Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

Arthroscopic Resection for Extra-articular Ganglion Cysts of Gastrocnemius Near Vessels.

Extra-articular ganglion cysts arising from the gastrocnemius tendon near popliteal vessels can cause pain and claudication. Open resection of this kind of cyst has been described frequently because the vessels can be well protected with a retractor. However, it's a challenge to remove cysts that are near vessels under arthroscopy, because a retractor cannot be used in arthroscopic surgery. This article will report a method of arthroscopic resection for extra-articular ganglion cysts near popliteal vessels.

Disease-modifying potential of diphenyl diselenide in an experimental osteoarthritis model.

Oxidative stress is a key factor in the disruption of cartilage homeostasis during the development of osteoarthritis (OA). Organic selenium (Se)-containing compounds such as diselenides have excellent antioxidant activity and may prevent related diseases. We aimed to examine the benefits of the synthetic small molecule diphenyl diselenide (DPDSe) in OA models in vitro and in vivo. Our findings showed that DPDSe could maintain extracellular matrix (ECM) homeostasis and inhibit reactive oxygen species (ROS) production in IL-1ß-treated chondrocytes. In a destabilization of the medial meniscus (DMM)-induced OA mouse model, intra-articular administration of DPDSe alleviated joint degeneration, as evidenced by a decrease in the OARSI score and the restoration of collagen II (COL2) and MMP-13 expression in cartilage tissues. We confirmed that DDS activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in IL-1ß-treated chondrocytes, and its chondroprotective effects were significantly counteracted when Nrf2 signaling was blocked by the inhibitor ML385 or by siRNA-mediated Nrf2 knockdown. The relatively strong performance of DPDSe makes it an ideal candidate for further trials as a disease-modifying OA drug (DMOAD).

A Hybrid Scaffold Induces Chondrogenic Differentiation and Enhances In Vivo Cartilage Regeneration.

Extensively researched tissue engineering strategies involve incorporating cells into suitable biomaterials, offering promising alternatives to boost tissue repair. In this study, a hybrid scaffold, Gel-DCM, which integrates a photoreactive gelatin-hyaluronic acid hydrogel (Gel) with an oriented porous decellularized cartilage matrix (DCM), was designed to facilitate chondrogenic differentiation and cartilage repair. The Gel-DCM exhibited excellent biocompatibility in vitro, promoting favorable survival and growth of human adipose-derived stem cells (hADSCs) and articular chondrocytes (hACs). Gene expression analysis indicated that the hACs expanded within the Gel-DCM exhibited enhanced chondrogenic phenotype. In addition, Gel-DCM promoted chondrogenesis of hADSCs without the supplementation of exogenous growth factors. Following this, in vivo experiments were conducted where empty Gel-DCM or Gel-DCM loaded with hACs/hADSCs were used and implanted to repair osteochondral defects in a rat model. In the control group, no implants were delivered to the injury site. Interestingly, macroscopic, histological, and microcomputed tomography scanning results revealed superior cartilage restoration and subchondral bone reconstruction in the empty Gel-DCM group compared with the control group. Moreover, both hACs-loaded and hADSCs-loaded Gel-DCM implants exhibited superior repair of hyaline cartilage and successful reconstruction of subchondral bone, whereas defects in the control groups were predominantly filled with fibrous tissue. These observations suggest that the Gel-DCM can provide an appropriate three-dimensional chondrogenic microenvironment, and its combination with reparative cell sources, ACs or ADSCs, holds great potential for facilitating cartilage regeneration.

Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer.

We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18 and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared to non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared to NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A Phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

Supramolecular Genome Editing: Targeted Delivery and Endogenous Activation of CRISPR/Cas9 by Dynamic Host-Guest Recognition.

We synthesize supramolecular poly(disulfide) (CPS) containing covalently attached cucurbit[7]uril (CB[7]), which is exploited not only as a carrier to deliver plasmid DNA encoding destabilized Cas9 (dsCas9), but also as a host to include trimethoprim (TMP) by CB[7] moieties through the supramolecular complexation to form TMP@CPS/dsCas9. Once the plasmid is transfected into tumor cells by CPS, the presence of polyamines can competitively trigger the decomplexation of TMP@CPS, thereby displacing and releasing TMP from CB[7] to stabilize dsCas9 that can target and edit the genomic locus of PLK1 to inhibit the growth of tumor cells. Following the systemic administration of TMP@CPS/dsCas9 decorated with hyaluronic acid (HA), tumor-specific editing of PLK1 is detected due to the elevated polyamines in tumor microenvironment, greatly minimizing off-target editing in healthy tissues and non-targeted organs. As the metabolism of polyamines is dysregulated in a wide range of disorders, this study offers a supramolecular approach to precisely control CRISPR/Cas9 functions under particular pathological contexts.

Portable Raman spectroscopy coupled with PLSR analysis for monitoring and predicting of the quality of fresh-cut Chinese yam at different storage temperatures.

Portable Raman spectroscopy coupled with partial least squares regression (PLSR) model was performed for monitoring and predicting four quality indicators, moisture content, water activity, polysaccharide content and microbial content of the fresh-cut Chinese yam at different storage temperatures. The variations in the four key indicators were first depicted through a spider web diagram as the storage temperature changed. More importantly, the four key indicators can be accurately monitored and predicted through optimized PLSR models combining with Raman spectroscopy. Among all of the PLSR models for the four indicators, the regression model for moisture content was relatively the best. In addition, storage temperature played a significant role on the model performance of PLSR. The model performance for all indicators at room temperature and high temperature was better than the corresponding PLSR models at refrigeration and freezing conditions. Especially at 25 ℃, the R2 in the calibration set basically reached 0.9. These observations indicated that portable Raman spectroscopy, a simple and easy-to-use detection technique, can monitor and predict the multiple quality indicators of fresh-cut Chinese yam combined with effectively PLSR model, which would be conducive to their applications in food industry.

Associations of dietary inflammatory index with low estimated glomerular filtration rate, albuminuria and chronic kidney disease in U.S adults: Results from the NHANES 2011-2018.

BACKGROUND AND AIMS: Chronic Kidney Disease (CKD) is characterized by a high inflammation status with ever-increasing prevalence, and defined as low estimated glomerular filtration rate (eGFR) or albuminuria. Both low eGFR and albuminuria can have independent effects on the body. The dietary inflammatory index (DII) is a validated tool used to assess the inflammatory potential of the diet. We aim to explore not only the association between DII and CKD, but also the associations of DII with low eGFR and albuminuria, respectively. In addition, their associations in different subgroups remain to be explored. METHODS AND RESULTS: 18,070 participants from the 2011-2018 NHANES with complete data of dietary intake and laboratory data were involved in our study. The data of 24-hour dietary recall interview was used to calculate DII, CKD could be reflected by laboratory data of creatinine and albumin. Then weighted multivariate logistic regression models and subgroup analyses were performed. The prevalence of low eGFR, albuminuria and CKD were 6.8%, 9.8% and 14.5%, respectively. A positive association between DII and low eGFR was observed (OR=1.12, 95%CI: 1.05-1.21), Q2, Q3 and Q4 are positively associated with a significant 39%, 65% and 71% increased risk of low eGFR compared with Q1 (P for trend<0.05). DII was also associated with CKD (OR=1.06, 95%CI: 1.01-1.11). CONCLUSION: Significant positive associations of DII with CKD and low eGFR were observed. But we didn't find such association between DII and albuminuria.

Reconstructive interpolation for pulse wave estimation to improve local PWV measurement of carotid artery.

Ultrasonic transit time (TT)-based local pulse wave velocity (PWV) measurement is defined as the distance between two beam positions on a segment of common carotid artery (CCA) divided by the TT in the pulse wave propagation. However, the arterial wall motions (AWMs) estimated from ultrasonic radio frequency (RF) signals with a limited number of frames using the motion tracking are typically discrete. In this work, we develop a method involving motion tracking combined with reconstructive interpolation (MTRI) to reduce the quantification errors in the estimated PWs, and thereby improve the accuracy of the TT-based local PWV measurement for CCA. For each beam position, normalized cross-correlation functions (NCCFs) between the reference (the first frame) and comparison (the remaining frames) RF signals are calculated. Thereafter, the reconstructive interpolation is performed in the neighborhood of the NCCFs' peak to identify the interpolation-deduced peak locations, which are more exact than the original ones. According to which, the improved AWMs are obtained to calculate their TT along a segment of the CCA. Finally, the local PWV is measured by applying a linear regression fit to the time-distance result. In ultrasound simulations based on the pulse wave propagation models of young, middle-aged, and elderly groups, the MTRI method with different numbers of interpolated samples was used to estimate AWMs and local PWVs. Normalized root mean squared errors (NRMSEs) between the estimated and preset values of the AWMs and local PWVs were calculated and compared with ones without interpolation. The means of the NRMSEs for the AWMs and local PWVs based on the MTRI method with one interpolated sample decrease from 1.14% to 0.60% and 7.48% to 4.61%, respectively. Moreover, Bland-Altman analysis and coefficient of variation were used to validate the performance of the MTRI method based on the measured local PWVs of 30 healthy subjects. In conclusion, the reconstructive interpolation for the pulse wave estimation improves the accuracy and repeatability of the carotid local PWV measurement.

Analysis of differentially expressed genes in torn rotator cuff tendon tissues in diabetic patients through RNA-sequencing.

BACKGROUND: Rotator cuff tears (RCT) is a common musculoskeletal disorder in the shoulder which cause pain and functional disability. Diabetes mellitus (DM) is characterized by impaired ability of producing or responding to insulin and has been reported to act as a risk factor of the progression of rotator cuff tendinopathy and tear. Long non-coding RNAs (lncRNAs) are involved in the development of various diseases, but little is known about their potential roles involved in RCT of diabetic patients. METHODS: RNA-Sequencing (RNA-Seq) was used in this study to profile differentially expressed lncRNAs and mRNAs in RCT samples between 3 diabetic and 3 nondiabetic patients. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed to annotate the function of the differentially expressed genes (DEGs). LncRNA-mRNA co-expression network and competing endogenous RNA (ceRNA) network were constructed to elucidate the potential molecular mechanisms of DM affecting RCT. RESULTS: In total, 505 lncRNAs and 388 mRNAs were detected to be differentially expressed in RCT samples between diabetic and nondiabetic patients. GO functional analysis indicated that related lncRNAs and mRNAs were involved in metabolic process, immune system process and others. KEGG pathway analysis indicated that related mRNAs were involved in ferroptosis, PI3K-Akt signaling pathway, Wnt signaling pathway, JAK-STAT signaling pathway and IL-17 signaling pathway and others. LncRNA-mRNA co-expression network was constructed, and ceRNA network showed the interaction of differentially expressed RNAs, comprising 5 lncRNAs, 2 mRNAs, and 142 miRNAs. TF regulation analysis revealed that STAT affected the progression of RCT by regulating the apoptosis pathway in diabetic patients. CONCLUSIONS: We preliminarily dissected the differential expression profile of lncRNAs and mRNAs in torn rotator cuff tendon between diabetic and nondiabetic patients. And the bioinformatic analysis suggested some important RNAs and signaling pathways regarding inflammation and apoptosis were involved in diabetic RCT. Our findings offer a new perspective on the association between DM and progression of RCT.

Rational design of a polypropylene composite foam with open-cell structure via graphite conductive network for sound absorption.

An exciting result is reported in this study where a polypropylene (PP) foam with a high open-cell content was achieved by constructing a thermally conductive network for the first time. PP and nano-graphite particles were used as substrate and filler, respectively, to prepare the PP-graphite (PP-G) composite foam by twin-screw blending, hot pressing, and supercritical CO2 foaming. The nano-graphite particles can effectively adjust the microstructure of the PP-G foam and achieve a high porosity. When the amount of nano-graphite is 10.0 wt%, the PP-G foam exhibits optimal sound absorption performance, compression resistance, heat insulation, and hydrophobic properties. In the human-sensitive frequency range of 1000-6000 Hz, the corresponding average SAC is above 0.9, and the internal tortuosity is 5.27. After 50 cycles of compression, the compressive stress is 980 kPa and the SAC loss is only 7.8%. This study also innovatively proposed a new strategy to achieve the simple and rapid preparation of open-cell PP foams by increasing the thermal conductivity of the foaming substrate.

Preparation of berberine hydrochloride-Ag nanoparticle composite antibacterial dressing based on 3D printing technology.

In recent years, Ag nanoparticle (Ag NP)-loaded antibacterial dressings have attracted much attention in high-level medical dressings. However, the high cytotoxicity of Ag NP has always been a problem. In this paper, we examined the improvement of antibacterial activity of berberine hydrochloride (BBR) with Ag NP, the results showed that the combined use of BBR and Ag NP can effectively reduce the dosage of Ag NP while ensuring the inhibition of bacterial growth, thus an intermediate layer dressing containing combined drugs were prepared. At the same time, the top dressing of polyvinyl alcohol (PVA) solid film and the PVA bottom dressings with three kinds of leakage structures were prepared by 3D printing technology. Three kinds of PVA bottom dressings showed high quality consistency, and the greater the number of leak holes, the higher the porosity value of the dressing, while the swelling ratio value of the bottom layer dressing with three holes was the lowest. Finally, three types of BBR-Ag NP composite antibacterial dressings (3D-BBR-Ag NP) can be obtained by self-assembling of the top dressing, the intermediate layer dressing, and the bottom dressings with three kinds of leakage structures. The cumulative drug release results showed that dressing with more holes had a faster drug release rate compared to the other two ones with fewer leakage holes. Besides, five drug release kinetic models were used to investigate the cumulative BBR release profiles for three types of 3D-BBR-Ag NP. And the three types of composite dressings showed strong antibacterial activity after 6 h of cultivation with staphylococcus aureus. The study showed that the antibacterial activity of the self-assembled dressing prepared by combination of BBR with Ag NP can be improved, and the drug release rate of the hydrogel dressing can be flexibly controlled through 3D printing technology.

A novel L-shaped ortho-quinone analog as PLK1 inhibitor blocks prostate cancer cells in G2 phase.

Prostate cancer is the most common malignant tumor among men worldwide. Currently, the main treatments are radical prostatectomy, radiotherapy, chemotherapy, and endocrine therapy. However, most of them are poorly effective and induce side effects. Polo-like kinase 1 (PLK1) regulates cell cycle and mitosis. Its inhibitor BI2536 promotes the therapeutic effect of nilotinib in chronic myeloid leukemia, enhances the sensitivity of neural tube cell tumors to radiation therapy and PLK1 silencing enhances the sensitivity of squamous cell carcinoma to cisplatin. Therefore, the aim of this study was to evaluate the effect of the PLK1 inhibitor L-shaped ortho-quinone analog TE6 on prostate cancer. In vitro on prostate cancer cells showed that TE6 inhibited PLK1 protein expression and consequently cell proliferation by blocking the cell cycle at G2 phase. In vivo on a subcutaneous tumor model in nude mice confirmed that TE6 effectively inhibited tumor growth in nude mice, inhibited PLK1 expression and regulated the expression of cell cycle proteins such as p21, p53, CDK1, Cdc25C, and cyclinB1. Thus, PLK1 was identified as the target protein of TE6, these results reveal the critical role of PLK1 in the growth and survival of prostate cancer and point out the ability of TE6 on targeting PLK1, being a potential drug for prostate cancer therapy.

Ultra-fast ultrasound blood flow velocimetry for carotid artery with deep learning.

Accurate measurement of blood flow velocity is important for the prevention and early diagnosis of atherosclerosis. However, due to the uncertainty of parameter settings, the autocorrelation velocimetry methods based on clutter filtering are prone to incorrectly filter out the near-wall blood flow signal, resulting in poor velocimetric accuracy. In addition, the Doppler coherent compounding acts as a low-pass filter, which also leads to low values of blood flow velocity estimated by the above methods. Motivated by this status quo, here we propose a deep learning estimator that combines clutter filtering and blood flow velocimetry based on the adaptive property of one-dimensional convolutional neural network (1DCNN). The estimator is operated by first extracting the blood flow signal from the original Doppler echo signal through an affine transformation of the 1D convolution, and then converting the extracted signal into the desired blood flow velocity using a linear transformation function. The effectiveness of the proposed method is verified by simulation as well as in vivo carotid artery data. Compared with typical velocimetry methods such as high-pass filtering (HPF) and singular value decomposition (SVD), the results show that the normalized root means square error (NRMSE) obtained by 1DCNN is reduced by 54.99 % and 53.50 % for forward blood flow velocimetry, and 70.99 % and 69.50 % for reverse blood flow velocimetry, respectively. Consistently, the in vivo measurements demonstrate that the goodness-of-fit of the proposed estimator is improved by 8.72 % and 4.74 % for five subjects. Moreover, the estimation time consumed by 1DCNN is greatly reduced, which costs only 2.91 % of the time of HPF and 12.83 % of the time of SVD. In conclusion, the proposed estimator is a better alternative to the current blood flow velocimetry, and is capable of providing more accurate diagnosis information for vascular diseases in clinical applications.

Molecular Imaging of ACE2 Expression in Infectious Disease and Cancer.

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that plays a critical role in the pathogenesis of SARS-CoV-2 infection. Through the use of ligands engineered for the receptor, ACE2 imaging has emerged as a valuable tool for preclinical and clinical research. These can be used to visualize the expression and distribution of ACE2 in tissues and cells. A variety of techniques including optical, magnetic resonance, and nuclear medicine contrast agents have been developed and employed in the preclinical setting. Positron-emitting radiotracers for highly sensitive and quantitative tomography have also been translated in the context of SARS-CoV-2-infected and control patients. Together this information can be used to better understand the mechanisms of SARS-CoV-2 infection, the potential roles of ACE2 in homeostasis and disease, and to identify potential therapeutic modulators in infectious disease and cancer. This review summarizes the tools and techniques to detect and delineate ACE2 in this rapidly expanding field.

A Self-Assembly Nano-Prodrug for Combination Therapy in Triple-Negative Breast Cancer Stem Cells.

Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.

Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia.

The majority of patients with acute myeloid leukemia (AML) succumb to the disease or its complications, especially among older patients. Natural killer (NK) cells have been shown to have antileukemic activity in patients with AML; however, to our knowledge, primary NK cells armed with a chimeric antigen receptor (CAR) targeting antigens associated with AML as an "off-the-shelf" product for disease control have not been explored. We developed frozen, off-the-shelf allogeneic human NK cells engineered with a CAR recognizing FLT3 and secreting soluble interleukin-15 (IL-15) (FLT3 CAR_sIL-15 NK) to improve in vivo NK cell persistence and T-cell activation. FLT3 CAR_sIL-15 NK cells had higher cytotoxicity and interferon gamma secretion against FLT3+ AML cell lines when compared with activated NK cells lacking an FLT3 CAR or soluble IL-15. Frozen and thawed allogeneic FLT3 CAR_sIL-15 NK cells prolonged survival of both the MOLM-13 AML model as well as an orthotopic patient-derived xenograft AML model when compared with control NK cells. FLT3 CAR_sIL-15 NK cells showed no cytotoxicity against healthy blood mononuclear cells or hematopoietic stem cells. Collectively, our data suggest that FLT3 is an AML-associated antigen that can be targeted by frozen, allogeneic, off-the-shelf FLT3 CAR_sIL-15 NK cells that may provide a novel approach for the treatment of AML.

RNA Hydrolysis at Mineral-Water Interfaces.

As an essential biomolecule for life, RNA is ubiquitous across environmental systems where it plays a central role in biogeochemical processes and emerging technologies. The persistence of RNA in soils and sediments is thought to be limited by enzymatic or microbial degradation, which occurs on timescales that are orders of magnitude faster than known abiotic pathways. Herein, we unveil a previously unreported abiotic pathway by which RNA rapidly hydrolyzes on the timescale of hours upon adsorption to iron (oxyhydr)oxide minerals such as goethite (α-FeOOH). The hydrolysis products were consistent with iron present in the minerals acting as a Lewis acid to accelerate sequence-independent hydrolysis of phosphodiester bonds comprising the RNA backbone. In contrast to acid- or base-catalyzed RNA hydrolysis in solution, mineral-catalyzed hydrolysis was fastest at circumneutral pH, which allowed for both sufficient RNA adsorption and hydroxide concentration. In addition to goethite, we observed that RNA hydrolysis was also catalyzed by hematite (α-Fe2O3) but not by aluminum-containing minerals (e.g., montmorillonite). Given the extensive adsorption of nucleic acids to environmental surfaces, we anticipate previously overlooked mineral-catalyzed hydrolysis of RNA may be prevalent particularly in iron-rich soils and sediments, which must be considered across biogeochemical applications of nucleic acid analysis in environmental systems.