Six-Gene Signature for Differential Diagnosis and Therapeutic Decisions in Non-Small-Cell Lung Cancer-A Validation Study.

Non-small-cell lung cancer (NSCLC) poses a challenge due to its heterogeneity, necessitating precise histopathological subtyping and prognostication for optimal treatment decision-making. Molecular markers emerge as a potential solution, overcoming the limitations of conventional methods and supporting the diagnostic-therapeutic interventions. In this study, we validated the expression of six genes (MIR205HG, KRT5, KRT6A, KRT6C, SERPINB5, and DSG3), previously identified within a 53-gene signature developed by our team, utilizing gene expression microarray technology. Real-time PCR on 140 thoroughly characterized early-stage NSCLC samples revealed substantial upregulation of all six genes in squamous cell carcinoma (SCC) compared to adenocarcinoma (ADC), regardless of clinical factors. The decision boundaries of the logistic regression model demonstrated effective separation of the relative expression levels between SCC and ADC for most genes, excluding KRT6C. Logistic regression and gradient boosting decision tree classifiers, incorporating all six validated genes, exhibited notable performance (AUC: 0.8930 and 0.8909, respectively) in distinguishing NSCLC subtypes. Nevertheless, our investigation revealed that the gene expression profiles failed to yield predictive value regarding the progression of early-stage NSCLC. Our molecular diagnostic models manifest the potential for an exhaustive molecular characterization of NSCLC, subsequently informing personalized treatment decisions and elevating the standards of clinical management and prognosis for patients.

Flake Graphene-Based Nanomaterial Approach for Triggering a Ferroptosis as an Attractive Theranostic Outlook for Tackling Non-Small Lung Cancer: A Mini Review.

Lung cancer is a highly aggressive neoplasm that is now a leading cause of cancer death worldwide. One of the major approaches for killing cancer cells is related with activation of apoptotic cell death with anti-cancer drugs. However, the efficiency of apoptosis induction in tumors is limited. Consequently, the development of other forms of non-apoptotic cell death is up to date challenge for scientists worldwide. This situation motivated us to define the aim of this mini-review: gathering knowledge regarding ferroptosis-newly defined programmed cell death process characterized by the excessive accumulation of iron-and combining it with yet another interesting nanomaterial-based graphene approach. In this manuscript, we presented brief information about non-small lung cancer and ferroptosis, followed by a section depicting the key-features of graphene-based nanomaterials influencing their biologically relevant properties.

Anti-Jagged-1 immunotherapy in cancer.

Notch signaling is a highly conserved pathway and it plays an essential role in regulating cellular proliferation, differentiation, and apoptosis. The human Notch family includes four receptors, Notch 1-4, and five ligands, delta-like ligand 1 (DLL1), delta-like ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2). It is widely known, that Notch signaling components are often mutated and have deregulated expression in many types of cancer and other diseases. Thus, various therapeutic approaches targeting receptors and ligands of the Notch pathway are being investigated. Human JAG1 is closely related to tumor biology among the Notch ligands, and recent studies have shown potential for monoclonal antibodies targeting JAG1 in cancer therapy. Therefore, this review focuses on current reports on the significance of JAG1 directed cancer treatment, emphasizing immunotherapy.

A brief overview of clinical significance of novel Notch2 regulators.

The Notch pathway is an essential signaling system allowing neighboring cells to communicate and accomplish their proper developmental role in physiological condition. Nevertheless, there are many controversies conferring its function in pathological condition, particularly in cancer. It has been discovered that epigenetic regulation, posttranslational modifications, gene overexpression, and mutations may lead to the dysregulation of the Notch pathway. Additionally, Notch-mediated signaling can support tumor-suppressing mechanisms in certain types of cancer or may have oncogenic functions in others. Notch2 is one of the receptors commonly expressed in a variety of cancer cells, including gastric, hematological, and lung cancer. Moreover, it can be dysregulated in other diseases. In efforts to explain the role of Notch2 in the pathogenesis of cancer, recent studies indicated an association between this receptor and dysregulation of miRNAs, tumor-associated stromal cell, and modulation in tumor cells. Consequently, Notch2 function in the carcinogenesis process is unquestionable, whereas information according to the effect of its inhibition in tumor is still obscure. Hence, the aim of our study was to evaluate the current state of knowledge conferring Notch2 inhibition, with a particular focus on its role in cancer.

JAG1 overexpression contributes to Notch1 signaling and the migration of HTLV-1-transformed ATL cells.

BACKGROUND: HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms. METHODS: We analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells. RESULTS: Here, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells. CONCLUSIONS: Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.

Current views on the role of Notch signaling and the pathogenesis of human leukemia.

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.

Epidemiological features of patients infected with HCV genotype 4 in Poland: Epidemiology of HCV genotype 4 in Poland.

BACKGROUND: Hepatitis C genotype 4 (HCV-4) is considered to be rare outside northern Africa and southern Europe. OBJECTIVES: To describe the epidemiological characteristics of patients infected with HCV-4 in Poland. PATIENTS AND METHODS: The study group included 290 patients with HCV-related chronic liver disease and intravenous drug users with HCV infection recruited in years 2002-2006 in Podlaskie region, north-eastern Poland. In all cases, HCV infection was confirmed by HCV-RNA detection by qualitative nested RT-PCR. HCV genotype was determined by 5'UTR sequencing and comparison with known genotype-specific sequences. RESULTS: HCV 4 was found in 45 (15.5%) of 290 HCV-infected and HCV RNA-positive individuals. 60% of HCV 4 infections occurred in intravenous drug users; 51% of HCV 4-infected patients were also HIV-positive. Among 119 patients whose source of infection was other than drug use, there were 16 (10.5%) HCV 4 cases. Seven (46%) of 13 HCV 4-positive and HIV-negative patients who received combined antiviral treatment had sustained viral response. CONCLUSIONS: HCV 4 exists in eastern Poland, and the infection is frequently related to intravenous drug use and accompanied by HIV infection. HCV 4 also causes a proportion of non-drug-related HCV infections.

Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair.

Whereas oncogenic retroviruses are common in animals, human T-lymphotropic virus 1 (HTLV-1) is the only transmissible retrovirus associated with cancer in humans and is etiologically linked to adult T-cell leukemia. The leukemogenesis process is still largely unknown, but relies on extended survival and clonal expansion of infected cells, which in turn accumulate genetic defects. A common feature of human tumor viruses is their ability to stimulate proliferation and survival of infected pretumoral cells and then hide by establishing latency in cells that have acquired a transformed phenotype. Whereas disruption of the DNA repair is one of the major processes responsible for the accumulation of genomic abnormalities and carcinogenesis, the absence of DNA repair also poses the threat of cell-cycle arrest or apoptosis of virus-infected cells. This study describes how the HTLV-1 p30 viral protein inhibits conservative homologous recombination (HR) DNA repair by targeting the MRE11/RAD50/NBS1 complex and favors the error-prone nonhomologous-end-joining (NHEJ) DNA-repair pathway instead. As a result, HTLV-1 p30 may facilitate the accumulation of mutations in the host genome and the cumulative risk of transformation. Our results provide new insights into how human tumor viruses may manipulate cellular DNA-damage responses to promote cancer.

HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression.

BACKGROUND: Human T-cell leukemia virus type I (HTLV-I) has efficiently adapted to its host and establishes a persistent infection characterized by low levels of viral gene expression and slow proliferation of HTLV-I infected cells over decades. We have previously found that HTLV-I p30 is a negative regulator of virus expression. RESULTS: In this study we show that p30 targets multiple cell cycle checkpoints resulting in a delayed entry into S phase. We found that p30 binds to cyclin E and CDK2 and prevents the formation of active cyclin E-CDK2 complexes. In turn, this decreases the phosphorylation levels of Rb and prevents the release of E2F and its transcriptional activation of genes required for G1/S transition. Our studies also show that HTLV-II p28 does not bind cyclin E and does not affect cell cycle progression. CONCLUSIONS: In contrast to HTLV-I, the HTLV-II-related retrovirus is not oncogenic in humans. Here we report that the HTLV-I p30 delays cell cycle progression while its homologue, HTLV-II p28, does not, providing evidence for important differences between these two related retrovirus proteins.

Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia.

The Notch signaling pathway plays an important role in cellular proliferation, differentiation, and apoptosis. Unregulated activation of Notch signaling can result in excessive cellular proliferation and cancer. Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). The disease has a dismal prognosis and is invariably fatal. In this study, we report a high frequency of constitutively activated Notch in ATL patients. We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. Compared with the exclusive activating frameshift mutations in the proline, glutamic acid, serine, and threonine (PEST) domain in T-ALLs, those in ATLs have, in addition, single-substitution mutations in this domain leading to reduced CDC4/Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch1 (ICN1). Finally, we demonstrated that inhibition of Notch signaling by γ-secretase inhibitors reduced tumor cell proliferation and tumor formation in ATL-engrafted mice. These data suggest that activated Notch may be important to ATL pathogenesis and reveal Notch1 as a target for therapeutic intervention in ATL patients.

Evaluation of distant results after lamivudine discontinuation in children with chronic hepatitis B.

The aim of this study was to estimate distant results after discontinuation of long term lamivudine treatment in children with chronic hepatitis B. Furthermore, the emergence of HBV polymerase gene variants in YMDD motif during therapy was examined. Additionally, the most commonly occurring type of mutation in the polymerase YMDD region were investigated. The study involved 27 HBeAg positive children with chronic hepatitis B. Children included to lamivudine therapy were previously treated without effects with interferon alpha.