• Toxoplasma
• Intestinal Protozoan
• Survival
• Therapeutic
• miRNA

• Toxoplasma/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Animals
• Intestines/parasitology
• Toxoplasmosis/parasitology
• Host-Parasite Interactions
• Intestinal Diseases, Parasitic/parasitology

• Apoptosis
• BCL2
• C. parvum
• MiR-181d
• Parasite burden

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Cryptosporidium parvum/genetics
• Cryptosporidium parvum/physiology
• Apoptosis
• Humans
• Cryptosporidiosis/parasitology
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Animals
• Cell Line, Tumor

• Cryptosporidium muris
• Glandular stomach
• Microarray
• Mouse
• microRNA

• Animals
• Humans
• Mice
• Cryptosporidiosis
• Cryptosporidium
• Computational Biology
• Mice, Inbred BALB C
• MicroRNAs/genetics
• Stomach

• Apoptosis
• BCL2A1
• Cryptosporidium parvum
• Parasite burden
• miR-3976

• 2022YFD1800200 National Key Research and Development Program of China
• U2004155 National Natural Science Foundation of China
• 222300420010 Science Fund for Distinguished Young Scholars of Henan Province

• Immunity
• Leishmania major
• Luciferase assay

• Humans
• Programmed Cell Death 1 Receptor/metabolism
• B7-H1 Antigen/metabolism
• Immunosuppression Therapy
• Immune Tolerance
• Sepsis

• National Natural Science Foundation of China
• Tianjin Municipal Health Commission

• PD-1/PD-L1
• chemotherapy
• head and neck squamous cell carcinoma
• immunotherapy
• immunotherapy molecular marker
• immunotherapy resistance
• nivolumab
• pembrolizumab

• Cryptosporidium parvum
• DNA methylation
• Toxoplasma gondii
• epidrugs
• histone modification
• malaria
• miRNA
• non-coding RNA
• parasite infection
• protist

• PD-1/PD-L1
• chemotherapy
• head and neck squamous cell carcinoma
• immunotherapy
• immunotherapy molecular mechanism
• immunotherapy resistance
• metastatic head and neck cancer
• nivolumab
• pembrolizumab

• Cryptosporidium parvum
• HCT-8 cells
• Non-coding RNAs
• RNA-Seq
• Whole transcriptome
• ceRNA

• Apoptosis
• Cryptosporidium parvum
• HCT-8 cell
• Parasite burden
• miR-942-5p

The pathophysiological mechanisms of Cryptosporidium infection are multifactorial and not completely understood. Some advances achieved recently revealed that the infection by Cryptosporidium parvum induces cytoskeleton remodeling and actin reorganization through the implication of several intracellular signals involving, for example, PI3K, Src, Cdc42 and GTPases. It has also been reported that the infection by C. parvum leads to the activation of NF-κβ, known to induce anti-apoptotic mechanisms and to transmit oncogenic signals to epithelial cells. Despite the growing evidence about the hijacking of cellular pathways, potentially being involved in cancer onset, this information has rarely been linked to the tumorigenic potential of the parasite. However, several evidences support an association between Cryptosporidium infection and the development of digestive neoplasia. To explore the dynamics of Cryptosporidium infection, an animal model of cryptosporidiosis using corticoid dexamethasone-treated adult SCID (severe combined immunodeficiency) mice, orally infected with C. parvum or Cryptosporidium muris oocysts was implemented. C. parvum-infected animals developed digestive adenocarcinoma. When mechanisms involved in this neoplastic process were explored, the pivotal role of the Wnt pathway together with the alteration of the cytoskeleton was confirmed. Recently, a microarray assay allowed the detection of cancer-promoting genes and pathways highly up regulated in the group of C. parvum infected animals when compared to non-infected controls. Moreover, different human cases/control studies reported significant higher prevalence of Cryptosporidium infection among patients with recently diagnosed colon cancer before any treatment when compared to the control group (patients without colon neoplasia but with persistent digestive symptoms). These results suggest that Cryptosporidium is a potential oncogenic agent involved in cancer development beyond the usual suspects. If Cryptosporidium is able to hijack signal transduction, then is very likely that this contributes to transformation of its host cell. More research in the field is required in order to identify mechanisms and molecular factors involved in this process and to develop effective treatment interventions.

• Epigenetics
• Hepatocellular carcinoma
• Immunotherapies
• Liver cancer
• Resistance

• CISH
• anti-PD-1/PD-L1 drug resistance
• epitranscriptomics
• immune checkpoint blockage (ICB) therapy
• microRNAs
• personalized medicine

• Adenosine/analogs & derivatives
• Adenosine/chemistry
• Animals
• DNA Methylation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/pathology
• RNA Processing, Post-Transcriptional
• Transcriptome

• 2018R1D1A1B07048567 National Research Foundation of Korea
• SRC-2017R1A5A1014560 National Research Foundation of Korea

• Apoptosis
• Breast cancer
• Migration
• PD-L-1
• Proliferation
• miR-138–5p

MicroRNAs (miRNAs) are a class of non-coding RNAs containing 18–24 nucleotides that are involved in the regulation of many biochemical mechanisms in the human body. The level of miRNAs in body fluids and tissues increases because of altered pathophysiological mechanisms, thus they are employed as biomarkers for various diseases and conditions. In recent years, miRNAs obtained a great interest in many fields of forensic medicine given their stability and specificity. Several specific miRNAs have been studied in body fluid identification, in wound vitality in time of death determination, in drowning, in the anti-doping field, and other forensic fields. However, the major problems are (1) lack of universal protocols for diagnostic expression testing and (2) low reproducibility of independent studies. This review is an update on the application of these molecular markers in forensic biology.

• anti-doping
• biomarkers
• body fluids
• drowning
• microRNAs
• monozygotic twins
• sepsis
• time of death
• wound vitality

• Toll-like Receptor
• microRNA
• sepsis

Micro (mi)RNAs are small noncoding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. This study investigated host miRNA activity in the innate immune response to Cryptosporidium parvum infection.

In vitro infection model adopts HCT-8 human ileocecal adenocarcinoma cells infected with C. parvum. The expression of miR-942-5p was estimated using quantitative real-time polymerase chain reaction (qPCR). The TLRs-NF-κB signaling was confirmed by qPCR, western blotting, TLR4- and TLR2-specific short-interfering (si)RNA, and NF-κB inhibition.

HCT-8 cells express all known toll-like receptors (TLRs). Cryptosporidium parvum infection of cultured HCT-8 cells upregulated TLR2 and TLR4, and downstream TLR effectors, including NF-κB and suppressed IκBα (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha). The expression of miR-942-5p was significantly upregulated at 4, 8, 12 and 24 h post-infection, and especially at 8 hpi. The results of TLR4- and TLR2-specific siRNA and NF-κB inhibition showed that upregulation of miR-942-5p was promoted by p65 subunit-dependent TLR2/TLR4-NF-κB pathway signaling.

miR-942-5p of HCT-8 cells was significantly upregulated after C. parvum infection, especially at 8 hpi, in response to a p65-dependent TLR2/TLR4-NF-κB signaling. TLR4 appeared to play a dominant role.

• Cryptosporidium parvum
• HCT-8
• NF-κB
• TLRs
• miR-942-5p

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

• cancer
• combination approaches
• epigenetics
• immune checkpoint inhibitors
• immunotherapy
• predictive biomarkers
• resistance mechanisms
• tumor immune escape
• tumor microenvironment
• tumor resistance

Breast cancer is the most common type of cancer in women, and the occurrence of metastasis drastically worsens the prognosis and reduces overall survival. Understanding the biological mechanisms that regulate the transformation of malignant cells, the consequent metastatic transformation, and the immune surveillance in the tumor progression would contribute to the development of more effective and targeted treatments. In this context, microRNAs (miRNAs) have proven to be key regulators of the tumor-immune cells crosstalk for the hijack of the immunosurveillance to promote tumor cells immune escape and cancer progression, as well as modulators of the metastasis formation process, ranging from the preparation of the metastatic site to the transformation into the migrating phenotype of tumor cells. In particular, their deregulated expression has been linked to the aberrant expression of oncogenes and tumor suppressor genes to promote tumorigenesis. This review aims at summarizing the role and functions of miRNAs involved in antitumor immune response and in the metastasis formation process in breast cancer. Additionally, miRNAs are promising targets for gene therapy as their modulation has the potential to support or inhibit specific mechanisms to negatively affect tumorigenesis. With this perspective, the most recent strategies developed for miRNA-based therapeutics are illustrated.

• NK cells
• bone metastases
• breast cancer
• immune evasion
• miRNA-based therapeutics
• miRNAs

• AKT pathway
• PD-1
• PD-L1 (B7-H1)
• immune checkpoint inhibitors
• monoclonal gammopathy of undetermined significance (MGUS)
• multiple myeloma

• PD-1
• PD-L1
• exosome
• immune checkpoint blockade
• immunotherapy
• microRNAs
• transcriptional factors

• Immune checkpoint blockade
• Noncoding RNA
• PD-1/PD-L1 pathway
• microRNA

• Animals
• B7-H1 Antigen/immunology
• Humans
• Neoplasms/immunology
• Programmed Cell Death 1 Receptor/immunology
• RNA, Untranslated

• 81572122 National Natural Science Foundation of China

Based on genome sequencing, it is estimated that over 90% of genes stored in human genetic material are transcribed, but only 3% of them contain the information needed for the production of body proteins. This group also includes micro RNAs representing about 1%–3% of the human genome. Recent studies confirmed the hypothesis that targeting molecules called Immune Checkpoint (IC) open new opportunities to take control over glioblastoma multiforme (GBM). Detection of markers that indicate the presence of the cancer occupies a very important place in modern oncology. This function can be performed by both the cancer cells themselves as well as their components and other substances detected in the patients’ bodies. Efforts have been made for many years to find a suitable marker useful in the diagnosis and monitoring of gliomas, including glioblastoma.

• glioblastoma multiforme
• glioma
• immune checkpoints
• micro RNA
• tumor

• Biomarkers, Tumor/genetics
• Brain Neoplasms/diagnosis
• Brain Neoplasms/genetics
• Brain Neoplasms/therapy
• Gene Expression Regulation, Neoplastic
• Genome, Human/genetics
• Glioblastoma/diagnosis
• Glioblastoma/genetics
• Glioblastoma/therapy
• Glioma/diagnosis
• Glioma/genetics
• Glioma/therapy
• Humans
• Medical Oncology/methods
• Medical Oncology/statistics & numerical data
• MicroRNAs/genetics
• Sensitivity and Specificity

• Cancer immune evasion
• PD-1
• PD-L1
• Self-tolerance
• T cell inhibition

• Animals
• B7-H1 Antigen/metabolism
• Humans
• Immunotherapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Programmed Cell Death 1 Receptor/metabolism
• Signal Transduction
• Tumor Microenvironment

• PD-L1 expression
• anti-PD-1/PD-L1
• extrinsic signals
• immune checkpoint therapy
• intrinsic signals

• Animals
• Antineoplastic Agents, Immunological/therapeutic use
• B7-H1 Antigen/genetics
• B7-H1 Antigen/immunology
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/therapy
• Programmed Cell Death 1 Receptor/genetics
• Programmed Cell Death 1 Receptor/immunology
• Programmed Cell Death 1 Receptor/metabolism
• Signal Transduction

• cancer
• checkpoint molecules
• microRNAs
• therapy

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

• Inflammatory factor
• PD-1
• PD-L1
• Tumor immune escape
• Tumor microenvironment

For years, procalcitonin (PCT) has been employed as a diagnostic biomarker for the severity of sepsis and septic shock, as well as for guiding the application of antibiotics. However, the molecular/cellular basis for the regulation of PCT production is not fully understood. In this study, we identified the signalling pathway by which the expression of PCT was induced by lipopolysaccharide in human hepatocytes at the mRNA and protein levels. This expression was dependent on nuclear transcription factor κB (NF-κB), as indicated by a NF-κB binding site (nt −53 to −44) found in the PCT promoter region. We also showed that microRNA-513b (miR-513b) was also able to bind to the 3′-untranslated region (UTR) of the PCT promoter sequence. Meanwhile, the activation of NF-κB down-regulated the expression of miR-513b. In conclusion, we suggest that NF-κB is capable of enhancing the expression of PCT by either directly activating the transcription of the PCT gene or indirectly modulating the expression of its regulatory component, miR-513b. Our results indicate a molecular mechanism responsible for the regulation of PCT production.

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

• Bromodomain and extraterminal inhibitors
• Histone deacetylase
• Immune checkpoint inhibitors
• MicroRNA
• Multiple myeloma
• Oncolytic reovirus
• PD-1
• PD-L1

• Animals
• B7-H1 Antigen/antagonists & inhibitors
• B7-H1 Antigen/physiology
• Gene Expression Regulation
• Humans
• Immunotherapy
• Lymphocyte Activation/drug effects
• Lymphocyte Activation/genetics
• Lymphocyte Activation/immunology
• Molecular Targeted Therapy
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/therapy
• Programmed Cell Death 1 Receptor/metabolism
• Signal Transduction
• T-Lymphocytes/drug effects
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism

• 742259 European Research Council

• immune checkpoint
• microRNAs
• programmed death 1(PD-1)
• programmed death-ligand 1 (PD-L1)

• Animals
• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• Humans
• Immunotherapy/methods
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/therapy
• Programmed Cell Death 1 Receptor/genetics
• Programmed Cell Death 1 Receptor/metabolism

• biomarker
• critical illness
• miRNA
• sepsis

• Animals
• Biomarkers/blood
• Gene Expression Regulation
• Humans
• MicroRNAs/blood
• MicroRNAs/genetics
• Prognosis
• Sepsis/blood
• Sepsis/diagnosis
• Sepsis/genetics
• Sepsis/physiopathology

• 208237 European Research Council

• Akt
• HIF-1Α
• MAPK
• NF-κB
• STAT3
• immune checkpoint

Toll-like receptor 4 (TLR4), as one of the most important pathogen pattern recognitions (PPRs) plays a central role in elicitation of innate immunity and mediation of adaptive responses against foreign antigens. However, little is known of the roles of TLR4 in the immune responses of biliary epithelial cells (BECs) induced by Clonorchis sinensis, a parasite of significance in human health.

In the present study, the primary mouse intrahepatic biliary epithelial cells (MIBECs) were pre-treated with TLR4 inhibitor peptide or control peptide and then stimulated by excretory/secretory products (ESP) of C. sinensis, respectively. The expressions of TLR4 and relative cytokines were determined using western blot and a bead-based analytic detection system, respectively.

The results showed that ESP of C. sinensis significantly increased the expression of TLR4 which promoted the expression of MyD88 and NF-κB in BECs; the levels of TNF-α but not IL-6 from MIBECs stimulated by ESP alone were also considerably increased, compared with the group of the medium stimulated. However, the concentration of TNF-α was significantly decreased when MIBECs were pre-treated with TLR4 inhibitor. In addition, ESP could depress the level of IL-6 in MIBECs which was elevated by LPS.

Our data for the first time demonstrate that ESP of C. sinensis can potently induce secretion of pro-inflammatory cytokines via TLR4 in MIBECs, which suggests that TLR4 plays an important role in host defenses against C. sinensis and the pathogenesis of clonorchiasis.

MicroRNAs (miRNAs) are small, non-coding single-stranded RNAs that can modulate target gene expression at post-transcriptional level and participate in cell proliferation, differentiation, and apoptosis. T cells have important functions in acquired immune response; miRNAs regulate this immune response by targeting the mRNAs of genes involved in T cell development, proliferation, differentiation, and function. For instance, miR-181 family members function in progression by targeting Bcl2 and CD69, among others. MiR-17 to miR-92 clusters function by binding to CREB1, PTEN, and Bim. Considering that the suppression of T cell-mediated immune responses against tumor cells is involved in cancer progression, we should investigate the mechanism by which miRNA regulates T cells to develop new approaches for cancer treatment.

• MicroRNA
• T cell
• gene expression

Simple, reliable tools for diagnosis of human African Trypanosomiases could ease field surveillance and enhance patient care. In particular, current methods to distinguish patients with (stage II) and without (stage I) brain involvement require samples of cerebrospinal fluid. We describe here an exploratory study to find out whether miRNAs from peripheral blood leukocytes might be useful in diagnosis of human trypanosomiasis, or for determining the stage of the disease. Using microarrays, we measured miRNAs in samples from Trypanosoma brucei gambiense-infected patients (9 stage I, 10 stage II), 8 seronegative parasite-negative controls and 12 seropositive, but parasite-negative subjects. 8 miRNAs (out of 1205 tested) showed significantly lower expression in patients than in seronegative, parasite-negative controls, and 1 showed increased expression. There were no clear differences in miRNAs between patients in different disease stages. The miRNA profiles could not distinguish seropositive, but parasitologically negative samples from controls and results within this group did not correlate with those from the trypanolysis test. Some of the regulated miRNAs, or their predicted mRNA targets, were previously reported changed during other infectious diseases or cancer. We conclude that the changes in miRNA profiles of peripheral blood lymphocytes in human African trypanosomiasis are related to immune activation or inflammation, are probably disease-non-specific, and cannot be used to determine the disease stage. The approach has little promise for diagnostics but might yield information about disease pathology.

• Biomarkers/blood
• Gene Expression Profiling
• Humans
• Leukocytes/metabolism
• MicroRNAs/blood
• Microarray Analysis
• Models, Molecular
• RNA, Messenger/blood
• Real-Time Polymerase Chain Reaction
• Transcriptome
• Trypanosoma brucei gambiense
• Trypanosomiasis, African/blood

• Androgen receptor
• Phenethyl isothiocyanate
• Prostate cancer
• miR-17
• p300/CBP-associated factor

• cholangiocytes
• cholangiopathy
• biliary
• reactivity
• repair

• Bile Duct Diseases/etiology
• Bile Duct Diseases/pathology
• Biliary Tract/cytology
• Cystic Fibrosis Transmembrane Conductance Regulator/physiology
• Epithelial Cells/physiology
• Humans
• Toll-Like Receptors/physiology

• R01 AI089713 NIAID NIH HHS
• R01 DK057993 NIDDK NIH HHS
• P30DK084567 NIDDK NIH HHS
• P30 DK084567 NIDDK NIH HHS
• R01 DK024031 NIDDK NIH HHS
• DK024031 NIDDK NIH HHS

• helminth
• miRNA
• neoblast
• protozoan
• snoRNA

• Blotting, Western
• Cell Line, Tumor
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Isothiocyanates/pharmacology
• Male
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Oligonucleotides, Antisense/genetics
• Oligonucleotides, Antisense/pharmacology
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• RNA/genetics
• RNA/metabolism
• Real-Time Polymerase Chain Reaction
• Receptors, Androgen/genetics
• Receptors, Androgen/metabolism
• Receptors, Cytoplasmic and Nuclear/biosynthesis
• Receptors, Cytoplasmic and Nuclear/genetics
• Receptors, Cytoplasmic and Nuclear/metabolism
• Transcription, Genetic
• Up-Regulation