The role of immune cells in resistance to oncolytic viral therapy.

Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we introduce deterministic differential equation models to explore the effect of resistance on oncolytic viral therapy. Specifically, we classify tumor cells into resistant, sensitive, or infected with respect to oncolytic viruses for our analysis. Immune cells can eliminate both tumor cells and viruses. Our research shows that the introduction of immune cells into the tumor-virus interaction prevents all tumor cells from becoming resistant in the absence of conversion from resistance to sensitivity, given that the proliferation rate of immune cells exceeds their death rate. The inclusion of immune cells leads to an additional virus-free equilibrium when the immune cell recruitment rate is sufficiently high. The total tumor burden at this virus-free equilibrium is smaller than that at the virus-free and immune-free equilibrium. Therefore, immune cells are capable of reducing the tumor load under the condition of sufficient immune strength. Numerical investigations reveal that the virus transmission rate and parameters related to the immune response significantly impact treatment outcomes. However, monotherapy alone is insufficient for eradicating tumor cells, necessitating the implementation of additional therapies. Further numerical simulation shows that combination therapy with chimeric antigen receptor (CAR T-cell) therapy can enhance the success of treatment.

Mathematical modeling of SARS-nCoV-2 virus in Tamil Nadu, South India.

The purpose of this paper is to build a mathematical model for the study of the roles of lock-down, social distancing, vaccination, detection efficiency, and health care capacity planning of the COVID-19 pandemic taking into account the demographic topology of the State of Tamil Nadu, India. Two mathematical models are proposed for the evolution of the first and second wave of COVID-19 pandemic. The model for the first wave considers lock-down orders, social distancing measures, and detection efficiency. The model for the second wave considers more sub-populations and incorporates two more elements, vaccination and health care capacity. Daily reported data on the evolution of the COVID-19 pandemic are used to determine the parameter values. The dynamics produced by the mathematical model closely follow the evolution of COVID-19 in the State of Tamil Nadu. Numerical simulation shows that the lock-down effect is limited. Social distancing implementation and detection of positive cases are relatively ineffective compared with other big cities. Shortage of health care resources is one of the factors responsible for rapidly spreading in the second wave in Tamil Nadu.

Bistability in a model of tumor-immune system interactions with an oncolytic viral therapy.

A mathematical model of tumor-immune system interactions with an oncolytic virus therapy for which the immune system plays a twofold role against cancer cells is derived. The immune cells can kill cancer cells but can also eliminate viruses from the therapy. In addition, immune cells can either be stimulated to proliferate or be impaired to reduce their growth by tumor cells. It is shown that if the tumor killing rate by immune cells is above a critical value, the tumor can be eradicated for all sizes, where the critical killing rate depends on whether the immune system is immunosuppressive or proliferative. For a reduced tumor killing rate with an immunosuppressive immune system, that bistability exists in a large parameter space follows from our numerical bifurcation study. Depending on the tumor size, the tumor can either be eradicated or be reduced to a size less than its carrying capacity. However, reducing the viral killing rate by immune cells always increases the effectiveness of the viral therapy. This reduction may be achieved by manipulating certain genes of viruses via genetic engineering or by chemical modification of viral coat proteins to avoid detection by the immune cells.

Mathematical modeling of tumor growth: the MCF-7 breast cancer cell line.

Breast cancer is the second most commonly diagnosed cancer in women worldwide. MCF-7 cell line is an extensively studied human breast cancer cell line. This cell line expresses estrogen receptors, and the growth of MCF-7 cells is hormone dependent. In this study, a mathematical model, which governs MCF-7 cell growth with interaction among tumor cells, estradiol, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) or CD8+ T cells, and white blood cells (WBCs), is proposed. Experimental data are used to determine functional forms and parameter values. Breast tumor growth is then studied using the mathematical model. The results obtained from numerical simulation are compared with those from clinical and experimental studies. The system has three coexisting stable equilibria representing the tumor free state, a microscopic tumor, and a large tumor. Numerical simulation shows that an immune system is able to eliminate or control a tumor with a restricted initial size. A healthy immune system is able to effectively eliminate a small tumor or produces long-term dormancy. An immune system with WBC count at the low parts of the normal ranges or with temporary low NK cell count is able to eliminate a smaller tumor. The cytotoxicity of CTLs plays an important role in immune surveillance. The association between the circulating estradiol level and cancer risk is not significant.

A mathematical model of tumour growth with Beddington-DeAngelis functional response: a case of cancer without disease.

A previously published mathematical model, governing tumour growth with mixed immunotherapy and chemotherapy treatments, is modified and studied. The search time, which is assumed to be neglectable in the previously published model, is incorporated into the functional response for tumour-cell lysis by effector cells. The model exhibits bistability where a tumour-cell population threshold exists. A tumour with an initial cell population below the threshold can be controlled by the immune system and remains microscopic and asymptomatic called cancer without disease while that above the threshold grows to lethal size. Bifurcation analysis shows that (a) the chemotherapy-induced damage may cause a microscopic tumour, which would never grow to become lethal if untreated, to grow to lethal size, (b) applying chemotherapy alone requires a large dosage to be successful,

Periodically Pulsed Immunotherapy in a Mathematical Model of Tumor, CD4+ T Cells, and Antitumor Cytokine Interactions.

Immunotherapy is one of the most recent approaches for controlling and curing malignant tumors. In this paper, we consider a mathematical model of periodically pulsed immunotherapy using CD4+ T cells and an antitumor cytokine. Mathematical analyses are performed to determine the threshold of a successful treatment. The interindividual variability is explored by one-, two-, and three-parameter bifurcation diagrams for a nontreatment case. Numerical simulation conducted in this paper shows that (i) the tumor can be regulated by administering CD4+ T cells alone in a patient with a strong immune system or who has been diagnosed at an early stage, (ii) immunotherapy with a large amount of an antitumor cytokine can boost the immune system to remit or even to suppress tumor cells completely, and (iii) through polytherapy the tumor can be kept at a smaller size with reduced dosages.

Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells.

Although it has been previously reported that bee venom (BV) can induce apoptosis in many cancer cell lines, there is no information on the effect of BV on human cervical cancer cells and its molecular mechanisms of action are not fully elucidated. In this study, the possible mechanisms of apoptosis by which BV acts on human cervical cancer Ca Ski cells were investigated. BV induced morphological changes and decreased the percentage of viable Ca Ski cells in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BV induced the production of reactive oxygen species, increased the level of cytoplasmic Ca2+, reduced mitochondrial membrane potential which led to cytochrome c release, and promoted the activation of caspase-3 which then led to apoptosis. BV also induced an increase in the levels of Fas, p53, p21 and Bax, but a decrease in the level of Bcl-2. The activities of both caspase-8 and caspase-9 were enhanced by BV, promoting caspase-3 activation, leading to DNA fragmentation. Based on the DNA fragmentation and DAPI staining, BV-induced apoptosis was mitochondrial-dependent and caspase-dependent. BV also promoted the expression of AIF and Endo G in the Ca Ski cells. Both AIF and Endo G proteins were released from the mitochondria, and then induced apoptosis which was not through activation of caspase. In conclusion, our data demonstrated that BV-induced apoptosis occurs via a Fas receptor pathway involving mitochondrial-dependent pathways and is closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.

Ethyl 2- [N-p-chlorobenzyl- (2'-methyl)] anilino-4-oxo-4,5-dihydrofuran-3-carboxylate (JOT01007)induces apoptosis in human cervical cancer Ca Ski cells.

The cytotoxic effects of a new compound, ethyl 2-[N-p-chlorobenzyl-(2'-methyl)] aniline-4-oxo-4,5-dihydrofuran-3-carboxylate (JOT01007) have been tested in mouse leukemia WEHI-3 cells. In this study, the mechanisms by which JOT01007 acts on a human cervical cancer cell line (Ca Ski) to bring about an increase in the ratio of Bax/Bcl-2, reduction of the mitochondrial membrane potential (MMP), increase in the levels of cytoplasmic Ca2+, activation of caspases and fragmentation of DNA, and apoptosis were investigated. Flow cytometric analysis demonstrated that JOT01007 induced a decrease of MMP in Ca Ski cells. JOT01007 induced an increase in the level of cytoplasmic Ca2+, which was inhibited by BAPTA (calcium chelator), and BAPTA accelerated the MMP reduction, and significantly blocked JOT01007-induced apoptosis. Western blotting demonstrated that JOT01007 induced an increase in the levels of p53, p2I, cytochrome-c, caspase-3 and Bax, but decreased the level of Bcl-2. In conclusion, our data demonstrate that JOT01007-induced apoptosis occurs via a mitochondria-dependent pathway closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.