseases, including viral infections and cancer. These studies showed that m6A modifications and m6A modifying proteins play a critical role in pathogen recognition, immune cell activation, immune cell fate decisions, and immune reactions. m6A is a novel regulator of immune system homeostasis and activation. [ABSTRACT FROM AUTHOR]

Cancer therapy is moving beyond traditional chemotherapy to include epigenetic approaches. KDM6 demethylases are dynamic regulation of gene expression by histone demethylation in response to diverse stimuli, and thus their dysregulation has been observed in various cancers. In this review, we first briefly introduce structural features of KDM6 subfamily, and then discuss the regulation of KDM6, which involves the coordinated control between cellular metabolism (intrinsic regulators) and tumor microenvironment (extrinsic stimuli). We further describe the aberrant functions of KDM6 in human cancers, acting as either a tumor suppressor or an oncoprotein in a context-dependent manner. Finally, we propose potential therapy of KDM6 enzymes based on their structural features, epigenetics, and immunomodulatory mechanisms, providing novel insights for prevention and treatment of cancers. [ABSTRACT FROM AUTHOR]

Background: Bortezomib, a selective inhibitor of 26S proteasome, is commonly used as a chemotherapeutic agent against different types of human cancer cells. While cancer during pregnancy is a rare condition, the trends in becoming pregnant at an advanced age increase the risk of cancer associated with pregnancy. Cancers need to be treated carefully without harming the fetus during pregnancy for the patients who desire to continue their pregnancy. The aim of this study is to demonstrate the potential side effects of bortezomib as this drug has so far not been investigated during preimplantation embryo development. Materials and methods: Two cell stage embryos were flushed from mated female CD1 mice and were cultured. Two‐cell, eight‐cell, and morula stage embryos were exposed to different concentrations of bortezomib in vitro. Morphologic alterations of the embryos were evaluated and the data were statistically analyzed. Results: Our study showed that bortezomib exposure caused a statistically significant decrease in embryo survival and developmental competence and potential rate. We detected those early stages of embryos are more susceptible to bortezomib exposure than later stages. Conclusion: We indicated that bortezomib adversely affects preimplantation embryo development in a dose, time, and developmental stage dependent manner. Moreover, bortezomib treatment inhibits preimplantation embryo development and induces cytoplasmic fragmentation and cell‐cycle arrest on embryos. [ABSTRACT FROM AUTHOR]

Cells contain several proteins that routinely fulfill multiple requirements for normal physiological survival. Proteostasis dysfunction is linked with different complex human disorders, like cancer, neuron degeneration, and imperfect aging. The ubiquitin proteasome system (UPS) forms the primary proteostasis mechanism taking part in cytoprotection. Cancer cells are well known to possess enhanced cytoprotective properties, and different UPS elements are implicated to be dysregulated at several stages of tumor progression. Furthermore, many studies have found tumor cells to exhibit higher levels of various UPS components, possibly contributing to their robust endurance. In this article, we have presented different cellular protein quality control strategies, essential for maintaining healthy proteome. Here, we have also discussed key contributions and functions of UPS involved in molecular pathomechanisms for establishing cancer conditions. Along with this, the emerging different therapeutic strategies against defective proteome linked with improper cellular proliferation and cancer progression are also reviewed. UPS performs critical regulatory functions in modulating the cellular apoptotic pathways. The proteasomal system involvement as probable therapeutic targets influencing cancer cell apoptosis is also discussed. Our article summarizes the recent developments in proteasome-associated pathways regulating tumor cell proteome and survival. Additionally, how the engagement and cross functions of these physiological processes can induce apoptosis and may develop regulation over tumor progression. A better understanding of multifaceted protein quality control pathways may inform therapeutic interventions based on cellular proteostasis response determined against complex diseases. [ABSTRACT FROM AUTHOR]

Liver development is controlled by key signals and transcription factors that drive cell proliferation, migration, differentiation and functional maturation. In the adult liver, cell maturity can be perturbed by genetic and environmental factors that disrupt hepatic identity and function. Developmental signals and fetal genetic programmes are often dysregulated or reactivated, leading to dedifferentiation and disease. Here, we highlight signalling pathways and transcriptional regulators that drive liver cell development and primary liver cancers. We also discuss emerging models derived from pluripotent stem cells, 3D organoids and bioengineering for improved studies of signalling pathways in liver cancer and regenerative medicine. [ABSTRACT FROM AUTHOR]

Immunocompromised patients are a heterogeneous and diffuse category frequently presenting to the emergency department with acute surgical diseases. Diagnosis and treatment in immunocompromised patients are often complex and must be multidisciplinary. Misdiagnosis of an acute surgical disease may be followed by increased morbidity and mortality. Delayed diagnosis and treatment of surgical disease occur; these patients may seek medical assistance late because their symptoms are often ambiguous. Also, they develop unique surgical problems that do not affect the general population. Management of this population must be multidisciplinary. This paper presents the World Society of Emergency Surgery (WSES), Surgical Infection Society Europe (SIS-E), World Surgical Infection Society (WSIS), American Association for the Surgery of Trauma (AAST), and Global Alliance for Infection in Surgery (GAIS) joined guidelines about the management of acute abdomen in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as "erasers" which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR)-modified T cell therapy has shown great potential in the immunotherapy of patients with hematologic malignancies. In spite of this striking achievement, there are still major challenges to overcome in CAR T cell therapy of solid tumors, including treatment-related toxicity and specificity. Also, other obstacles may be encountered in tackling solid tumors, such as their immunosuppressive microenvironment, the heterogeneous expression of cell surface markers, and the cumbersome arrival of T cells at the tumor site. Although several strategies have been developed to overcome these challenges, aditional research aimed at enhancing its efficacy with minimum side effects, the design of precise yet simplified work flows and the possibility to scale-up production with reduced costs and related risks is still warranted. Conclusions: Here, we review main strategies to establish a balance between the toxicity and activity of CAR T cells in order to enhance their specificity and surpass immunosuppression. In recent years, many clinical studies have been conducted that eventually led to approved products. To date, the FDA has approved two anti-CD19 CAR T cell products for non-Hodgkin lymphoma therapy, i.e., axicbtagene ciloleucel and tisagenlecleucel. With all the advances that have been made in the field of CAR T cell therapy for hematologic malignancies therapy, ongoing studies are focused on optimizing its efficacy and specificity, as well as reducing the side effects. Also, the efforts are poised to broaden CAR T cell therapeutics for other cancers, especially solid tumors. [ABSTRACT FROM AUTHOR]

Macrophages are phagocytic sentinel cells of the immune system that are central to both innate and adaptive immune responses and serve as the first line of defense against pathogenic insults to tissues. In the tumor microenvironment, tumor-derived factors induce monocyte polarization towards a pro-tumor phenotype. The pro-tumor macrophages regulate key steps in tumorigenicity including tumor growth, angiogenesis, immune suppression, and metastasis. Macrophage infiltration in solid tumors correlates with poor prognosis and resistance to chemotherapy in most cancers. Here in this review, we will shed light on tumor-associated macrophages (TAMs) in regulating tumorigenicity and TAMs as a prognostic biomarker. Also, we will review the recent advances in targeting TAMs to increase the prognosis of cancer patients. [ABSTRACT FROM AUTHOR]