The cell survival pathways of the primordial RNA-DNA complex remain conserved in the extant genomes and may function as proto-oncogenes.

Malignantly transformed (cancer) cells of multicellular hosts, including human cells, operate activated biochemical pathways that recognizably derived from unicellular ancestors. The descendant heat shock proteins of thermophile archaea now chaperon oncoproteins. The ABC cassettes of toxin-producer zooxantella Symbiodinia algae pump out the cytoplasmic toxin molecules; malignantly transformed cells utilize the derivatives of these cassettes to get rid of chemotherapeuticals. High mobility group helix-loop-helix proteins, protein arginine methyltransferases, proliferating cell nuclear antigens, and Ki-67 nuclear proteins, that protect and repair DNA in unicellular life forms, support oncogenes in transformed cells. The cell survival pathways of Wnt-ß-catenin, Hedgehog, PI3K, MAPK-ERK, STAT, Ets, JAK, Pak, Myb, achaete scute, circadian rhythms, Bruton kinase and others, which are physiological in uni- and early multicellular eukaryotic life forms, are constitutively encoded in complex oncogenic pathways in selected single cells of advanced multicellular eukaryotic hosts. Oncogenes and oncoproteins in advanced multicellular hosts recreate selected independently living and immortalized unicellular life forms, which are similar to extinct and extant protists. These unicellular life forms are recognized at the clinics as autologous "cancer cells".

"Up-dating the monograph." [corrected] Cytolytic immune lymphocytes in the armamentarium of the human host.

The author of the monograph "Cytolytic Immune Lymphocytes..." (published in 2008 by Schenk Buchverlag Campus Dialog, Budapest, Passau, Pécs) proposed several research projects and described certain clinical events that require further elaboration and documentation. In this article the author provides what is required and has since become available. The first subject matter in question concerns the fusogenic viruses. The ancient fusogenic viruses might have created the first eukaryotic cell(s) by uniting archaeabacterial and prokaryotic/protobacterial protospheroplasts. Extant fusogenic viruses either produce tumor cell syncytia and lyse them, thus practicing viral oncolysis. Or, create chimaeric fusion products, the so-called "natural hybridomas", of lymphoma cells exhibiting transmembrane budding of retrovirus particles or envelope proteins, and anti-viral specific antibody-producing plasma cells. The second topic concerns the horizontal-lateral mode of acquisition of those genes, which were "present in the waiting" in the amphioxus, sea urchin, and the agnathans, and met in the primitive gnatostomata sharks to encode in unison the entire adaptive immune system. The consensus of opinion is such that these genes derived from newly acquired transposons/retrotransposons. The author points out that the extant Epstein-Barr virus harbors genes displaying sequence homology with those genes from the sharks up to mammals that regulate the somatic hypermutation of specific antibody production. The author proposes that an ancient herpesvirus might have propagated the V(D)J and RAG genes from sea urchins to sharks. The third area is that of lymphocytes cytotoxic/cytolytic to virally infected or malignantly transformed host cells. This discovery led to the adoptive immune lymphocyte therapy of tumors. Installed in the adaptive immune system are regulatory T cells and myeloid-derived suppressor cells for he protection of "self". Tumor cells masquerading as "self" are protected by these cells from attacks launched by immune T cells. The author supports the replacement of IL-2 by IL-15, inasmuch as IL-2 stimulates not only immune T cells, but also regulatory T cells expressing the CD25 IL-2 receptor. The administration of low dose whole body radiotherapy prior to immune lymphocyte therapy increases the efficacy of immune lymphocyte therapy. The author observed this phenomenon in the mid-1960s. The explanation of this phenomenon revealed itself just recently. In pre-irradiated hosts the intestinal wall becomes permeable to the gut flora; the intestinal bacteria activate the entire innate immune system in the mesenteric lymph nodes and a rapid activation of the adaptive immune faculties follows.

The molecular biology and immunology of glioblastoma multiforme (GBM) with the presentation of an immunotherapy protocol for a clinical trial.

After a short explanatory Introduction, an immunotherapy protocol is presented for glioblastoma multiforme (GBM). GBM is considered to be an incurable tumor; tumor-free survival over 2 to 3 years is so rare that when it happens the original diagnosis is questioned. It is known that the type of the genetic mutation that a given GBM tumor harbors strongly influences the length of survival. However, most patients with GBM are receiving treatment without the preparation of a microarray gene map of their tumors. It is possible that the reason for a rare and exceptional long survival was not the treatment that the patient received, but the type of gene mutations that the tumor was exposed to. It is recognized that any therapeutic approach should ideally be evaluated against the background of all prognostic factors of each individual case, prominent among them the microarray gene map of the tumor. In practice, this is not easily achieved, while the patient is in need of, and is expecting, prompt therapy. Insurance companies do not reimburse the patient, or the clinical investigators, or their institutions for investigational diagnostic tests, or such treatment modalities. A temporary compromise is possible. The emergence of empirically administered treatment modalities with extraordinary efficacy has occasionally been recorded in the history of medical oncology. In some of these rare clinical trials, the control groups were discontinued (to the dismay of the statisticians), and the control patients were enrolled in the treatment groups so to escape doom and share the benefit of the unfolding high remission inductions experienced in the treatment group. Chemo-radiotherapy of Hodgkin's disease and cisplatin therapy of certain testicular carcinomas provided the first éclat examples. More recently, the rapidly approved and marketed imitanib mesylate for Ph-chromosome-positive chronic myelogenous leukemia and the anti-HER2/neu monoclonal antibody trastuzumab, and the not yet marketed double tyrosine kinase (ErbB1/2) inhibitor lapatinib (Tykerb, GlaxoSmithKline) for a subgroup of breast carcinoma patients excelled. Thus, a clinical trial for GBM, but without precise pre-identification of all its prognostic factors, however with a great deal of evidence-based empirical expectations of benefits, for patients with rapid advarcement toward a fatal outcome, implying an element of urgency, appears to be justified.

A notable phenomenon recapitulated. A fusion product of a murine lymphoma cell and a leukemia virus-neutralizing antibody-producer host plasma cell formed spontaneously and secreting the specific antibody continuously.

In the mid-1960s the #620 cell passage line of a murine lymphoma-leukemia was developed at the Section of Clinical Tumor Virology and Immunology, Department of Medicine, The University of Texas M.D. Anderson Hospital in Houston, TX. The diploid lymphoma cells released a retrovirus and were antigenic in young adult Swiss (YAS) mice. Small lymphoma cell inocula were rejected with immunity acquired against large inocula of lymphoma cells. Tissue sections revealed the "starry sky" configurations. In one of the tissue cultures set up from lymphoma #620, a cell line consisting of large round poly- or tetraploid cells arose and was referred to as lymphoma cell line #818. The #818 cells grew in suspension cultures and in the form of large, lethal ascitic tumors in YAS mice. Diploid #620 lymphoma cells stained for retroviral antigens; #818 cells stained both for retroviral antigens and immunoglobulins. Fluids withdrawn from #818 cultures neutralized the leukemia virus in spleen focus assays. Immunoglobulin precipitated from #818 suspension culture fluids strongly and specifically neutralized the leukemia virus. The growth of #620 or #818 cells in YAS mice treated with rabbit anti-lymphoma cell immune sera was strongly inhibited but culture fluids of #818 cells showed weak and insignificant inhibition against leukemia-lymphoma #620 (in one experiment, unpublished). In two experiments #620 lymphoma cells were co-inoculated with immune spleen cells into the peritoneal cavities of YAS mice. The immune spleen cells derived from mice that rejected #620 cell inocula or were actively immunized with a photodynamically inactivated mouse leukemia virus vaccine. In the peritoneal cavities of mice co-inoculated with #620 cells and immune spleen cells, clones of large round cells emerged with tetra- or polyploid chromosomal modes. These cells stained for leukemia viral antigens and immunoglobulins. When passaged in YAS mice these cells induced lethal ascites tumors. It was concluded as early as in 1968-69 that an immune plasma cell can fuse with a lymphoma cell, if the lymphoma cell expresses retroviral antigens against which the plasma cell is producing a specific antibody. Some human lymphoma-leukemia cells express retroviral antigens and/or budding retroviral particles, whether due to the acquisition of new env sequences by incomplete resident endogenous retroviral genomes or due to the entry of exogenous retroviruses into lymphopoietic stem cells. In the Discussion illustrations are provided for the human cell line #778 established from a patient with "lymphosarcoma cell leukemia" in 1966. The malignant cells released unidentified retrovirus-like particles and fused with one another and with reactive lymphoid cells of the host. It should be investigated further if human lymphoma-leukemia cells could fuse with an immune plasma cell of the host and thus alter the clinical course of the disease.

Virological and immunological connotations of apoptotic and anti-apoptotic forces in neoplasia.

Against the background of its earliest recognition, programmed cell death (PCD) or apoptosis (A) is presented in its fundamental biological contexts. Techniques of its demonstration are listed. Former original works of the authors encompass designs for genetically engineered oncolytic viruses. Presented here are observations on mesenchymal stromal cells of the bone marrow serving as feeder layers to chronic lymphocytic leukemia (CLL) cells (recently rediscovered elsewhere as subverted "nurse cells" protecting CLL cells from A). A-resistant human melanoma cells are shown to expropriate the Fas ligand to Fas receptor (CD95; APO-1) (FasL-->FasR) system for their autocrine growth loop not only in melanoma cells coexpressing CD95 and its ligand but also in CD95-positive melanoma cells undergoing divisions when exposed to CD95 ligand. Bi-directional A-induction is demonstrated upon the encounter of cytotoxic lymphocytes and targeted tumor cells as exemplified with lymphomas; and chemotherapy-induced A of malignant cells as exemplified by paclitaxel-induced PCD of Reed-Sternberg (RS) cells in a case of chemotherapy-resistant Hodgkin's disease (HD). A list of interventions capable of inducing A in tumor cells is provided. These interventions are of potential therapeutic value. The balance of apoptotic and anti-apoptotic forces in virally infected normal and malignant cells is discussed.

The place of viruses in the "tree of life".

Ribozymal entry into vesicle containing autocatalytically replicating oligopeptides engendered RNA proliferation and enzyme synthesis within units whose RNA genomes derived from ancestors of viroids. There is good reason to consider the coexistence of proto- or spheroplastic forms of ancient prokaryotes and archaeons. Predecessors of extant mycoplasmavirus L3 or archaeal fuselloviruses could induce cell fusions among these entities. The possibility that the first eukaryotic cells arose consequentially to virally mediated fusions of prokaryotic and archaeal proto- or spheroplasts is presented. Retrotransposons and endogenous retroviruses might have emerged in theropod dinosaurs when Aves evolved; and directed the development of syncytiotrophoblasts in the placentae of the first mammals. As viruses coevolved with their hosts descendants of ancient viruses diverged from one another. Certain phenotypical features could connect extant phages and eukaryotic viruses to common ancestors.

Newcastle disease virus (NDV): brief history of its oncolytic strains.

BACKGROUND: While genetically engineered viruses are now being tested for the virus therapy of human cancers, some naturally occurring viruses display unmatched oncolytic activity. Newcastle disease virus (NDV) excels as an oncolytic agent. OBJECTIVES: As its virulence versus attenuation can be explained on molecular biological bases, it may be possible to develop or select highly oncolytic strains of NDV without adverse toxicity. STUDY DESIGN: Questions are posed as to the mechanisms of viral oncolysis, the appropriateness of tests to predict oncolytic activity of a given NDV strain and the best modes of administration for oncolytic effects. Answers are provided based on specific data or on considerations drawn from experience (the authors use NDV oncolysates to immunize against melanoma and kidney carcinoma) or from analogous clinical situations (therapeutic use of mumps or measles viruses). RESULTS AND CONCLUSIONS: NDV oncolysates probably suit better for immunotherapy (providing also active tumor-specific immunization) than massive repeated inoculations of NDV strains, especially when the NDV strain used is not proven to be oncolytic by appropriate pre-clinical tests.

Vaccination against human cancers (review).

Classical and molecular immunological means of active tumor-specific immunization against human cancers yielded whole cell or tumor cell lysate vaccines of preventive value (reduced relapse rates) and dendritic cell-peptide or genetically engineered vaccines that may induce remissions even in metastatic disease. Active tumor-specific immunization was often successful in the past 50 years against experimental tumors maintained in the laboratory. During the epochs of classical and molecular immunology several vaccines were generated and used for the reduction of relapse rates of human cancer after surgical removal of the primary or metastatic tumors. Whole cell vaccines consist of X-irradiated autologous or allogeneic tumor cells coadministered with immunostimulants (BCG, Detox). Tumor cells haptenized biologically (as in viral oncolysates) or chemically were also used. Dendritic cell vaccines are prepared by transfection or transduction with tumor antigen-encoding DNA or by pulsing the cells with antigenic peptides in vitro; or collecting dendritic cells that engulfed apoptotic tumor cell DNA and/or peptide antigens in vivo for reinjection into the patient. Genetically engineered tumor cells are prepared in vitro to express MHC and peptides, costimulatory molecules (B7.1) and cyto- or lymphokines (interferons, interleukins, hematopoietic growth factors) for vaccination of patients. Antibody- and immune T cell-mediated immune reactions to autologous tumor cells are newly generated and/or quantitatively increased in immunized patients but do not always correlate with clinical response. Most vaccines are claimed to have reduced relapse rates presumably by inducing effective host immunity against micrometastases. Dendritic cell-peptide vaccines could induce partial or occasionally complete remissions in metastatic disease. The wrong antigenic presentation may result in tolerance induction toward the tumor; occasionally tumor enhancement may occur. Human tumor antigens when presented appropriately (with costimulatory molecules and with IL-2, IL-12) break the host's natural tolerance toward its tumor and induce rejection strength immune reactions even in patients with metastatic disease. Immune T cells thus generated could be collected for adoptive immunotherapy. For successful active specific immunization against human cancers the understanding of the immunoevasive maneuvers of the tumor cell (through FasL --> Fas; TRAIL; CD40L --> CD40; TGFbeta etc. systems) is essential.

Cancer vaccines with emphasis on a viral oncolysate melanoma vaccine.

Biotherapy of malignant diseases has become the fourth treatment modality besides surgery, chemo- and radiotherapy. Whole cell melanoma vaccines with or without BCG and other adjuvants, purified ganglioside and shed antigens, recombinant viruses carrying tumor antigens, dendritic cells pulsed with antigenic peptides etc. are in clinical trials. Efficacious viral oncolysate vaccines induce the host to mount tumor-specific cytotoxic T-cell response and prevention of relapses is supported by clinical trials. The use of "polyvalent" whole cell vaccines vs. purified or genetically engineered single antigen vaccines is justified as i. only very few single tumor antigens are present in all tumors of a given histological type; and ii. antigen modulation occurs in tumors rendering them resistant to immune attack generated by vaccine against a single antigen. Thus polyvalent vaccines immunize against several antigens vs. against a selected antigen.

Kaposi's sarcoma: breeding ground of herpesviridae - A tour de force over viral evolution (review).

After reviewing the molecular biological basis of prominent theories for the integration of viruses into the earliest forms of living matter, an account is given on the immunoevasive strategies viruses have had to acquire in order to secure their existence against the most sophisticated anti-viral defensive mechanisms evolving in their hosts. Herpes-viridae and Kaposi's sarcoma illustrate the complexity of host-virus relationship. In following the evolutionary steps of simians and hominoids to Homo, it becomes evident that: a) Epstein-Barr virus evolved in Africa and its ancestral viruses are present in cercopithecines and hominoids; b) human herpes-virus-8-related viruses are present in macaques, in S. American primates and in Homo but such isolates from the great apes are missing. Thus interspecies transfer occurred from lower monkeys to Homo but when and at what geographical location? The human retrolentiviruses also jumped species barriers: this occurred recently in Africa, from great apes (chimpanzee and bonobo) to Homo sapiens (except when HIV-2 was transferred to mankind from sooty mangabeys). The matter is further complicated by the long coevolutionary cooperative interactions between herpes- and retrolentiviruses. Of pathological entities suspected to be etiologically affected by such complex viral cooperation, the origin of Reed-Sternberg cells of Hodgkin's disease is singled out for critical analysis. In this article the senior author summarizes his own 52 years of studentship in virology.