Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.

Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Computational analysis of radiative engine oil-based Prandtl-Eyring hybrid nanofluid flow with variable heat transfer using the Cattaneo-Christov heat flux model.

In the present analysis, we study the energy transference through engine oil-based Prandtl-Eyring nanofluid flow through a heated stretching surface. The nanofluid is prepared by adding copper (Cu) and titanium dioxide (TiO2) nanoparticles (NPs) to the base fluid engine oil. The flow mechanism and thermal transmission are observed by exposing the nanofluid flow through the heated slippery surface. The influences of permeable surface, radiative flux and heat absorption/generation are also elaborated in this study. The flow of nanofluids has been designed using a PDEs system, which are then transformed into a set of ODEs via resemblance modification. The numerical technique "shooting method" is used to solve the acquired nonlinear set of non - dimensional ODEs. The results are physically exemplified through tables and plots. It has been detected that the accumulation of nanomaterials in the engine oil, reduces the skin friction while accelerating the energy transfer rate. The velocity field significantly decelerates with the encouragement of the porosity factor, and volume fraction of NPs. However, the temperature profile significantly escalates with the encouragement of the porosity factor, and volume fraction of NPs.

Effect of Thermal Radiation on Three-Dimensional Magnetized Rotating Flow of a Hybrid Nanofluid.

The effect of thermal radiation on the three-dimensional magnetized rotating flow of a hybrid nanofluid has been numerically investigated. Enhancing heat transmission is a contemporary engineering challenge in a range of sectors, including heat exchangers, electronics, chemical and biological reactors, and medical detectors. The main goal of the current study is to investigate the effect of magnetic parameter, solid volume fraction of copper, Eckert number, and radiation parameter on velocity and temperature distributions, and the consequence of solid volume fraction on declined skin friction and heat transfer against suction and a stretching/shrinking surface. A hybrid nanofluid is a contemporary type of nanofluid that is used to increase heat transfer performance. A linear similarity variable is−applied to convert the governing partial differential equations (PDEs) into corresponding ordinary differential equations (ODEs). Using the three-stage Labatto III-A method included in the MATLAB software's bvp4c solver, the ODE system is solved numerically. In certain ranges of involved parameters, two solutions are received. The temperature profile θη upsurges in both solutions with growing values of EC and Rd. Moreover, the conclusion is that solution duality exists when the suction parameter S≥Sci, while no flow of fluid is possible when S

Modeling and Analysis of Breast Cancer with Adverse Reactions of Chemotherapy Treatment through Fractional Derivative.

The abnormal growth of cells in the breast is called malignancy or breast cancer; it is a life-threatening and dangerous cancer in women around the world. In the treatment of cancer, the doctors apply different techniques to stop cancer cell development, remove cancer cells through surgery, or kill cancer cells. In chemotherapy treatment, powerful drugs are used to kill abnormal cells; however, it has adverse reactions on the patient heart which is called cardiotoxicity. In this paper, we formulate the dynamics of cancer in the breast with adverse reactions of chemotherapy treatment on the heart of a patient in the fractional framework to visualize its dynamical behaviour. We listed the fundamental results of the fractional calculus for the analysis of our model. The model is then analyzed for the basic properties, and the existence and uniqueness of the proposed breast cancer system are investigated through fixed point theory. Furthermore, the Adams-Bashforth numerical technique is presented for the solution of fractional-order system to illustrate the time series of breast cancer model. The dynamical behaviour of different stages of breast cancer is then highlighted numerically to show the effect of fractional-order ϑ and to visualize the role of input parameter on the dynamics of breast cancer.

Impact of thermal radiation and non-uniform heat flux on MHD hybrid nanofluid along a stretching cylinder.

The current research investigates the thermal radiations and non-uniform heat flux impacts on magnetohydrodynamic hybrid nanofluid (CuO-Fe2O3/H2O) flow along a stretching cylinder, which is the main aim of this study. The velocity slip conditions have been invoked to investigate the slippage phenomenon on the flow. The impact of induced magnetic field with the assumption of low Reynolds number is imperceptible. Through the use of appropriate non-dimensional parameters and similarity transformations, the ruling PDE's (partial differential equations) are reduced to set of ODE's (ordinary differential equations), which are then numerically solved using Adams-Bashforth Predictor-Corrector method. Velocity and temperature fields with distinct physical parameters are investigated and explored graphically. The main observations about the hybrid nanofluid and non-uniform heat flux are analyzed graphically. A decrease in the velocity of the fluid is noted with addition of Hybrid nanofluid particles while temperature of the fluid increases by adding the CuO-Fe2O3 particles to the base fluid. Also, velocity of the fluid decreases when we incorporate the effects of magnetic field and slip. Raise in curvature parameter γ caused enhancement of velocity and temperature fields at a distance from the cylinder but displays opposite behavior nearby the surface of cylinder. The existence of heat generation and absorption for both mass dependent and time dependent parameters increases the temperature of the fluid.

Entropy optimization and heat transfer analysis in MHD Williamson nanofluid flow over a vertical Riga plate with nonlinear thermal radiation.

The entropy generation for a reactive Williamson nanofluid flow past a vertical Riga system is the subject of this article. The effects of MHD, thermophoresis, nonlinear heat radiation and varying heat conductivity are modeled into the heat equation in the established model. Suitable similarity transformations are examined to bring down the partial differential equations into ordinary differential equations. The Homotopy analysis approach is used to solve the dimensionless transport equations analytically. The graphic information of the various parameters that emerged from the model is effectively collected and deliberated. The temperature field expands with thermophoresis, Brownian motion and temperature ratio parameters as the modified Hartmann number forces an increase in velocity, according to the findings of this analysis. With the increase in the fluid material terms, the entropy generation and Bejan number increase. Riga plate has numerous applications in improving the thermo-physics features of a fluid, the value of magnetic field embraces an important role in fluid mechanics. An external electric field can be used to control flow in weak electrically conductive fluids. The Riga plate is one of the devices used in this regard. It's a device that creates electromagnetic fields. They produce the Lorentz force which is a force that directs fluid flow. The authors have discussed the entropy optimization for a reactive Williamson nanofluid flow past a vertical Riga plate is addressed. This is the first investigation on mass and heat transfer flow that the authors are aware of, and no similar work has yet been published in the literature. A thorough mathematical examination is also required to demonstrate the model's regularity. The authors believe that the results acquired are novel and have not been plagiarized from any other sources.

Recapitulative haematopoietic development of human pluripotent stem cells in the absence of exogenous haematopoietic cytokines.

To improve the recapitulative quality of human pluripotent stem cell (hPSC) differentiation, we removed exogenous haematopoietic cytokines from the defined differentiation system. Here, we show that endogenous stimuli and VEGF are sufficient to induce robust hPSC-derived haematopoiesis, intensive generation of haematopoietic progenitors, maturation of blood cells and the emergence of definitive precursor cells including those that phenotypically identical to early human embryonic haematopoietic stem cells (HSCs). Moreover, the cytokine-free system produces significantly higher numbers of haematopoietic progenitors compared to the published protocols. The removal of cytokines revealed a broad developmental potential of the early blood cells, stabilized the hPSC-derived definitive precursors and led to spontaneous activation of inflammatory signalling. Our cytokine-free protocol is simple, efficient, reproducible and applicable for embryonic stem cells (ESCs) and induced PSCs. The spectrum of recapitulative features of the novel protocol makes the cytokine-free differentiation a preferred model for studying the early human haematopoietic development.

MYB bi-allelic targeting abrogates primitive clonogenic progenitors while the emergence of primitive blood cells is not affected.

MYB is a key regulator of definitive hematopoiesis and it is dispensable for the development of primitive hematopoietic cells in vertebrates. To delineate definitive versus primitive hematopoiesis during differentiation of human embryonic stem cells, we have introduced reporters into the MYB locus and inactivated the gene by bi-allelic targeting. To recapitulate the early developmental events more adequately, the mutant and wild type human embryonic stem cell lines were differentiated in defined culture conditions without the addition of hematopoietic cytokines. The differentiation of the reporter cell lines demonstrated that MYB is specifically expressed throughout emerging hematopoietic cell populations. Here we show that the disruption of the MYB gene leads to severe defects in the development and proliferation of primitive hematopoietic progenitors while the emergence of primitive blood cells is not affected. We also provide evidence that MYB is essential for neutrophil and T cell development and the upregulation of innate immunity genes during hematopoietic differentiation. Our results suggest that the endothelial origin of primitive blood cells is direct and does not include the intermediate step of primitive hematopoietic progenitors.

Numerical investigation for rotating flow of MHD hybrid nanofluid with thermal radiation over a stretching sheet.

This research investigates the heat and mass transfer in 3-D MHD radiative flow of water based hybrid nanofluid over an extending sheet by employing the strength of numerical computing based Lobatto IIIA method. Nanoparticles of aluminum oxide (Al2O3) and silver (Ag) are being used with water (H2O) as base fluid. By considering the heat transfer phenomenon due to thermal radiation effects. The physical flow problem is then modeled into set of PDEs, which are then transmuted into equivalent set of nonlinear ODEs by utilizing the appropriate similarity transformations. The system of ODEs is solved by the computational strength of Lobatto IIIA method to get the various graphical and numerical results for analyzing the impact of various physical constraints on velocity and thermal profiles. Additionally, the heat transfers and skin friction analysis for the fluid flow dynamics is also investigated. The relative errors up to the accuracy level of 1e-15, established the worth and reliability of the computational technique. It is observed that heat transfer rate increases with the increase in magnetic effect, Biot number and rotation parameter.

TALEN-mediated biallelic inactivation of MYB in human embryonic stem cell lines WAe001-A-45 and WAe001-A-46.

MYB/c-MYB is a proto-oncogene encoding a helix-turn-helix transcription factor that plays a critical role in controlling proliferation and multilineage differentiation of hematopoietic progenitor and stem cells. Deregulation of MYB expression is associated with several types of leukemias and lymphomas. In an attempt to explore the role of the gene in the early human hematopoiesis, we have achieved bi-allelic targeting of MYB in human embryonic stem cells (hESCs) by TALEN-mediated homologous recombination. Furthermore, the gene targeting introduced eYFP Venus reporter gene into the MYB locus to delineate the expression pattern of MYB. The resulting two cell lines, WAe001-A-45 and WAe001-A-46, passed the standard assays for human pluripotent stem cells. Hematopoietic differentiation of these cell lines provides a model to study the role of MYB in human hematopoietic development.

Generation of RUNX1-null reporter human embryonic stem cell line GIBHe008-A.

RUNX1/AML1/CBFA2 (runt-related transcription factor 1/acute myeloid leukemia 1 protein/core-binding factor subunit alpha-2), is a transcription factor that plays a critical role in the development of normal hematopoiesis. RUNX1 is also essential for the development of immune cells and sensory neurons. Chromosomal translocations involving the gene have been associated with several types of leukemia. To investigate the role of RUNX1 in human hematopoietic development we generated RUNX1-null human embryonic stem cell reporter line GIBHe008-A by TALEN mediated homologous recombination. This cell line GIBHe008-A was subjected to detailed characterization by standard assays for human pluripotent stem cells. It provides an ideal model to study the role of RUNX1 in the hESC-derived developmental models.

PEGylated doped- and undoped-TiO2 nanoparticles for photodynamic Therapy of cancers.

Titanium dioxide has been widely known for its phototoxicity in the environmental context, but little is known for its use in the photodynamic therapy of cancers. Previous studides have shown the hazardous effects of undoped-titanium dioxide nanoparticles (undoped-TiO2 NPs) in the ecosystem; however, it remains to explore the effect of polyethylene glycol (PEG) conjugation and doping of metal and non-metal on the photodynamic activity of TiO2. Here we report the synthesis, characterizations, and applications of doped- and undoped-TiO2 NPs stabilized by PEG in the photodynamic therapy of cancers. Our results demonstrate that in vitro PEG-NPs significantly reduced the survival of human cervical cancer cells (HeLa) upon solar and ultraviolet (UV) radiations. We found that doping of the metal (cobalt) and non-metal (nitrogen) onto TiO2 nanocrystals enhanced the photoactivation of doped-TiO2 NPs in the visible/near infrared (Vis/NIR) region, but these nanocrystals were revealed by cytotoxicity assays to be less potent in killing cancer cells compared to PEGylated undoped-TiO2. The significant photodynamic effect was shown by PEGylated undoped-TiO2 synthesized through the sol-gel method with 75% killing of HeLa cells at 5.5 µg/mL concentrations in exposure to UV or sunlight radiations. In vitro cytotoxicity was measured by Sulforhodamine B (SRB) and 3-(4, 5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays after irradiations with IR, UV, and sunlight for 15-30 minutes (min). All the synthesized NPs were characterized by XRD, AFM, SEM, EDX and DRS chemical analysis. Taken together, our data demonstrate that water-soluble PEGylated TiO2 NPs maybe a good candidate for the photodynamic therapy of cervical cancer cells. Our data propose that the use of PEG surfactant can enhance the potency of already available photochemical therpeutic agents.

Entropy Generation and Heat Transfer Analysis in MHD Unsteady Rotating Flow for Aqueous Suspensions of Carbon Nanotubes with Nonlinear Thermal Radiation and Viscous Dissipation Effect.

The impact of nonlinear thermal radiations rotating with the augmentation of heat transfer flow of time-dependent single-walled carbon nanotubes is investigated. Nanofluid flow is induced by a shrinking sheet within the rotating system. The impact of viscous dissipation is taken into account. Nanofluid flow is assumed to be electrically conducting. Similarity transformations are applied to transform PDEs (partial differential equations) into ODEs (ordinary differential equations). Transformed equations are solved by the homotopy analysis method (HAM). The radiative source term is involved in the energy equation. For entropy generation, the second law of thermodynamics is applied. The Bejan number represents the current investigation of non-dimensional entropy generation due to heat transfer and fluid friction. The results obtained indicate that the thickness of the boundary layer decreases for greater values of the rotation parameter. Moreover, the unsteadiness parameter decreases the temperature profile and increases the velocity field. Skin friction and the Nusselt number are also physically and numerically analyzed.

Entropy Generation on Nanofluid Thin Film Flow of Eyring-Powell Fluid with Thermal Radiation and MHD Effect on an Unsteady Porous Stretching Sheet.

This research paper investigates entropy generation analysis on two-dimensional nanofluid film flow of Eyring-Powell fluid with heat amd mass transmission over an unsteady porous stretching sheet in the existence of uniform magnetic field (MHD). The flow of liquid films are taken under the impact of thermal radiation. The basic time dependent equations of heat transfer, momentum and mass transfer are modeled and converted to a system of differential equations by employing appropriate similarity transformation with unsteady dimensionless parameters. Entropy analysis is the main focus in this work and the impact of physical parameters on the entropy profile are discussed in detail. The influence of thermophoresis and Brownian motion has been taken in the nanofluids model. An optima approach has been applied to acquire the solution of modeled problem. The convergence of the HAM (Homotopy Analysis Method) has been presented numerically. The disparity of the Nusslet number, Skin friction, Sherwood number and their influence on the velocity, heat and concentration fields has been scrutinized. Moreover, for comprehension, the physical presentation of the embedded parameters are explored analytically for entropy generation and discussed.

Targeting tumor-associated immune suppression with selective protein kinase A type I (PKAI) inhibitors may enhance cancer immunotherapy.

Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.

TNF/TNFR1 pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes.

BACKGROUND AND PURPOSE: Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR1 pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes. EXPERIMENTAL APPROACH: Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR1, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR1 was suppressed with its siRNA. The protein levels of TNFα, TNFR1 and caspase-12 were assayed using Western blotting. KEY RESULTS: The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR1 and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR1, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR1-siRNA interference. CONCLUSIONS AND IMPLICATIONS: Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR1 pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage.