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Cell therapies comprise one of the most important advances in oncology. One of the biggest challenges in the early development of cell therapies is to recommend safe and feasible doses to carry forward to middle development. The treatment involves extracting cells from a patient, expanding the cells and infusing the cells back into the patient. Each dose level being studied is defined by the number of cells infused into the trial participant. The manufacturing process may not generate enough cells for a given patient to receive their assigned dose level, making it infeasible to administer their intended dose. The primary design challenge is to efficiently use accumulated data from participants treated away from their assigned dose to efficiently allocate future trial participants and recommend a feasible maximum tolerated dose (FMTD) at the study conclusion. Currently, there are few available options for designing and implementing Phase I trials of cell therapies that can incorporate a dose feasibility endpoint. Moreover, the application of these designs is limited to a traditional dose-finding framework, where the dose-limiting toxicity (DLT) endpoint is observed in early cycles of therapy. This paper presents a novel phase I trial design for adoptive cell therapy that simultaneously accounts for dose feasibility and late-onset toxicities. We apply our design to a phase I dose-escalation trial of Rituximab-based bispecific activated T-cells combined with a fixed dose of Nivolumab. Our simulation results demonstrate that our proposed method can reduce trial duration without significantly hindering trial accuracy. [ABSTRACT FROM AUTHOR]

In a recent paper in Science, Fidelle et al. unravel a gut immune checkpoint that is subverted by antibiotic treatment. Post-antibiotic dysbiosis of the ileum causes an increase in bile acids that downregulate MAdCAM−1, thereby triggering the exodus of immunosuppressive T cells from gut-associated lymphoid tissues toward tumors. [ABSTRACT FROM AUTHOR]

Hepatitis B and C are viruses causing liver infections and resulting in grave secondary diseases. While there are different treatments for chronic liver infections, the process of evolving chronic diseases is still not fully understood. This paper presents an economic-inspired model for the overall health of an infected organism. The health model is based on the results of a reaction diffusion model for describing the space-dependent dynamics of virus and T cells during a liver infection. The different treatments affect the parameters of the reaction diffusion model and influence therefore the well-being of the infected person during an infection. The health model is selected in a detailed process out of a class of possible models. The presented work provides a foundation for an optimal control problem for finding the best treatment strategy. [ABSTRACT FROM AUTHOR]

Latently infected CD 4 + T cells represent one of the major obstacles to HIV eradication even after receiving prolonged highly active anti-retroviral therapy (HAART). Long-term use of HAART causes the emergence of drug-resistant virus which is then involved in HIV transmission. In this paper, we develop mathematical HIV models with staged disease progression by incorporating entry inhibitor and latently infected cells. We find that entry inhibitor has the same effect as protease inhibitor on the model dynamics and therefore would benefit HIV patients who developed resistance to many of current anti-HIV medications. Numerical simulations illustrate the theoretical results and show that the virus and latently infected cells reach an infected steady state in the absence of treatment and are eliminated under treatment whereas the model including homeostatic proliferation of latently infected cells maintains the virus at low level during suppressive treatment. Therefore, complete cure of HIV needs complete eradication of latent reservoirs. [ABSTRACT FROM AUTHOR]

This systematic review assesses the literature regarding beneficial and potential detrimental effects of bioactive peptides (BPs), focusing on evidence of regulatory T cells (T-regs) mediated oral tolerance (OT), collagen hydrolysate (CH) supplementation in osteoarthritis (OA) and the association of T-regs with chronic disease. The systematic search was done for articles published from inception to April 2019 using the PubMed and Scopus databases. About 3081 papers were identified by three different search strategies and screened against inclusion criteria which resulted in the inclusion of 22 articles. From the included articles, 12 papers were related to treatment of different disease in vivo by oral administration of BPs, six articles evaluated the effects of CH supplementation, as a rich source of BPs, on OA pain-relief and four observational studies assessed the association of circulating T-regs and risk of cancer and cardiovascular disease (CVD). The evidence obtained from first search strategy, indicated that oral administration of BPs improve clinical manifestations of animal models of allergy, arthritis, atherosclerosis, ulcerative colitis and allograft rejection by T-regs expansion; while, observational studies showed that although higher levels of circulating T-regs reduced risk of CVD and allergy, but, increased risk of solid cancers. [ABSTRACT FROM AUTHOR]

Stability and performance of conventional SRAM cells operating at low voltages are severely affected due to enhanced process variations. This paper proposes a Transmission Gate (TG) based 9 T SRAM cell with independent read/write operation and compares its performance with 6 T, 8 T and 10 T SRAM cells. The enhanced read and write ability of the cell is due to the selective use of positive feedback loop. To show the efficacy of the proposed technique, simulations are carried out using 130 nm UMC technology files on Cadence Virtuoso and HSPICE. The transistor size with minimum length and width is used in each configuration using the UMC 130 nm technology file for all the simulations. Various body biasing techniques (Reverse Body Bias and Forward Body Bias) are applied to reduce active and standby power. It has been observed that the proposed cell shows better results in terms of enhanced read, write and hold stability and for reduced power also. Further, the write access time is less for the proposed cell. The layout of the proposed architecture is also shown. [ABSTRACT FROM AUTHOR]

In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

Interleukin-2 (IL-2) is a cytokine involved in the development and maturation of the subsets of T cells, critically associated with the progression of several immune-related diseases (e.g. liver disease, bowel disease). Interestingly, a recent study suggests that coffee may contain several compounds to inhibit IL-2 expression in activated T-lymphocytic cells. However, there is little information about the potential effects of several coffee compounds (e.g. kahweol, cafestol, trigonelline, niacin and chlorogenic acids) on IL-2 expression in activated T-lymphocytic cells. Therefore, in this paper, their effects on IL-2 expression were evaluated in PHA/PMA-activated lymphocytic Jurkat cells. Among the tested compounds, only kahweol and cafestol were able to reduce IL-2 production significantly in the cells (p < 0.05). However, the inhibition of kahweol was a bit stronger than cafestol. Therefore, the molecular mechanism underlying the IL-2 inhibition was investigated using kahweol. Kahweol (≤ 20 µM) was able to inhibit the phosphorylations of ERK and c-Fos (p < 0.05) with little effects on p38 and JNK phosphorylations in the Jurkat cells. Subsequently, the inhibition of ERK/c-Fos led to the reduction of IL-2 mRNA expression in the Jurkat cells. In summary, the data suggest that kahweol may be a potential coffee compound to reduce IL-2 production via inhibiting the phosphorylations of ERK/c-Fos in PHA/PMA-activated lymphocytic Jurkat cells. [ABSTRACT FROM AUTHOR]