Progressively Enhancing Stemness of Adoptively Transferred T Cells with PI3Kδ Blockade Improves Metabolism and Antitumor Immunity.

Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf1 and Lef1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only T-cell receptor-specific or chimeric antigen receptor (CAR)-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor-infiltrating lymphocytes and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef1 and Tcf1 sustained antitumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors. SIGNIFICANCE: Elevating T-cell stemness by progressively blocking PI3Kδ signaling during ex vivo manufacturing of adoptive cell therapies alters metabolic and functional properties to enhance antitumor immunity dependent on Tcf1 and Lef1.

Angiographic description of the anatomy and clinical aspects of the anterior interventricular artery in a group of Colombians individuals / Descripción angiográfica de los aspectos anatómicos y clínicos de la arteria interventricular anterior en un grupo de personas colombianas

Introduction: The anterior interventricular artery originates from the left coronary artery and irrigates the anterior surface of the ventricles, apex, and interventricular septum, making it the second most relevant artery of the heart. Objective: To describe the anatomical and clinical aspects of the anterior interventricular artery through angiography. Materials and methods: A descriptive study was conducted using 200 angiographic reports of Colombian individuals. The anterior interventricular artery's origin, course, patency, and coronary dominance were evaluated. Data related to chest pain, acute myocardial infarction, dyslipidemia, and electrocardiographic abnormalities were included. Statistical tests could not be performed due to this artery's low prevalence of anatomical variations. Results: One anterior interventricular artery was found to have originated from the left coronary sinus without a myocardial bridge, with no alteration in permeability, and with left dominance. The frequency of bridges was 2%, and the most frequent dominance was right in 86%; permeability alterations occurred in 43% mainly affecting S13. Twentyfive per cent presented chest pain; 40%, echocardiographic alterations; 5%, ischemic heart disease, and 59%, electrocardiographic alterations. Conclusions: Variations of origin of the anterior interventricular artery have a low prevalence according to reports from Chile, Colombia, and Spain. anterior interventricular artery myocardial bridges were scarce compared to other studies, suggesting better specificity of computed tomography angiography or direct dissection for these findings. The assessment of coronary permeability is graded with the thrombolysis in myocardial infarction scale; values 0 and 1 indicate occlusive lesion associated with ischemic heart disease. According to various techniques, the most frequent coronary dominance the right, followed by the left in men and balanced circulation in women.

Introducción: La arteria interventricular anterior se origina en la coronaria izquierda, irriga la cara anterior de los ventrículos, el ápex y el tabique interventricular; es la segunda arteria más relevante del corazón. OBJETIVO: Describir las características anatómicas y clínicas de la arteria interventricular anterior mediante angiografía. Materiales y métodos: Se realizó un estudio descriptivo con 200 reportes angiográficos de personas colombianas; se valoraron el origen, el trayecto y la permeabilidad de la arteria interventricular anterior, así como la dominancia coronaria. Se incluyeron datos relacionados con dolor precordial, infarto agudo de miocardio, dislipidemia y alteración electrocardiográfica. No fue posible hacer pruebas estadísticas, debido a la escasa prevalencia de variaciones anatómicas de dicha arteria. RESULTADOS: Se encontró una arteria interventricular anterior con su origen en el seno aórtico izquierdo, sin puente miocárdico, sin alteración de la permeabilidad y con dominancia izquierda. La frecuencia de los puentes fue del 2 % y la dominancia más frecuente fue la derecha en el 86 %. Se presentaron alteraciones de permeabilidad en el 43 % de los casos, las cuales afectaron principalmente al S13. El 25 % de los pacientes presentó dolor precordial; el 40 %, alteraciones ecocardiográficas; el 5 %, cardiopatía isquémica, y el 59 %, alguna alteración electrocardiográfica. CONCLUSIONES: Las variaciones en el origen de la arteria interventricular anterior son poco prevalentes, según reportes de Chile, Colombia y España. Los puentes miocárdicos de esta arteria fueron escasos respecto a otros estudios, lo cual sugiere mejor especificidad de los hallazgos de la angiotomografía o de la disección directa. La permeabilidad coronaria se valora con la escala TIMI (Thrombolysis in Myocardial Infarction); puntajes de 0 y 1 indican una lesión oclusiva asociada con cardiopatía isquémica. La dominancia coronaria más frecuente, según diversas técnicas, es la derecha, seguida de la izquierda en hombres y de una circulación balanceada en mujeres.

Descripción angiográfica de los aspectos anatómicos y clínicos de la arteria interventricular anterior en un grupo de personas colombianas

Introducción. La arteria interventricular anterior se origina en la coronaria izquierda, irriga la cara anterior de los ventrículos, el ápex y el tabique interventricular; es la segunda arteria más relevante del corazón. Objetivo. Describir las características anatómicas y clínicas de la arteria interventricular anterior mediante angiografía. Materiales y métodos. Se realizó un estudio descriptivo con 200 reportes angiográficos de personas colombianas; se valoraron el origen, el trayecto y la permeabilidad de la arteria interventricular anterior, así como la dominancia coronaria. Se incluyeron datos relacionados con dolor precordial, infarto agudo de miocardio, dislipidemia y alteración electrocardiográfica. No fue posible hacer pruebas estadísticas, debido a la escasa prevalencia de variaciones anatómicas de dicha arteria. Resultados. Se encontró una arteria interventricular anterior con su origen en el seno aórtico izquierdo, sin puente miocárdico, sin alteración de la permeabilidad y con dominancia izquierda. La frecuencia de los puentes fue del 2 % y la dominancia más frecuente fue la derecha en el 86 %. Se presentaron alteraciones de permeabilidad en el 43 % de los casos, las cuales afectaron principalmente al S13. El 25 % de los pacientes presentó dolor precordial; el 40 %, alteraciones ecocardiográficas; el 5 %, cardiopatía isquémica, y el 59 %, alguna alteración electrocardiográfica. Conclusiones. Las variaciones en el origen de la arteria interventricular anterior son poco prevalentes, según reportes de Chile, Colombia y España. Los puentes miocárdicos de esta arteria fueron escasos respecto a otros estudios, lo cual sugiere mejor especificidad de los hallazgos de la angiotomografía o de la disección directa. La permeabilidad coronaria se valora con la escala TIMI (Thrombolysis in Myocardial Infarction); puntajes de 0 y 1 indican una lesión oclusiva asociada con cardiopatía isquémica. La dominancia coronaria más frecuente, según diversas técnicas, es la derecha, seguida de la izquierda en hombres y de una circulación balanceada en mujeres.

Introduction. The anterior interventricular artery originates from the left coronary artery and irrigates the anterior surface of the ventricles, apex, and interventricular septum, making it the second most relevant artery of the heart. Objective. To describe the anatomical and clinical aspects of the anterior interventricular artery through angiography. Materials and methods. A descriptive study was conducted using 200 angiographic reports of Colombian individuals. The anterior interventricular artery's origin, course, patency, and coronary dominance were evaluated. Data related to chest pain, acute myocardial infarction, dyslipidemia, and electrocardiographic abnormalities were included. Statistical tests could not be performed due to this artery's low prevalence of anatomical variations. Results. One anterior interventricular artery was found to have originated from the left coronary sinus without a myocardial bridge, with no alteration in permeability, and with left dominance. The frequency of bridges was 2%, and the most frequent dominance was right in 86; permeability alterations occurred in 43% mainly affecting S13. Twenty-five per cent presented chest pain; 40%, echocardiographic alterations; 5%, ischemic heart disease, and 59%, electrocardiographic alterations. Conclusions. Variations of origin of the anterior interventricular artery have a low prevalence according to reports from Chile, Colombia, and Spain. anterior interventricular artery myocardial bridges were scarce compared to other studies, suggesting better specificity of computed tomography angiography or direct dissection for these findings. The assessment of coronary permeability is graded with the thrombolysis in myocardial infarction scale; values 0 and 1 indicate occlusive lesion associated with ischemic heart disease. According to various techniques, the most frequent coronary dominance the right, followed by the left in men and balanced circulation in women.

Multiplex Portable Biosensor for Bacteria Detection.

An advanced, cost-effective, and portable DNA biosensor capable of detecting multiple bacteria simultaneously has been developed. The biosensor comprises a fast and inexpensive potentiostat that controls the applied potential to a screen-printed electrochemical array platform functionalized with MoS2 flakes and bacterial DNA probes. The current response obtained by à la carte thionine functionalized carbon nanodots (Ty-CDs) is monitored as an electrochemical indicator of the hybridization event. The design of the potentiostat prioritizes achieving an optimal signal-to-noise ratio and incorporates a user-friendly interface compatible with various devices, including computers, mobile phones, and tablets. The device is compact, lightweight, and manufactured at a low cost. The key components of the potentiostat include a data acquisition board capable of analyzing multiple samples simultaneously and a controller board. The results of this study confirm the ability of the multiplex portable biosensor to successfully detect specific bacterial DNA sequences, demonstrating its reliability and superior performance compared with a traditional, more complex, and laboratory-oriented potentiostat.

Augmenting TCR signal strength and ICOS costimulation results in metabolically fit and therapeutically potent human CAR Th17 cells.

IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4+ T cells, the degree to which T cell antigen receptor (TCR) and costimulation signal strength influences Th17 immunity remains unknown. We discovered that decreasing TCR/costimulation signal strength by incremental reduction of αCD3/costimulation beads progressively altered Th17 phenotype. Moreover, Th17 cells stimulated with αCD3/inducible costimulator (ICOS) beads produced more IL-17A, IFNγ, IL-2, and IL-22 than those stimulated with αCD3/CD28 beads. Compared with Th17 cells stimulated with the standard, strong signal strength (three beads per T cell), Th17 cells propagated with 30-fold fewer αCD3/ICOS beads were less reliant on glucose and favored the central carbon pathway for bioenergetics, marked by abundant intracellular phosphoenolpyruvate (PEP). Importantly, Th17 cells stimulated with weak αCD3/ICOS beads and redirected with a chimeric antigen receptor that recognizes mesothelin were more effective at clearing human mesothelioma. Less effective CAR Th17 cells generated with high αCD3/ICOS beads were rescued by overexpressing phosphoenolpyruvate carboxykinase 1 (PCK1), a PEP regulator. Thus, Th17 therapy can be improved by using fewer activation beads during manufacturing, a finding that is cost effective and directly translatable to patients.

The degree of T cell stemness differentially impacts the potency of adoptive cancer immunotherapy in a Lef-1 and Tcf-1 dependent manner.

Generating stem memory T cells (T SCM ) is a key goal for improving cancer immunotherapy. Yet, the optimal way to modulate signaling pathways that enrich T SCM properties remains elusive. Here, we discovered that the degree to which the PI3Kδ pathway is blocked pharmaceutically can generate T cells with differential levels of stemness properties. This observation was based on the progressive enrichment of transcriptional factors of stemness (Tcf-1 and Lef-1). Additional investigation revealed that T cells with high stemness features had enhanced metabolic plasticity, marked by heightened mitochondrial function and glucose uptake. Conversely, T cells with low or medium features of stemness expressed more inhibitory checkpoint receptors (Tim-3, CD39) and were vulnerable to antigen-induced cell death. Only TCR-antigen specific T cells with high stemness persisted following adoptive transfer in vivo and mounted protective immunity to melanoma tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor infiltrating lymphocytes (TILs) and CAR T cells with heightened stemness properties, in turn bolstering their capacity to regress human mesothelioma tumors. We find that the level of stemness T cells possess in vitro differentially impacts their potency upon transfer in three tumor models. Mechanistically, both Lef-1 and Tcf-1 sustain anti-tumor protection by high T SCM , as deletion of either one compromised cellular therapy. Collectively, these findings highlight the therapeutic potential of carefully modulating PI3Kδ signaling in T cells to confer high stemness and mediate protective responses to solid tumors.

Spectra, fluence and absorbed doses in sensitive organs due to scattered X-rays during a chest CT.

The use of ionizing radiation for the treatment and diagnosis of diseases is becoming more frequent. The technologies associated with diagnostic imaging are constantly evolving, allowing faster and cheaper diagnoses to benefit the patient. However, this has caused an increase in the exposure to ionizing radiation of patients and health professionals. One of the diagnostic techniques for obtaining high-resolution anatomical images of patients is computed tomography (CT). Due to the detail and quality of the images obtained with CT, its use is becoming more frequent. The information provided by these images allows the specialist to make better diagnoses; however, exposure to X-rays deposits a dose in the patient. CT represents approximately 20% of all X-ray examinations but it is responsible for 70% of the medical dose accumulated by the patient. During the acquisition of the images, the highest dose is deposited in the area of the body whose image is to be obtained. During the incidence of X-rays, there is dispersion of these that reach sensitive organs whose dose is not evaluated. The objective of this work was to estimate, using Monte Carlo methods, the fluence and X-ray spectra and to obtain a factor that allows knowing the absorbed dose in sensitive organs due to scattered radiation during a chest CT. With the MCNP5 code, the CT equipment and a hybrid anthropomorphic phantom, type BOMAB it was found that the absorbed dose in these organs depends on the size of the organ and the distance between the organ and the surface of the slice on the thorax where the X-rays are incident.

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells.

Background: Mechanisms by which distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown. Methods: CD4 + T cells with a transgenic TCR that recognize TRP-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy. Results: We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (CTX at 200 mg/kg) at augmenting therapeutic activity of anti-tumor TRP-1 Th17 cells. Anti-tumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. IL-17 and IFN-g produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (G-CSF, IL-6, MCP-1, IL-5, and KC) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. Conclusions: Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by ACT, particularly as CD4 + based T cell therapies are now emerging in the clinic.

Doses and spectra, of leaking-out and scattered photons from X-ray tubes used in dentistry.

Diagnosis by X-ray image are procedures widely used to improve the diagnosis or to follow the evolution of a medical procedure, also are used to support the cancer treatment with linear accelerators. The procedure involves the X-ray unit and the detection system, while the X-ray beam is projected onto the patient; along this procedure X-rays are scattered out from the patient body and X-rays leak-out from the X-ray unit. Both, the scattered and the leaking out radiation, are important during the evaluation or the design of the shielding barriers. X-ray tube features like voltage, electric current, target and filter are related to the dose due to the scattered and leakage radiation. Also, the dose due to the scattered radiation depends upon the scattering angle; while the dose due to the leaking out radiation, depend upon the X-ray tube housing. The objective of this work was to estimate, using Monte Carlo methods, the X-ray spectra and doses (air Kerma and Ambient dose equivalent) produced by scattered and leaking out radiation of 70, 80 and 90 kV X-ray units.

Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer.

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy. SIGNIFICANCE: Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment.

Effect of changing the neutron moderator in a thermal subcritical nuclear reactor.

Subcritical thermal nuclear reactor is the combination of nuclear fuel, moderator and external neutron source. Nevertheless, the amount of neutrons increases through nuclear fissions in the 235U in the fuel, the absorption and leakage of neutrons maintain the subcriticality condition. There are several subcritical reactors with different features and purposes. The open tank subcritical reactor Nuclear Chicago model 9000 is the heterogeneous combination of natural uranium, in hexagonal lattice, and light water, acting as moderator and reflector of neutrons, that uses a239PuBe neutron source. Worldwide there are several of these reactors mainly used in education, where due to the contact with water the Al tubes have corrosion. A possible solution is to use polyethylene as moderator. Aiming to evaluate the effect of changing the moderator, in this work Monte Carlo methods were used to model the reactor with polyethylene and water as moderators increasing the fuel load. For each model were estimated the keff and the µ parameters, and for Case 10a model was calculated the power, the Ambient dose equivalent and the fluence, of neutrons and γ-rays at five sites outside the reactor.

Paving the way to point of care (POC) devices for SARS-CoV-2 detection.

In this work we present a powerful, affordable, and portable biosensor to develop Point of care (POC) SARS-CoV-2 virus detection. It is constructed from a fast, low cost, portable and electronically automatized potentiostat that controls the potential applied to a disposable screen-printed electrochemical platform and the current response. The potentiostat was designed to get the best signal-to-noise ratio, a very simple user interface offering the possibility to be used by any device (computer, mobile phone or tablet), to have a small and portable size, and a cheap manufacturing cost. Furthermore, the device includes as main components, a data acquisition board, a controller board and a hybridization chamber with a final size of 10 × 8 × 4 cm. The device has been tested by detecting specific SARS-CoV-2 virus sequences, reaching a detection limit of 22.1 fM. Results agree well with those obtained using a conventional potentiostat, which validate the device and pave the way to the development of POC biosensors. In this sense, the device has finally applied to directly detect the presence of the virus in nasopharyngeal samples of COVID-19 patients and results confirm its utility for the rapid detection infected samples avoiding any amplification process.

B cells imprint adoptively transferred CD8+ T cells with enhanced tumor immunity.

BACKGROUND: Adoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity. METHODS: In this study we investigated how tumor-specific murine CD8+ T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG. RESULTS: Herein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+ T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell-B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+ T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39low phenotype. CpG fostered the expansion of potent CD8+ T cells with the signature phenotype and antitumor ability via empowering a direct B-T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture. CONCLUSIONS: Our results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+ T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.

Psychiatric beds and prison populations in 17 Latin American countries between 1991 and 2017: rates, trends and an inverse relationship between the two indicators.

BACKGROUND: In 1990, Latin American countries committed to psychiatric reforms including psychiatric bed removals. Aim of the study was to quantify changes in psychiatric bed numbers and prison population rates after the initiation of psychiatric reforms in Latin America. METHODS: We searched primary sources to collect numbers of psychiatric beds and prison population rates across Latin America between the years 1991 and 2017. Changes of psychiatric bed numbers were compared against trends of incarceration rates and tested for associations using fixed-effects regression of panel data. Economic variables were used as covariates. Reliable data were obtained from 17 Latin American countries: Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Honduras, Guatemala, Mexico, Nicaragua, Panama, Paraguay, Peru, El Salvador, Uruguay and Venezuela. RESULTS: The number of psychiatric beds decreased in 15 out of 17 Latin American countries (median -35%) since 1991. Our findings indicate the total removal of 69 415 psychiatric beds. The prison population increased in all countries (median +181%). Panel data regression analyses showed a significant inverse relationship -2.70 (95% CI -4.28 to -1.11; p = 0.002) indicating that prison populations increased more when and where more psychiatric beds were removed. This relationship held up when introducing per capita income and income inequality as covariates -2.37 (95% CI -3.95 to -0.8; p = 0.006). CONCLUSIONS: Important numbers of psychiatric beds have been removed in Latin America. Removals of psychiatric beds were related to increasing incarceration rates. Minimum numbers of psychiatric beds need to be defined and addressed in national policies.

Modeling ex vivo tumor-infiltrating lymphocyte expansion from established solid malignancies.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) elicits the regression of metastatic malignancies, yet a low proportion of patients achieve complete durable responses. The high incidence of relapse in these patients highlights the need to better understand mechanisms of tumor escape from T cell control. While melanoma has provided the foundation for developing TIL therapy, much less is known about TIL efficacy and relapse in other malignancies. We sought to investigate TIL characteristics in mouse tumors which have not been studied in this setting. Here, we expanded murine TIL ex vivo in IL-2 from fragments of multiple tumor models, including oral cavity cancer models of varying immunogenicity. Additionally, TIL was expanded from pmel-1 mice bearing B16F10 melanoma, yielding an enriched population of tumor-infiltrating TCR transgenic T cells. Murine TIL are similar to human TIL in that they express high levels of inhibitory receptors (PD-1, Tim-3, etc.) and can be expanded ex vivo in IL-2 extensively. Of clinical relevance, we draw parallels between murine and human oral cavity cancer TIL, evaluating relationships between inhibitory receptor expression and function. This platform can be used by labs even in the absence of clinical specimens or clean cell facilities and will be important to more broadly understand TIL phenotypes across many different malignancies.

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy.

Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.

Microplastic pollution on sandy beaches of Puerto Rico.

Caribbean islands, including Puerto Rico, are biodiversity hotspots threatened by microplastics (<5 mm). Little is known about the extent of microplastic pollution in coastal sandy beaches of Puerto Rico. Sand from six northern beaches was collected in the high tide line to determine microplastic abundance (0.3-4.75 mm). Península La Esperanza, the most polluted beach, exhibited higher average abundance (17 items/kg dw) and diversity. High urbanization, industrial/port activities, and riverine input are likely sources of plastic debris on this beach. The other beaches showed lower and similar average abundance (3 to 7 items/kg dw) despite having distinct potential point and non-point sources. Overall, fibers (40%), fragments (28%) and foams (27%) predominated (n = 102 particles). Results showed comparable levels to other world beaches, some classified as highly contaminated, but only when transforming units to items/m2. Preliminary ATR-FTIR analysis identified mainly polyethylene. It is imperative to have plastics source reduction through waste management.

Shielding features of seven types on natural quartz.

The shielding features of amethyst, chalcedony, crystal rock, milky, pink, flint, and jasper quartz were calculated. The seven varieties of quartz were collected within the territory of the state of Zacatecas in Mexico. Shielding characteristics include the linear attenuation coefficients, the effective atomic numbers and the mass interaction coefficients for 1 keV to 100 GeV photons. The interaction coefficients were calculated for the coherent scattering, the photoelectric absorption, the Compton scattering, and the pair production occurring in the electric field of the atomic nucleus and the electrons. The linear attenuation coefficients were compared with those of the Portland concrete widely used as radiation shielding. In the low energy region where the photoelectric absorption is dominant the mass interaction coefficients and the total linear attenuation coefficients have three resonances due to the Si, Ca and Fe concentration, these resonances are also noticed in the effective atomic number. For photons below 60 keV the shielding performance of quartz can be used to shield X-ray devices working with less than 60 kV.

IL6 Fuels Durable Memory for Th17 Cell-Mediated Responses to Tumors.

The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo. While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3+ donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo. Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors. SIGNIFICANCE: An abbreviated, 4-day ex vivo expansion method licenses Th17 cells to confer long-lived immunity against solid malignancies via induction of systemic IL6 in the host.See related commentary by Fiering and Ho, p. 3795.