Normal Host Cells Research Articles

ON THE CHAOTIC NATURE OF A CAPUTO FRACTIONAL MATHEMATICAL MODEL OF CANCER AND ITS CROSSOVER BEHAVIORS

In this paper, a three-dimensional mathematical model of cancer, incorporating tumor cells, host normal cells, and effector immune cells, is examined. The chaotic nature of this cancer model is explored within the framework of Caputo fractional calculus. The analysis employs local stability assessment using the Matignon criteria, Lyapunov exponents (LEs) for various fractional orders of derivatives, bifurcation plots reflecting changes in the fractional derivative order, simulation outcomes of a novel chaotic attractor, Kaplan–Yorke dimension, and sensitivity to initial conditions. The results demonstrate that the Caputo fractional cancer model exhibits chaotic behavior for selected parameters. Moreover, the fractional derivative orders significantly influence the extent of chaotic behavior. Specifically, as the fractional derivative order increases from zero to one, the intensity of chaos diminishes, evidenced by a decrease in both the LE and the Kaplan–Yorke dimension. A piecewise modeling approach is applied to the cancer model, incorporating deterministic, stochastic, and power-law behaviors. Three distinct scenarios are developed within this framework, revealing several novel crossover behaviors through simulation. Notably, it is observed that when cancer dynamics initially follow a power-law behavior and subsequently transition into a stochastic process, the disease dynamics can stabilize, suggesting a positive outlook for disease control. Conversely, if the cancer dynamics begin with a deterministic process and then shift to a stochastic process, the system may enter a chaotic state, complicating disease management efforts.

Abstract 7641: Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network analysis

Abstract Background: An accurate prognostic algorithm based on germline whole exome sequencing (WES) would complement tumor omics as a non-invasive source of biomarkers for guiding cancer patient therapy. In a previous study, we used WES and RNA-seq data from muscle-invasive bladder cancer (MIBC) and normal host cells to train a survival model, wherein we discovered that mutated germline genes accounted for 90% of feature importance. We have since defined a larger cohort to identify key germline biomarkers of overall survival (OS) that may be scalable for application in the clinic. Methods: 169 patients from The Cancer Genome Atlas (TCGA) with MIBC stages T2-T4 that underwent radical cystectomy (RC) w/o neoadjuvant treatment were eligible. OS at 4 years was the primary clinical endpoint as it is associated with death due to metastatic tumor recurrence. Patients were dichotomized to control survivors who were alive at 4+ years, and cases who died within 4 years but no less than 4 months after RC. 49 qualifying survivors were propensity matched against 49 dead patients by stage, adjuvant treatment, gender, race, and age. The remaining 71 dead patients served as a holdout. Only high (e.g. frameshift) and moderate (e.g. indel) impact germline variants were included. Mutations were weighted for allele frequency (penalize common) and genotype (reward homozygous) before grouping at the gene level. A panel of the 21 most differential genes in stratified patients were selected for neural network training using AIQC. The model forced protective/pathogenic genes to interact and produced individual survival probabilities. Gene importance was determined via permutation. Results: OS was accurately predicted for 98.2% of patients: 1 FN, 2 FP, 37 TN, 119 TP. The top 3 permuted genes (and related pathways) were: SORL1 (Aβ), KIF27 (hedgehog), CUL7 (p53). The most differential gene was CUL7: 31% of survivors mutated vs 2% of dead. Conclusion: Neural network analysis identified the promise of germline genetics as an accurate predictor of survival and tumor recurrence in MIBC patients. Upon validation in an external cohort, these biomarkers could be used to inform adjuvant therapy and complement molecular residual disease alongside circulating tumor (ct)-DNA. Citation Format: Guru P. Sonpavde, Amin H. Nassar, Arvind Ravi, Layne Sadler. Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7641.

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer.

Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP. Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues. Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid-derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP. LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

Drosophila melanogaster as a Model Organism to Facilitate Rare Disease Diagnosis and Therapeutic Research

Cancer is one of the leading causes of death worldwide accounting for around 10 million deaths in 2020. Cancer is caused by abnormal growth of cells in any part of the body. Genetic causes of cancer can be due to mutations in the genes. Rare mutations in genes show rare types of tumors like Neurofibromatosis and Tuberous sclerosis. The study of model organisms has been pivotal in understanding the causes of various diseases. The studies involve a variety of different methods and out of them the WES (Whole Exome Sequencing) model of research is the most common. Herein lies the future of integrating human genomics with studies in model organisms. It is essential to maintain and expand the current Drosophila melanogaster databases this houses the genomic, molecular, and cell biological knowledge on the organism. This can be done by collaboration with the NIH. The understanding of the characteristics of cancer cells plays an important role in terms of how to go about with research tumor and normal host cell motility plays a multifaceted role in the metastasis of cancer by allowing the tumor to spread to distant organs, migrate to blood and lymphatic arteries, breach the basement membrane, and escape from the original tumor. The ability to migrate towards favourable environments is a fundamental and evolutionarily conserved cellular behaviour from unicellular organisms to humans. Both normal and cancer cells migrate using diverse modes including amoeboid, mesenchymal, epithelial, collective and individual. Simple model organisms also exhibit these diverse modes of motility and offer experimental advantages such as low cost, amenability to large-scale genetic and pharmacological screening and live imaging of cells interacting within their native environments. This article goes into detail about how drosophila can be used as a model organism to study various diseases such as Duchenne Muscular Dystrophy, Parkinsons disease, Prions diseases, Polyglutamine disorders, Huntington's disease, Machado-Josephs disease, Kennedy disease, Amyotrophic lateral sclerosis, Leigh Disease, Nieman-Pick Disease and a few rare tumours

Unlocking the Potential of Antibody-Drug Conjugates

One hundred years ago, Paul Ehrlich*, a German biochemist and Nobel laureate who created the field of chemotherapy, coined the term “magic bullet.” He envisioned that a drug could specifically target a particular pathogen without affecting normal host cells. Antibody drug conjugates (ADCs) are the realization of Ehrlich’s vision for therapies that target tumor cells with precision and specificity.

Antineoplastic activity of plant-derived compounds mediated through inhibition of histone deacetylase: a review.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.

A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit.

Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis (Mtb) infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein from Mtb, Rv1813c, manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c-expressing cells. This study reveals a novel class of mitochondria targeting effectors from Mtb that might participate in host cell metabolic reprogramming and apoptosis control during Mtb infections. IMPORTANCE In this article, using a combination of techniques (bioinformatics, structural biology, and cell biology), we identified and characterized a new class of effectors present only in intracellular mycobacteria. These proteins specifically target host cell mitochondria when ectopically expressed in cells. We showed that one member of this family (Rv1813c) affects mitochondria metabolism in a way that might twist the immune response. This effector also inhibits the cytochrome c exit from mitochondria, suggesting that it might alter normal host cell apoptotic capacities, one of the first defenses of immune cells against Mtb infection.

Sahachiro Hata (1873-1938) and his contributions to the birth of antimicrobial chemotherapy

Sahachiro Hata was a Japanese collaborator who helped Paul Ehrlich in his quest to develop a drug treatment for syphilis as a ‘magic bullet’ that specifically targets the pathogen without affecting normal host cells. Before the 1900s, syphilis was feared worldwide as a chronic contagious disease that caused major sequelae, including death. Under Ehrlich's direction, Hata screened all known synthetic arsenic derivatives for antisyphilitic properties and found ‘compound 606’ effective against syphilis. ‘Compound 606’ was the first-line drug for syphilis until the advent of penicillin. Their work marked the dawn of modern antimicrobial chemotherapy and served as a guidepost for the subsequent development of antimicrobials. This article provides a short overview of Sahachiro Hata's life and career from the perspective of his major contributions to the birth of antimicrobial chemotherapy. This article is dedicated to the achievements of Sahachiro Hata in honor of the 150th anniversary of his birth (March 23, 2023).

Breast cancer patient-derived explant cultures recapitulate in vivo drug responses.

Assessment of drug sensitivity in tumor tissue ex vivo may significantly contribute to functional diagnostics to guide personalized treatment of cancer. Tumor organoid- and explant-cultures have become attractive tools towards this goal, although culturing conditions for breast cancer (BC) tissue have been among the most challenging to develop. Validation of possibilities to detect concordant responses in individual tumors and their respective cultures ex vivo is still needed. Here we employed BC patient-derived xenografts (PDXs) with distinct drug sensitivity, to evaluate different conditions for tissue dissociation, culturing and monitoring of treatment efficacy ex vivo, aiming to recapitulate the in vivo drug responses. The common challenge of discriminating between tumor and normal cells in the cultured tissue was also addressed. Following conventional enzymatic dissociation of BC tissue, the tumor cells stayed within the non-disrupted tissue fragments, while the single cells represented mostly normal host cells. By culturing such fragments as explants, viable tumor tissue could be maintained and treated ex vivo, providing representative indications on efficacy of the tested treatment. Thus, drug sensitivity profiles, including acquired chemoresistance seen in the PDXs, were recapitulated in the respective explants. To detect the concordant responses, however, the effect monitoring had to be harmonized with the characteristics of the cultured tissue. In conclusion, we present the feasibility of BC explants ex vivo to capture differences in drug sensitivity of individual tumors. The established protocols will aid in setting up an analogous platform for BC patient biopsies with the aim to facilitate functional precision medicine.

Virulence Factors of the Periodontal Pathogens: Tools to Evade the Host Immune Response and Promote Carcinogenesis.

Periodontitis is the most common chronic, inflammatory oral disease that affects more than half of the population in the United States. The disease leads to destruction of the tooth-supporting tissue called periodontium, which ultimately results in tooth loss if uncured. The interaction between the periodontal microbiota and the host immune cells result in the induction of a non-protective host immune response that triggers host tissue destruction. Certain pathogens have been implicated periodontal disease formation that is triggered by a plethora of virulence factors. There is a collective evidence on the impact of periodontal disease progression on systemic health. Of particular interest, the role of the virulence factors of the periodontal pathogens in facilitating the evasion of the host immune cells and promotion of carcinogenesis has been the focus of many researchers. The aim of this review is to examine the influence of the periodontal pathogens Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), Porphyromonas gingivalis (P. gingivalis), and Fusobacterium nucleatum (F. nucleatum) in the modulation of the intracellular signaling pathways of the host cells in order to evade the host immune response and interfere with normal host cell death and the role of their virulence factors in this regard.

MO-TRANS: A Phase 2b Placebo-Controlled Study of Mocravimod As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant

Introduction: Mocravimod is a sphingosine 1-phosphate receptor (S1PR) immunomodulator that blocks lymphocyte egress from lymphoid organs via its phosphorylated active metabolite. Allogeneic hematopoietic cell transplant (allo-HCT) is a common treatment in AML, which is indicated as consolidation therapy for intermediate/high risk AML. The therapeutic benefit includes graft-versus-leukemia (GvL) effect of the donor's T cells against the leukemic cells of the patient. One of the major risks of allo-HCT is graft-versus-host disease (GvHD) and is regarded as the off-target effect of the desirable GvL effect, in which the donor T cells respond to and attack normal host cells other than the leukemic cells. The major causes of post-transplant mortality, morbidity and quality of life impairment, remain disease relapse and GvHD. S1PR modulation does not interfere with T cell cytotoxicity, hence function is maintained, and anti-leukemia response remains potent. Since mocravimod is not immunosuppressive, alloreactive T cells can retain anti-leukemia reactivity to boost GvL while being sequestered in the lymphatic organs and thus not promoting peripheral GvHD. Therefore, treatment with mocravimod as an adjunctive and maintenance therapy to allo-HCT may trigger two positive effects: 1) increase the GvL effect through the eradication of residual malignant cells by alloreactive T cells sequestered in the lymphoid tissues such as lymph nodes, the bone marrow, and the spleen white pulp, and 2) reduce the GvHD because alloreactive T cells are retained in the lymphoid tissues and thus do not migrate into peripheral tissues. Both effects will ultimately result in improving overall survival (OS). Based on the encouraging results of a phase Ib study with mocravimod in the allo-HCT setting, a phase 2b trial is planned. Study Design and Methods: In this multicenter, double-blind, phase 2b study, approximately 249 pts will be randomized 1:1:1 to receive mocravimod 1mg or mocravimod 3mg or placebo. Patients will be stratified by the complete remission status (CR1 versus CR2), the treatment used for GvHD prophylaxis cyclosporine A (CsA) versus tacrolimus (TAC), and the measurable residual disease (MRD) status (MRD pos versus MRD neg). Key eligibility criteria include age (> 18 years and < 75 years), diagnosis of AML (excluding acute promyelocytic leukemia) with European LeukemiaNet (ELN) high risk disease in CR1, intermediate risk in CR1 if MRD pos, or AML of any risk in CR2. Patients need to be planned to undergo allo-HCT, with either fully matched related or unrelated donor. The planned use of GvHD prophylaxis needs to be either methotrexate (MTX) plus CsA or MTX plus TAC. Treatment in all arms will consist of 28-day cycles with daily administration of either 1mg mocravimod or 3mg mocravimod or placebo. Treatment will start 2 days before conditioning treatment and will be ongoing for 12 cycles or until relapse, unacceptable toxicity, or consent withdrawal. Patients will be observed for overall survival after end of treatment. Primary efficacy endpoint is relapse free survival (RFS), which is calculated as the time from randomization to relapse or death. It will be assessed once 46 events are reached in one mocravimod arm and the placebo arm and will be observed by an unblinded independent data monitoring committee. The first key secondary objective is to assess the effect of mocravimod relative to placebo on Overall Survival (OS). A second key objective is the comparison of the effect on RFS between the second mocravimod arm and the placebo arm and it will be assessed once the primary endpoint analysis timepoint will be reached. The FDA activated the IND #127312 on 22 Apr 2022, and five European Health Authorities approved the study to date: France, the UK, Spain, Switzerland and Germany. Enrollment is expected to begin in Q3, 2022. The ClinicalTrials.gov identifier is NCT05429632.

Antioxidant activity of novel diosgenin derivatives: Synthesis, biological evaluation, and in silico ADME prediction

A series of novel diosgenin (DSG) derivatives has been synthesized and tested in vitro for their antioxidant activity. Initially, four analogues have been evaluated for their cytotoxicity using normal human skin fibroblast (NHDF) as model cells. As a result, 84% of NHDF cells were still alive at 5 µM, so these compounds can be considered as innoxious to fibroblasts at this concentration. Then, hemolytic activity against human erythrocytes was studied in order to evaluate the potential impact of tested compounds against normal host cells. The result < 5% of hemolysis rates suggest no lytic activity for most compounds. After that, the main test — evaluation the antioxidant effect of DSG and its new derivatives against lipid peroxidation in the o/w emulsion model — was performed. The most promising compound (8) exhibited the significant antioxidant activity and the biocompatibility towards normal human dermal fibroblasts and red bloods cells. This p–aminobenzoic derivative revealed 61.6% blocking of induced lipid oxidation. Furthermore, eleven predicted ADME properties were predicted for all tested compounds and revealed that they are in compliance with drug–likeness criteria.

Pleiotropic effects of cell competition between normal and transformed cells in mammalian cancers.

PurposeIn the course of tumor progression, cancer clones interact with host normal cells, and these interactions make them under selection pressure all the time. Cell competition, which can eliminate suboptimal cells and optimize organ development via comparison of cell fitness information, is found to take place between host cells and transformed cells in mammals and play important roles in different phases of tumor progression. The aim of this study is to summarize the current knowledge about the roles and corresponding mechanisms of different cell competition interactions between host normal cells and transformed cells involved in mammalian tumor development.MethodsWe reviewed the published relevant articles in the Pubmed.ResultsSo far, the role of several cell competition interactions have been well described in the different phases of mammalian tumor genesis and development. While cell competitions for trophic factors and epithelial defense against cancer (EDAC) prevent the emergence of transformed cells and suppress carcinogenesis, fitness-fingerprints-comparison system and Myc supercompetitors promote the local expansion of transformed cells after the early tumor lesion is formatted. In addition, various preclinical tumor-suppression models which based on the molecular mechanisms of these competition interactions show potential clinical value of boosting the fitness of host normal cells.ConclusionCell competition between host and transformed cells has pleiotropic effects in mammalian tumor genesis and development. The clarification of specific molecular mechanisms shed light on novel ideas for the prevention and treatment of cancer.

Targeting autophagy as a therapeutic strategy against pancreatic cancer

Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.

Three-dimensional insights into human enveloped viruses in vitro and in situ.

Viruses can be enveloped or non-enveloped, and require a host cell to replicate and package their genomes into new virions to infect new cells. To accomplish this task, viruses hijack the host-cell machinery to facilitate their replication by subverting and manipulating normal host cell function. Enveloped viruses can have severe consequences for human health, causing various diseases such as acquired immunodeficiency syndrome (AIDS), seasonal influenza, COVID-19, and Ebola virus disease. The complex arrangement and pleomorphic architecture of many enveloped viruses pose a challenge for the more widely used structural biology techniques, such as X-ray crystallography. Cryo-electron tomography (cryo-ET), however, is a particularly well-suited tool for overcoming the limitations associated with visualizing the irregular shapes and morphology enveloped viruses possess at macromolecular resolution. The purpose of this review is to explore the latest structural insights that cryo-ET has revealed about enveloped viruses, with particular attention given to their architectures, mechanisms of entry, replication, assembly, maturation and egress during infection. Cryo-ET is unique in its ability to visualize cellular landscapes at 3–5 nanometer resolution. Therefore, it is the most suited technique to study asymmetric elements and structural rearrangements of enveloped viruses during infection in their native cellular context.

Silver Nanoparticles Functionalized With Antimicrobial Polypeptides: Benefits and Possible Pitfalls of a Novel Anti-infective Tool.

Silver nanoparticles (AgNPs) and antimicrobial peptides or proteins (AMPs/APs) are both considered as promising platforms for the development of novel therapeutic agents effective against the growing number of drug-resistant pathogens. The observed synergy of their antibacterial activity suggested the prospect of introducing antimicrobial peptides or small antimicrobial proteins into the gelatinized coating of AgNPs. Conjugates with protegrin-1, indolicidin, protamine, histones, and lysozyme were comparatively tested for their antibacterial properties and compared with unconjugated nanoparticles and antimicrobial polypeptides alone. Their toxic effects were similarly tested against both normal eukaryotic cells (human erythrocytes, peripheral blood mononuclear cells, neutrophils, and dermal fibroblasts) and tumor cells (human erythromyeloid leukemia K562 and human histiocytic lymphoma U937 cell lines). The AMPs/APs retained their ability to enhance the antibacterial activity of AgNPs against both Gram-positive and Gram-negative bacteria, including drug-resistant strains, when conjugated to the AgNP surface. The small, membranolytic protegrin-1 was the most efficient, suggesting that a short, rigid structure is not a limiting factor despite the constraints imposed by binding to the nanoparticle. Some of the conjugated AMPs/APs clearly affected the ability of nanoparticle to permeabilize the outer membrane of Escherichia coli, but none of the conjugated AgNPs acquired the capacity to permeabilize its cytoplasmic membrane, regardless of the membranolytic potency of the bound polypeptide. Low hemolytic activity was also found for all AgNP-AMP/AP conjugates, regardless of the hemolytic activity of the free polypeptides, making conjugation a promising strategy not only to enhance their antimicrobial potential but also to effectively reduce the toxicity of membranolytic AMPs. The observation that metabolic processes and O2 consumption in bacteria were efficiently inhibited by all forms of AgNPs is the most likely explanation for their rapid and bactericidal action. AMP-dependent properties in the activity pattern of various conjugates toward eukaryotic cells suggest that immunomodulatory, wound-healing, and other effects of the polypeptides are at least partially transferred to the nanoparticles, so that functionalization of AgNPs may have effects beyond just modulation of direct antibacterial activity. In addition, some conjugated nanoparticles are selectively toxic to tumor cells. However, caution is required as not all modulatory effects are necessarily beneficial to normal host cells.

Co-chaperone involvement in knob biogenesis implicates host-derived chaperones in malaria virulence.

The pathology associated with malaria infection is largely due to the ability of infected human RBCs to adhere to a number of receptors on endothelial cells within tissues and organs. This phenomenon is driven by the export of parasite-encoded proteins to the host cell, the exact function of many of which is still unknown. Here we inactivate the function of one of these exported proteins, PFA66, a member of the J-domain protein family. Although parasites lacking this protein were still able to grow in cell culture, we observed severe defects in normal host cell modification, including aberrant morphology of surface knobs, disrupted presentation of the cytoadherence molecule PfEMP1, and a total lack of cytoadherence, despite the presence of the knob associated protein KAHRP. Complementation assays demonstrate that an intact J-domain is required for recovery to a wild-type phenotype and suggest that PFA66 functions in concert with a HSP70 to carry out host cell modification. Strikingly, this HSP70 is likely to be of host origin. ATPase assays on recombinant protein verify a functional interaction between PFA66 and residual host cell HSP70. Taken together, our data reveal a role for PFA66 in host cell modification, strongly implicate human HSP70s as being essential in this process and uncover a new KAHRP-independent molecular factor required for correct knob biogenesis.

Fully Retargeted, Myeloma-Specific Oncolytic Measles Viruses.

We previously reported that attenuated measles viruses have potent anti-tumor activity in primary myeloma cells and myeloma xenograft models. The viruses are selectively oncolytic because they cause extensive cell to cell fusion via CD46, a membrane complement regulatory protein that is more highly expressed on myeloma cells than on normal cells. A phase I clinical trial is planned at Mayo Clinic using an oncolytic measles virus engineered to express the thyroidal sodium iodide symporter gene (MV-NIS). Expected toxicities of MV-NIS include a mild measles-like illness due to residual infection of normal host cells via either of the two natural virus receptors, CD46 and SLAM. To facilitate the development of fully retargeted oncolytic measles viruses we recently developed the pseudoreceptor system “STAR”, which allows rescue and propagation of targeted viruses with modified H proteins that no longer bind to the native measles receptors (Nakamura T. et. al., Nature Biotechnology, 2005). Using the STAR system, we have now generated fully retargeted oncolytic measles viruses against two targets, CD38 or HM1.24 that are highly expressed on the surface of multiple myeloma cells. CD38 is expressed abundantly on myeloma plasma cells but is also expressed in a variety of normal human cells, such as myeloid progenitors and activated T cells. The HM1.24 antigen is highly expressed on terminally differentiated B-cells (including myeloma cells) and is not found on liver, spleen, kidney, or heart. To facilitate evaluation of the receptor specificity of the recombinant viruses, they were each constructed with an additional transgene insert coding for green fluorescent protein (GFP). Efficient viral incorporation of each of the recombinant H proteins was demonstrated by immunoblotting of pelleted virions. CHO cells were transfected with each of the targeted receptors and then infected with each of the targeted viruses. As expected, each virus demonstrated the predicted host range properties and was blind to CD46 and SLAM receptors, but efficiently entered cells through the respective targeted receptor. In addition, these retargeted viruses demonstrated myeloma-specific infection, syncytium formation and cytotoxicity for multiple myeloma cell lines RPIM8226 and KAS-6/1, but not on receptor-negative control cells such as K562 human erythroleukemic cells. These fully retargeted oncolytic measles viruses are promising candidates that may provide the basis for safer and more effective virotherapy in multiple myeloma.

Opportunities of Intersection for Cancer Genomics and Immunotherapy

Cancer is one of the most dangerous disease which made many lives disastrous physically, psychologically and in an unhealthy manner. Major challenge for the scientists and researchers is cancer treatment and still a huge research is going on in clinical trials. Earlier cancer treatments are surgery, radiation, and chemotherapy are moving to two new effective ways: Cancer genomics and immunotherapy. Cancer genomics is the study of gene expression, the totality of DNA sequence and differences between tumors cells and normal host cells. Immuno-oncology is a prominent field that has taken to fight against cancer, provide a refined understanding of how cancer tumors elude the natural immune response. The information on immunology of the host and genomics of tumor will had a drastic growth in the following decade.

Lysophospholipid Signalling and the Tumour Microenvironment.

Homeostasis is the key to survival. This is as true for the tumour cell as it is for the normal host cell. Tumour cells and normal host cells constantly interact with each other, and the balance of these interactions results in the prevailing homeostatic conditions. The interactions between the milieu of signalling molecules and their effects on the host and tumour cells are known as the tumour microenvironment. The predominant balance of effects within the tumour microenvironment will determine if the tumour cells can evade the host's responses to survive and grow or if the tumour cells will be eradicated. Lysophospholipids (LPLs) are a group of lipid signalling molecules which exert their effects via autocrinic and paracrinic mechanisms. Therefore, LPLs are being explored to determine if they are potentially key signalling molecules within the tumour microenvironment. The effects of LPLs within the tumour microenvironment include modulating cell proliferation, cell survival, cell motility, angiogenesis and the immune system. These are all important activities that affect the balance of host-tumour cell interactions. This chapter expands on these functions and also the role that LPLs could play as a potential treatment target in the future.