Advances in cell-based therapy, particularly CAR-T cell therapy, have transformed the treatment of hematological malignancies. Although an important step forward for the field, autologous CAR-T therapies are hindered by high costs, manufacturing challenges, and limited efficacy against solid tumors. With ongoing progress in gene editing and culture techniques, engineered stem cells and their application in cell therapy are poised to address some of these challenges. Here, we review stem cell-based immunotherapy approaches, stem cell sources, gene engineering and manufacturing strategies, therapeutic platforms, and clinical trials, as well as challenges and future directions for the field.

Type 2 inositol 1,4,5-trisphosphate receptor (IP₃R2) regulates the intracellular Ca²⁺ release from endoplasmic reticulum in human embryonic stem cells (hESCs), cardiovascular progenitor cells (CVPCs), and mammalian cardiomyocytes. However, the role of IP₃R2 in human cardiac development is unknown and its function in mammalian cardiomyocytes is controversial. hESC-derived cardiomyocytes have unique merits in disease modeling, cell therapy, and drug screening. Therefore, understanding the role of IP₃R2 in the generation and function of human cardiomyocytes would be valuable for the application of hESC-derived cardiomyocytes. In the current study, we investigated the role of IP₃R2 in the differentiation of hESCs to cardiomyocytes and in the hESC-derived cardiomyocytes. By using IP₃R2 knockout (IP₃R2KO) hESCs, we showed that IP₃R2KO did not affect the self-renewal of hESCs as well as the differentiation ability of hESCs into CVPCs and cardiomyocytes. Furthermore, we demonstrated the ventricular-like myocyte characteristics of hESC-derived cardiomyocytes. Under the α₁-adrenergic stimulation by phenylephrine (10 μmol/L), the amplitude and maximum rate of depolarization of action potential (AP) were slightly affected in the IP₃R2KO hESC-derived cardiomyocytes at differentiation day 90, whereas the other parameters of APs and the Ca²⁺ transients did not show significant changes compared with these in the wide-type ones. These results demonstrate that IP₃R2 has minimal contribution to the differentiation and function of human cardiomyocytes derived from hESCs, thus provide the new knowledge to the function of IP₃R2 in the generation of human cardiac lineage cells and in the early cardiomyocytes.

Physiologically based pharmacokinetic (PBPK) models are growing in popularity due to human food safety concerns and for estimating drug residue distribution and estimating withdrawal intervals for veterinary products originating from livestock species. This paper focuses on the physiological and anatomical data, including cardiac output, organ weight, and blood flow values, needed for PBPK modeling applications for avian species commonly consumed in the poultry market. Experimental and field studies from 1940 to 2019 for broiler chickens (1-70 days old, 40 g - 3.2 kg), laying hens (4-15 months old, 1.1-2.0 kg), and turkeys (1 day-14 months old, 60 g -12.7 kg) were searched systematically using PubMed, Google Scholar, ProQuest, and ScienceDirect for data collection in 2019 and 2020. Relevant data were extracted from the literature with mean and standard deviation (SD) being calculated and compiled in tables of relative organ weights (% of body weight) and relative blood flows (% of cardiac output). Trends of organ or tissue weight growth during different life stages were calculated when sufficient data were available. These compiled data sets facilitate future PBPK model development and applications, especially in estimating chemical residue concentrations in edible tissues to calculate food safety withdrawal intervals for poultry.

Physiologically based pharmacokinetic (PBPK) models for chemicals in food animals are a useful tool in estimating chemical tissue residues and withdrawal intervals. Physiological parameters such as organ weights and blood flows are an important component of a PBPK model. The objective of this study was to compile PBPK-related physiological parameter data in food animals, including cattle and swine. Comprehensive literature searches were performed in PubMed, Google Scholar, ScienceDirect, and ProQuest. Relevant literature was reviewed and tables of relevant parameters such as relative organ weights (% of body weight) and relative blood flows (% of cardiac output) were compiled for different production classes of cattle and swine. The mean and standard deviation of each parameter were calculated to characterize their variability and uncertainty and to allow investigators to conduct population PBPK analysis via Monte Carlo simulations. Regression equations using weight or age were created for parameters having sufficient data. These compiled data provide a comprehensive physiological parameter database for developing PBPK models of chemicals in cattle and swine to support animal-derived food safety assessment. This work also provides a basis to compile data in other food animal species, including goats, sheep, chickens, and turkeys.

This report is the third in a series of studies that aimed to compile physiological parameters related to develop physiologically based pharmacokinetic (PBPK) models for drugs and environmental chemicals in food-producing animals including swine and cattle (Part I), chickens and turkeys (Part II), and finally sheep and goats (the focus of this manuscript). Literature searches were conducted in multiple databases (PubMed, Google Scholar, ScienceDirect, and ProQuest), with data on relevant parameters including body weight, relative organ weight (% of body weight), cardiac output, relative organ blood flow (% of cardiac output), residual blood volume (% of organ weight), and hematocrit reviewed and statistically summarized. The mean and standard deviation of each parameter are presented in tables. Equations describing the growth curves of sheep and goats are presented in figures. When data are sufficient, parameter values are reported for different ages or production classes of sheep, including fetal sheep, lambs, and market-age sheep (mature sheep). These data provide a reference database for developing standardized PBPK models to predict drug withdrawal intervals in sheep and goats, and also provide a basis for extrapolating PBPK models from major species such as cattle to minor species such as sheep and goats.

Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16^Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16^Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16^Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.

Thiopurine dose optimization by thiopurine-S-methyltransferase (TPMT) or nudix hydrolase-15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6-thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA-thioguanine nucleotides (DNA-TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA-TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109 /L) were observed in 43 patients (14.0%), who had significantly higher DNA-TG concentration than those without leucopenia (P = 4.1 × 10-9 , 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/μg DNA). No difference in 6TGN concentrations between leucopenia and non-leucopenia was found. With a DNA-TG threshold of 340.1 fmol/μg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA-TG was an independent risk factor for late leucopenia. Quantification of DNA-TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

In response to the need for the Astro2020 Decadal Survey to explicitly engage early career astronomers, the National Academies of Sciences, Engineering, and Medicine hosted the Early Career Astronomer and Astrophysicist Focus Session (ECFS) on October 8-9, 2018 under the auspices of Committee of Astronomy and Astrophysics. The meeting was attended by fifty six pre-tenure faculty, research scientists, postdoctoral scholars, and senior graduate students, as well as eight former decadal survey committee members, who acted as facilitators. The event was designed to educate early career astronomers about the decadal survey process, to solicit their feedback on the role that early career astronomers should play in Astro2020, and to provide a forum for the discussion of a wide range of topics regarding the astrophysics career path. This white paper presents highlights and themes that emerged during two days of discussion. In Section 1, we discuss concerns that emerged regarding the coming decade and the astrophysics career path, as well as specific recommendations from participants regarding how to address them. We have organized these concerns and suggestions into five broad themes. These include (sequentially): (1) adequately training astronomers in the statistical and computational techniques necessary in an era of "big data", (2) responses to the growth of collaborations and telescopes, (3) concerns about the adequacy of graduate and postdoctoral training, (4) the need for improvements in equity and inclusion in astronomy, and (5) smoothing and facilitating transitions between early career stages. Section 2 is focused on ideas regarding the decadal survey itself, including: incorporating early career voices, ensuring diverse input from a variety of stakeholders, and successfully and broadly disseminating the results of the survey.

We present optical continuum lags for two Seyfert 1 galaxies, MCG+08-11-011 and NGC 2617, using monitoring data from a reverberation mapping campaign carried out in 2014. Our light curves span the ugriz filters over four months, with median cadences of 1.0 and 0.6 days for MCG+08-11-011 and NGC 2617, respectively, combined with roughly daily X-ray and near-UV data from Swift for NGC 2617. We find lags consistent with geometrically thin accretion-disk models that predict a lag-wavelength relation of τ ∝ λ 4/3. However, the observed lags are larger than predictions based on standard thin-disk theory by factors of 3.3 for MCG+08-11-011 and 2.3 for NGC 2617. These differences can be explained if the mass accretion rates are larger than inferred from the optical luminosity by a factor of 4.3 in MCG+08-11-011 and a factor of 1.3 in NGC 2617, although uncertainty in the SMBH masses determines the significance of this result. While the X-ray variability in NGC 2617 precedes the UV/optical variability, the long (2.6 day) lag is problematic for coronal reprocessing models.