Conserved angio-immune subtypes of the cancer microenvironment predict response to immune checkpoint blockade therapy

Tumor microenvironment (TME) shapes the tumor progression and therapy outcome. Particularly, tumor angiogenesis and immunity impact the effect of immune checkpoint blockade (ICB) therapy. Here, we analyzed the transcriptome from 11,069 patients from The Cancer Genome Atlas (TCGA) to assess 91 functional gene sets corresponding to endothelial and T-cell activity. Intriguingly, TME across 30 non-hematological tumors can be classified into three distinct conserved angio-immune subtypes: high angiogenesis with low immune activity, low angiogenesis with high immune activity, and the one in-between. Remarkably, patients displaying TME with poor angiogenic activity with corresponding high immune activity show the most significant responses to ICB therapy in many cancer types. Notably, re-evaluation of the Javelin Renal 101, renal cell carcinoma clinical trial, provided compelling evidence that the baseline angiogenic state is critical in determining responses to checkpoint blockade. This study offers a clear rationale for incorporating baseline angiogenic state for ICB treatment decision-making.

Application of Dynamic Enhanced Magnetic Resonance Imaging in the Diagnosis of Hematological Malignancies

The use of dynamic enhanced magnetic resonance imaging technology can effectively explore the diagnosis and clinical application of hematological malignancies. This paper selected 60 patients with hematological malignancies from 2015 to 2019; all of whom were diagnosed with hematological malignancies, including 40 men and 20 women, aged between 40 and 77 years. The main clinical manifestations of the patient are hematological malignancies, fever, and other symptoms. We used Siemens 3.0T to perform MRI and dynamic enhanced MRI examinations on 30 patients with hematological tumors. The PACS system was used to collect and organize clinical data. All patients were pathologically confirmed and clinically diagnosed with hematological malignancies. Based on the clinical data of the patients, retrospective analysis and summary were conducted and the clinical manifestations of hematological malignancies were discussed. The results showed that the diagnostic accuracy of 30 cases of dynamic enhanced MRI was 100%, while the diagnostic accuracy of ordinary MRI was lower than that of dynamic enhanced MRI, P < 0.05 , and the difference was statistically significant. In addition, compared with dynamic enhanced MRI and MRI, P > 0.05 , the difference was not statistically significant. Therefore, the application of dynamic enhanced MRI in the diagnosis of hematological malignancies is valuable.

A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC50 values ranging from 5.7 to 10.7 µM. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC.

Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML

The histone demethylase LSD1 is over-expressed in hematological tumors and has emerged as a promising target for anticancer treatment, so that several LSD1 inhibitors are under development and testing, in preclinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unraveled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the downregulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viability in vitro and of tumor growth in vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine-signaling pathways are upregulated by LSD1 inhibitors through GSE1-protein reduction and that LSD1 and GSE1 colocalize at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights into GSE1 as a novel therapeutic target for AML.

Intelligent Internet of Things Medical Technology in Implantable Intravenous Infusion Port in Children with Malignant Tumors

Due to the recent technological revolution that is centered around information technology, the Internet of Medical Things (IoMT) has become an important research domain. IoMT is a combination of Internet of Things (IoT), big data, cloud computing, ubiquitous network, and three-dimensional holographic technology, which is used to build a smart medical diagnosis and treatment system. Additionally, this system should automate various activities, such as the patient’s health record and health monitoring, which is an important issue in the development of modern and smart healthcare system. In this paper, we have thoroughly examined the role of a smart healthcare system architecture and other key supporting technologies in improving the health status of both indoor and outdoor patients. The proposed system has the capacity to investigate and predict (if feasible) the clinical application and nursing effects of totally implantable intravenous port (TIVAP) in pediatric hematological tumors. For this purpose, seventy children with hematologic tumors were treated with TIVAP, and IoMT-enabled care was provided to them, where the occurrence of adverse events, specifically after the treatment, was observed. The experimental results collected after the 70 children were treated and cared for by TIVAP show that there were five cases of adverse events, whereas the incidence rate of the adverse events was 7.14%. Moreover, TIVAP has significant efficacy in the treatment of hematologic tumors in children, and it equally reduces the vascular injury caused by chemotherapy in younger patients. Likewise, targeted care reduces the incidence of adverse events in children with expected ratio.

Hematologic Neoplasms As Risk Factor For Severe COVID-19: A Systematic Review Protocol

Background: Patients with hematologic neoplasm may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. However, the studies bring together patients with hematologic neoplasms and solid tumors into a single group, making no distinction about the types of hematological tumors and their treatments. This systematic review is designed to explore the risk of severe COVID-19 in patients with hematologic neoplasm. Studies about patients, adult or children, with hematologic neoplasm and COVID-19 will be included. Methods: A systematic review according to Joanna Briggs Institute methodology for systematic reviews of etiology and risk will be performed. The review will consider as participants adults or children with COVID-19 infection detected by RT-PCR or serology (SARS-CoV-2 antibody). We will be included studies without routine labs confirmation of COVID-19 if the patients presented clinical/physical exam and computed tomography suggesting COVID-19. The exposure of interest will be hematologic neoplasm, which include lymphomas, acute and chronic leukemias, myeloma, myelodysplastic syndrome, and myeloproliferative diseases. We will consider cohort, case-control, analytical cross-sectional studies. Outcomes among patients with COVID-19 are critical symptoms, hospitalizations, intensive care unit admissions, mechanical ventilation and deaths. We will exclude studies with other neoplasms than hematologic neoplasms. Search strategies have been created for the Embase, Medline and LILACS. Two reviewers independently will assess the studies for their eligibility, will extract data and will evaluate their risk of bias. Similar outcomes measured in at least two studies will be plotted in the meta-analysis using the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information. Discussion: This systematic review aims to evaluate if patients with hematologic neoplasm may be at elevated risk of severe COVID-19. This review will differ from the previous ones because we will include controlled studies and groups with only hematologic neoplasm, excluding other cancers. The main hypothesis of our research is that not all hematological cancer patients have high risk of severe COVID-19. Trial registration number: PROSPERO CRD42020199318.

Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges

Chimeric antigen receptor T (CAR-T) cell therapy has exhibited a substantial clinical response in hematological malignancies, including B-cell leukemia, lymphoma, and multiple myeloma. Therefore, the feasibility of using CAR-T cells to treat solid tumors is actively evaluated. Currently, multiple basic research projects and clinical trials are being conducted to treat lung cancer with CAR-T cell therapy. Although numerous advances in CAR-T cell therapy have been made in hematological tumors, the technology still entails considerable challenges in treating lung cancer, such as on−target, of−tumor toxicity, paucity of tumor-specific antigen targets, T cell exhaustion in the tumor microenvironment, and low infiltration level of immune cells into solid tumor niches, which are even more complicated than their application in hematological tumors. Thus, progress in the scientific understanding of tumor immunology and improvements in the manufacture of cell products are advancing the clinical translation of these important cellular immunotherapies. This review focused on the latest research progress of CAR-T cell therapy in lung cancer treatment and for the first time, demonstrated the underlying challenges and future engineering strategies for the clinical application of CAR-T cell therapy against lung cancer.

The Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors

NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based therapies are undergoing clinical trials and show considerable effectiveness for hematological tumors. In these types of cancers, the immune cells themselves often undergo malignant transformation, which determines the features of the disease. In contrast, the current use of NK cells as therapeutic agents for the treatment of solid tumors is much less promising. Most studies are at the stage of preclinical investigation, but few progress to clinical trials. Low efficiency of NK cell migration and functional activity in the tumor environment are currently considered the major barriers to NK cell anti-tumor therapies. Various therapeutic combinations, genetic engineering methods, alternative sources for obtaining NK cells, and other techniques are aiming at the development of promising NK cell anticancer therapies, regardless of tumorigenesis. In this review, we compare the role of NK cells in the pathogenesis of hematological and solid tumors and discuss current prospects of NK-cell-based therapy for hematological and solid tumors.

Nicotinamide Riboside for the Prevention and Treatment of Doxorubicin Cardiomyopathy. Opportunities and Prospects

Despite the progress in the development of new anticancer strategies, cancer is rapidly spreading around the world and remains one of the most common diseases. For more than 40 years, doxorubicin has been widely used in the treatment of solid and hematological tumors. At the same time, the problem of its cardiotoxicity remains unresolved, despite the high efficiency of this drug. Symptomatic therapy is used as a treatment for side-effects of doxorubicin or pathological conditions that have already appeared in their background. To date, there are no treatment methods for doxorubicin cardiomyopathy as such. A drug such as nicotinamide riboside can play an important role in solving this problem. Nicotinamide riboside is a pyridine nucleoside similar to vitamin B3 that acts as a precursor to NAD+. There is no published research on nicotinamide riboside effects on cardiomyopathy, despite the abundance of works devoted to the mechanisms of its effects in various pathologies. The review analyzes information about the effects of nicotinamide riboside on various experimental models of pathologies, its role in the synthesis of NAD+, and also considers the possibility and prospects of its use for the prevention of doxorubicin cardiomyopathy.

The Role of Gut Microbiota in Tumor Immunotherapy

Tumor immunotherapy is the fourth therapy after surgery, chemotherapy, and radiotherapy. It has made great breakthroughs in the treatment of some epithelial tumors and hematological tumors. However, its adverse reactions are common or even more serious, and the response rate in some solid tumors is not satisfactory. With the maturity of genomics and metabolomics technologies, the effect of intestinal microbiota in tumor development and treatment has gradually been recognized. The microbiota may affect tumor immunity by regulating the host immune system and tumor microenvironment. Some bacteria help fight tumors by activating immunity, while some bacteria mediate immunosuppression to help cancer cells escape from the immune system. More and more studies have revealed that the effects and complications of tumor immunotherapy are related to the composition of the gut microbiota. The composition of the intestinal microbiota that is sensitive to treatment or prone to adverse reactions has certain characteristics. These characteristics may be used as biomarkers to predict the prognosis of immunotherapy and may also be developed as “immune potentiators” to assist immunotherapy. Some clinical and preclinical studies have proved that microbial intervention, including microbial transplantation, can improve the sensitivity of immunotherapy or reduce adverse reactions to a certain extent. With the development of gene editing technology and nanotechnology, the design and development of engineered bacteria that contribute to immunotherapy has become a new research hotspot. Based on the relationship between the intestinal microbiota and immunotherapy, the correct mining of microbial information and the development of reasonable and feasible microbial intervention methods are expected to optimize tumor immunotherapy to a large extent and bring new breakthroughs in tumor treatment.