Diffuse large B-cell lymphoma associated with papillary thyroid carcinoma: a case report and systematic review on management and outcomes.

Primary thyroid lymphoma is a rare thyroid cancer, comprising ˂5% of thyroid neoplasms. Most cases are diffuse large B-cell lymphoma (DLBCL). Coexistence with papillary thyroid cancer (PTC) is extremely rare. This study presents a case of a 55-year-old woman with DLBCL and micropapillary thyroid cancer who underwent lobectomy, chemotherapy, and radiotherapy. Additionally, we performed a systematic review of 10 cases, including the reported case. The risk of bias in case reports varied. DLBCL diagnoses were mainly made after surgery, with total thyroidectomy being the most common surgical procedure. Chemotherapy was administered in most cases, and radiotherapy was used in some cases. Long-term outcomes indicated a low recurrence rate. While some debate the role of surgery in thyroid lymphoma, this study suggests that surgery should be considered in selected cases. Further research is needed to determine optimal treatment strategies for DLBCL with PTC.

Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report.

(1) Background and objectives: Maturity-onset diabetes of the young (MODY) is a group of diabetes caused by gene defects related to insulin secretion. MODY1, MODY2, and MODY3 are the most common and account for approximately 80% of all cases. Other types are relatively rare. This study describes the clinical, analytical, and genetic characteristics of a patient with MODY10, and diabetic nephropathy, retinopathy, and functional hypogonadism diagnosis. (2) Materials and methods: A clinical case was analyzed and whole exome generation sequencing (WES) was used to detect mutations related to a monogenic variant. (3) Results: A seventeen-year-old male patient, who was diagnosed with apparent type 1 diabetes at the age of eight was started with insulin therapy. He came to the emergency room with glycemic decompensation, facial, and lower limb edema. During his evaluation, he had near-nephrotic range proteinuria of 2902 mg/24 h, a kidney ultrasound showing mild pyelocalyceal dilation, proliferative diabetic retinopathy, and was also diagnosed with functional hypogonadotropic hypogonadism. These comorbidities improved with adequate glycemic control. WES showed missense variant c.94G>A (p.Gly32Ser) in the INS gene, according to Clinvar corresponding to MODY10. It was a "de novo" variant not reported in his parents. (4) Conclusions: Monogenic diabetes (MD) is rare and MODY10 is among the less frequent types. MODY should be suspected in patients with type 1 phenotype with negative autoimmunity even in the absence of a family history of diabetes. To the best of our knowledge, we present here the first patient with these phenotypic traits of MODY10 reported in Latin America.

Peptide-scFv antigen recognition domains effectively confer CAR T cell multiantigen specificity.

The emergence of immune escape is a significant roadblock to developing effective chimeric antigen receptor (CAR) T cell therapies against hematological malignancies, including acute myeloid leukemia (AML). Here, we demonstrate feasibility of targeting two antigens simultaneously by combining a GRP78-specific peptide antigen recognition domain with a CD123-specific scFv to generate a peptide-scFv bispecific antigen recognition domain (78.123). To achieve this, we test linkers with varying length and flexibility and perform immunophenotypic and functional characterization. We demonstrate that bispecific CAR T cells successfully recognize and kill tumor cells that express GRP78, CD123, or both antigens and have improved antitumor activity compared to their monospecific counterparts when both antigens are expressed. Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

Larvicidal and Adulticidal Activity of Essential Oils from Four Cuban Plants against Three Mosquito Vector Species.

Mosquitoes are one of the main vectors of many important diseases and their degree of resistance to chemical insecticides has increased. Nowadays, it has become crucial to identify novel plant larvicides with an eco-friendly impact. The components of essential oils from Croton linearis Jacq. (EO-Cl), Lantana involucrata L. (EO-Li), Ocimum sanctum var. cubensis M. Gómez. (EO-Os), and Zanthoxylum pistaciifolium Griseb. (syn. Zanthoxylum flavum subsp. pistaciifolium (Griseb.) Reynel (EO-Zp) were determined using gas chromatography-mass spectrometry (GC-MS) analysis. Larvicidal and adulticidal bioassays against Aedes aegypti, Anopheles albitarsis and Culex quinquefasciatus, were performed according to the World Health Organization standard methods. A high diversity of compounds was identified in the four oils, with a total of 152 compounds (33-70 components). EO-Cl, EO-Li, and EO-Os were classified as active against both insect forms, larvae and adults. Lantana involucrata showed the best results, with LC50 values from 33.8 to 41.7 mg/L. In most of the cases, it was not possible to associate the main compounds with the measured activity, supporting the hypothesis about probable synergistic interactions among major and minor compounds. The results indicate EO-Cl, EO-Os, and EO-Li as good eco-friendly insecticides with potential.

CAR T-cell Design-dependent Remodeling of the Brain Tumor Immune Microenvironment Modulates Tumor-associated Macrophages and Anti-glioma Activity.

Understanding the intricate dynamics between adoptively transferred immune cells and the brain tumor immune microenvironment (TIME) is crucial for the development of effective T cell-based immunotherapies. In this study, we investigated the influence of the TIME and chimeric antigen receptor (CAR) design on the anti-glioma activity of B7-H3-specific CAR T-cells. Using an immunocompetent glioma model, we evaluated a panel of seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, and activation domains. We then investigated changes in the TIME following CAR T-cell therapy using high-dimensional flow cytometry and single-cell RNA sequencing. Our results show that five out of six B7-H3 CARs with single costimulatory domains demonstrated robust functionality in vitro. However, these CARs had significantly varied levels of antitumor activity in vivo. To enhance therapeutic effectiveness and persistence, we incorporated 41BB and CD28 costimulation through transgenic expression of 41BBL on CD28-based CAR T-cells. This CAR design was associated with significantly improved anti-glioma efficacy in vitro but did not result in similar improvements in vivo. Analysis of the TIME revealed that CAR T-cell therapy influenced the composition of the TIME, with the recruitment and activation of distinct macrophage and endogenous T-cell subsets crucial for successful antitumor responses. Indeed, complete brain macrophage depletion using a CSF1R inhibitor abrogated CAR T-cell antitumor activity. In sum, our study highlights the critical role of CAR design and its modulation of the TIME in mediating the efficacy of adoptive immunotherapy for high-grade glioma. SIGNIFICANCE: CAR T-cell immunotherapies hold great potential for treating brain cancers; however, they are hindered by a challenging immune environment that dampens their effectiveness. In this study, we show that the CAR design influences the makeup of the immune environment in brain tumors, underscoring the need to target specific immune components to improve CAR T-cell performance, and highlighting the significance of using models with functional immune systems to optimize this therapy.

Psychometric properties of the self-efficacy scale for chronic disease management (SEMCD-S) in older Colombian adults.

BACKGROUND: Self-efficacy alludes to personal competence in an individual's effectiveness when facing stressful situations. This construct has been related to different domains of the health field, finding that high levels of self-efficacy benefit human functioning and enhance well-being. METHODS: The present study aimed to determine the psychometric properties of the self-efficacy scale for managing chronic diseases (SEMCD-S) by assessing factorial, convergent and divergent validity, reliability, and measurement invariance. Likewise, the comparison of self-efficacy according to socio-demographic characteristics was proposed by contrasting latent factors. An instrumental, transactional, descriptive, and non-experimental design study was carried out with the participation of 325 Colombian senior citizens. RESULTS: The findings suggest that the scale has appropriate psychometric properties. The one-factor structure exhibited a satisfactory fit, the mean-variance extracted reported acceptable figures and the correlation analysis with other constructs supported this instrument's convergent and discriminant validity. Likewise, it was invariant to the different socio-demographic aspects examined, while the internal consistency figures were high. Differences in the means of the latent factors were only detected in the academic grade. In this case, older adults with a primary school level attained higher self-efficacy values than those who had completed high school or university studies. CONCLUSIONS: It is concluded that the self-efficacy scale for chronic disease management is a valid and reliable instrument that can be used in the Colombian context to measure and compare this construct.

Epidemiology of Intracranial Meningiomas in Mexico: Cohort of the National Institute of Neurology and Neurosurgery During the Last Decade.

Introduction Meningiomas have been described as slow-growing neoplasms with benign behavior derived from the connective tissue surrounding the brain and spinal cord. Meningiomas represent one-third of primary central nervous system (CNS) tumors. The World Health Organization (WHO) initially classified them into three groups based on their histopathological characteristics, recently incorporating molecular patterns. Small cohorts have been reported in Latin America compared to the international literature. Ignoring the epidemiology of meningiomas in this region and considering this limitation, we aim to study the epidemiology of meningiomas in our country, Mexico. Material and methods A historical cohort was carried out on 916 patients diagnosed with intracranial meningiomas from January 2008 to January 2021, considering sociodemographic, topographic, and histopathological characteristics. Results In this study, 69.4% (n=636) of patients were women with a mean overall age of 47.53 (SD=14.85) years; 79.6% (n=729) of the lesions were supratentorial with convexity meningiomas being the most prevalent at 32.6% (n=299). Histopathologically, transitional (45.7%) (n=419), meningothelial (22.1%) (n=202), and fibroblastic (16.7%) (n=153) meningiomas were the most frequent. We found significant differences between men and women in age (p=0.01), infra or supratentorial presentation (p<0.001), location of the lesion (p<0.001), and histopathological characteristics (p<0.001). Conclusions Our results are consistent with what has been reported; however, until now, it appears as the largest series reported in our country and Latin America.

Ammonium affects the wet chemical network of HCN: feedback between prebiotic chemistry and materials science.

Prebiotic chemistry one-pot reactions, such as HCN-derived polymerizations, have been used as stimulating starting points for the generation of new multifunctional materials due to the simplicity of the processes, use of water as solvent, and moderate thermal conditions. Slight experimental variations in this special kind of polymerization tune the final properties of the products. Thus, herein, the influence of NH4Cl on the polymerization kinetics of cyanide under hydrothermal conditions and on the macrostructures and properties of this complex system is explored. The kinetics of the process is consistent with an autocatalytic model, but important variations in the polymerization reaction are observed according to a simple empirical model based on a Hill equation. The differences in the kinetic behaviour against NH4Cl were also revealed when the structural, morphological, thermal, electronic and magnetic properties of the synthesized cyanide polymers were compared, and these properties were evaluated by elemental analysis, FTIR, XPS, UV-vis, and ESR spectroscopies, X-ray diffraction, SEM and thermoanalytical techniques. As a result, this hydrothermal prebiotic polymerization is not only pH dependent, as previously thought, but also ammonium subservient. From this result, a hypothetical reaction mechanism was proposed, which involves the active participation of ammonium cations via formamidine and serves as a remarkable point against previous reports. The results discussed here expand the knowledge on HCN wet chemistry, offer an extended view of the relevant parameters during the simulation of hydrothermal scenarios and describe the production of promising paramagnetic and semiconducting materials inspired by prebiotic chemistry.

Left circumflex artery injury occurring during mitral valve surgery treated successfully with percutaneous intervention in a high surgical and bleeding risk patient.

Perioperative myocardial infarction is a complication of cardiac surgery, and the cause can be multifactorial. Injury of the left circumflex coronary artery has been described, particularly after mitral valve replacement. We present the case of a 72-year-old woman who underwent mitral valve replacement but developed a lesion in the proximal circumflex coronary artery related to partial mechanical kinking caused by a suture. The therapeutic options are surgical or percutaneous. In this patient, the percutaneous strategy was successful. Learning objective: • Percutaneous coronary intervention is an option in cases involving kinking of the left circumflex coronary artery after mitral valve replacement.• If unable to cross the lesion with a workhorse guide wire, one alternative is to use wires with good support properties and avoid very high tip loads to reduce the risk of perforation.In patients at high risk of bleeding, use of a drug-eluting stent and short-duration dual antiplatelet therapy is recommended.

Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia.

Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from the spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen, promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-ß secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity.

Understanding interactions between adoptively transferred immune cells and the tumor immune microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated the impact of the TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of B7-H3-specific CAR T-cells. We show that five out of six B7-H3 CARs with varying transmembrane, co-stimulatory, and activation domains, exhibit robust functionality in vitro. However, in an immunocompetent glioma model, these CAR T-cells demonstrated significantly varied levels of anti-tumor activity. We used single-cell RNA sequencing to examine the brain TIME after CAR T-cell therapy. We show that the TIME composition was influenced by CAR T-cell treatment. We also found that successful anti-tumor responses were supported by the presence and activity of macrophages and endogenous T-cells. Together, our study demonstrates that efficacy of CAR T-cell therapy in high-grade glioma is dependent on CAR structural design and its capacity to modulate the TIME.

In vivo active-targeting fluorescence molecular imaging with adaptive background fluorescence subtraction.

Using active tumor-targeting nanoparticles, fluorescence imaging can provide highly sensitive and specific tumor detection, and precisely guide radiation in translational radiotherapy study. However, the inevitable presence of non-specific nanoparticle uptake throughout the body can result in high levels of heterogeneous background fluorescence, which limits the detection sensitivity of fluorescence imaging and further complicates the early detection of small cancers. In this study, background fluorescence emanating from the baseline fluorophores was estimated from the distribution of excitation light transmitting through tissues, by using linear mean square error estimation. An adaptive masked-based background subtraction strategy was then implemented to selectively refine the background fluorescence subtraction. First, an in vivo experiment was performed on a mouse intratumorally injected with passively targeted fluorescent nanoparticles, to validate the reliability and robustness of the proposed method in a stringent situation wherein the target fluorescence was overlapped with the strong background. Then, we conducted in vivo studies on 10 mice which were inoculated with orthotopic breast tumors and intravenously injected with actively targeted fluorescent nanoparticles. Results demonstrated that active targeting combined with the proposed background subtraction method synergistically increased the accuracy of fluorescence molecular imaging, affording sensitive tumor detection.

Synapse-tuned CARs enhance immune cell anti-tumor activity.

Chimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics. Natural killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. In this study, we sought to tune CAR immune synapses by adding an intracellular scaffolding protein binding site to the CAR. We employ a PDZ binding motif (PDZbm) that enables additional scaffolding crosslinks that enhance synapse formation and NK CAR cell polarization. Combined effects of this CAR design result in increased effector cell functionality in vitro and in vivo. Additionally, we used T cells and observed similar global enhancements in effector function. Synapse-tuned CAR immune cells exhibit amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells and prolonged survival in numerous different tumor models, including solid tumors.

Vasa previa con inserción velamentosa de cordón: comunicación de un caso

La afección vasa previa es un hallazgo prenatal raro y poco frecuente de hemorragia en la segunda mitad del embarazo, en la que los vasos umbilicales desprovistos de la gelatina de Wharton se interponen entre la presentación fetal y el orificio cervical interno. Cuando no se la detecta y se produce la rotura de los vasos, se asocia a una alta tasa de mortalidad perinatal. Se describen 3 tipos; el caso presentado se trata de vasa previa de tipo 1 secundaria a inserción velamentosa de cordón. Fue diagnosticada prenatalmente mediante ecografía por vía transvaginal asociada a Doppler color. Se practicó una cesárea con evolución materno perinatal favorable.

Vasa previa is a rare and infrequent prenatal finding of hemorrhage in the second half of pregnancy, in which umbilical vessels devoid of Wharton's jelly interpose between the fetal presentation and the internal cervical os. When undetected and rupture of the vessels occurs, it is associated with a high perinatal mortality rate. Three types are described; the case presented is type 1 vasa previa secondary to velamentous insertion of the cord. It was diagnosed prenatally by transvaginal ultrasound associated with color Doppler. A cesarean section was performed with favorable maternal and perinatal evolution.

Distribución geográfica de la familia de caracoles terrestres Spiraxidae (Gastropoda: Pulmonata) en México / Geographic distribution of the land snail family Spiraxidae (Gastropoda: Pulmonata) in Mexico

Resumen Introducción: Spiraxidae es la familia de gasterópodos terrestres más diversa de México con una distribución principalmente neotropical. Sin embargo, la influencia de las condiciones ambientales de esta región en su distribución aún es poco conocida. Objetivo: Determinar las afinidades zoogeográficas y la influencia de factores ambientales en la distribución de Spiraxidae en México. Métodos: Compilamos registros de distribución de museos y usamos modelos para establecer áreas con composición de especies, concentración de especies, afinidades y relaciones con variables ambientales similares. Resultados: Encontramos 231 especies y subespecies, 96 en el estado de Veracruz y 74 en la Sierra Madre Oriental. La principal afinidad zoogeográfica fue neotropical. El bosque mesófilo de montaña tuvo la mayor cantidad de especies y subespecies (93). Tres de los grupos zonales tienen una composición particular de especies y el 67 % de las especies son especialistas de hábitat. La presencia de especies sigue un gradiente ambiental, con la cubierta de árboles de hoja perenne de hoja ancha y la precipitación media anual como variables determinantes. Las especies del norte tuvieron mayor tolerancia a la aridez y menor cobertura de hojas. Conclusiones: Spiraxidae tiene su mayor diversidad en los estados del Sur de México; sin embargo, la zona nororiental tiene más registros de especies. Estos caracoles se encuentran principalmente en bosques mesófilos de montaña y bosques tropicales siempre verdes. Las especies del norte de México tuvieron una mayor tolerancia a los sitios con poca lluvia y menos cobertura de árboles de hoja perenne de hoja ancha que las especies del sur.

Abstract Introduction: Spiraxidae is the most diverse family of terrestrial gastropods in Mexico with a mainly neotropical distribution. However, the influence of environmental conditions in this region on its distribution is still poorly known. Objective: To determine zoogeographic affinities and the influence of environmental factors on the distribution of Spiraxidae in Mexico. Methods: We compiled museum distribution records and used models to establish areas with similar species composition, species concentration, affinities and relationship with environmental variables. Results: We found 231 species and subspecies, 96 in Veracruz state and 74 in Sierra Madre Oriental. The main zoogeographic affinity was neotropical. Mountain mesophyll forest had the most species and subspecies (93). Three of zone groups have a particular species composition and 67 % of the species are habitat specialists. Species presence follows an environmental gradient, with broadleaf evergreen tree cover and average annual precipitation as determining variables. Northern species had greater tolerance to aridity and reduced leaf cover. Conclusions: Spiraxidae has its greatest diversity in the Southern states of Mexico; however, the Northeastern zone has more species records. These snails mostly occur in mesophyll mountain forest and tropical evergreen forest. Species from Northern Mexico had greater tolerance to sites with low rainfall and less broadleaf evergreen tree cover than Southern species.

Características clínicas, epidemiológicas y terapéuticas de pacientes con tumores malignos de células germinales en ovario. Instituto Oncológico Nacional

Objetivo: Determinar la características clínicas, epidemiológicas y terapéuticas de los tumores malignos de células germinales en ovario. Materiales y Métodos: Estudio descriptivo observacional transversal retrospectivo donde se evaluaron mediante expediente electrónico las características de 67 pacientes con diagnóstico de tumores malignos de células germinales de ovario atendidas en el Instituto Oncológico Nacional de enero 2012 a diciembre 2021. Resultados: La prevalencia de tumores malignos de células germinales de ovario en la población de estudio es de un 8.6%. El grupo etario predominante fue en la segunda y tercera década de la vida en un 80.59%. Casi un 40% de las pacientes son de grupo étnico originario. El tipo histológico más frecuente es el disgerminoma seguido de teratoma inmaduro, tumor mixto y tumor de seno endodérmico. 52% eran nuligestas. 96% de las pacientes presentaron algún síntoma al diagnóstico y el síntoma principal fue el dolor abdominal. No hubo asociación entre un marcador tumoral específico y tipo histológico. 95% recibió tratamiento quirúrgico. El 95.52% pudieron ser intervenidas quirúrgicamente, de esas un 89% se preservó la fertilidad. 60% ameritó quimioterapia y el esquema más usado fue Bleomicina, Etopósido y Platino. 6% recurrieron, 13% fallecieron, se obtuvo una supervivencia global de 86%.  Conclusión: Los tumores germinales malignos en nuestra población tienen una prevalencia de un 8.6%, predominan en la tercera década de la vida y en pacientes mestizas y originarias. Se desconoce la causa de la alta prevalencia en el grupo étnico originario. El tipo histológico más frecuente es el disgerminoma. No se evidenció correlación específica entre tipo histológico y marcador tumoral asociado. 6% de las pacientes con tumores malignos de células germinales recurren, 13% mueren, obteniendo una supervivencia global de 87%. (provisto por Infomedic International)

Objective: To determine the clinical, epidemiological and therapeutic characteristics of malignant ovarian germ cell tumors. Materials and Methods: Retrospective cross-sectional observational descriptive study where the characteristics of 67 patients with a diagnosis of malignant ovarian germ cell tumors attended at the National Oncologic Institute from January 2012 to December 2021 were evaluated by electronic file. Results: The prevalence of malignant ovarian germ cell tumors in the study population was 8.6%. The predominant age group was in the second and third decade of life in 80.59%. Almost 40% of the patients were of native ethnicity. The most frequent histologic type was dysgerminoma followed by immature teratoma, mixed tumor and endodermal breast tumor. 52% were nulligestosis. 96% of the patients had some symptoms at diagnosis and the main symptom was abdominal pain. There was no association between a specific tumor marker and histologic type. 95% received surgical treatment. 95.52% were able to undergo surgery, of which 89% had their fertility preserved. 60% required chemotherapy and the most commonly used scheme was Bleomycin, Etoposide and Platinum. 6% recurred, 13% died, an overall survival of 86% was obtained.  Conclusion: Malignant germinal tumors in our population have a prevalence of 8.6%, they predominate in the third decade of life and in mixed race and native patients. The cause of the high prevalence in the native ethnic group is unknown. The most frequent histological type is dysgerminoma. There was no specific correlation between histologic type and associated tumor marker. 6% of patients with malignant germ cell tumors recur, 13% die, obtaining an overall survival of 87%. (provided by Infomedic International)

Quantifying Radiosensitization of PSMA-Targeted Gold Nanoparticles on Prostate Cancer Cells at Megavoltage Radiation Energies by Monte Carlo Simulation and Local Effect Model.

Active targeting gold nanoparticles (AuNPs) are a very promising avenue for cancer treatment with many publications on AuNP mediated radiosensitization at kilovoltage (kV) photon energies. However, uncertainty on the effectiveness of AuNPs under clinically relevant megavoltage (MV) radiation energies hinders the clinical translation of AuNP-assisted radiation therapy (RT) paradigm. The aim of this study was to investigate radiosensitization mediated by PSMA-targeted AuNPs irradiated by a 6 MV radiation beam at different depths to explore feasibility of AuNP-assisted prostate cancer RT under clinically relevant conditions. PSMA-targeted AuNPs (PSMA-AuNPs) were synthesized by conjugating PSMA antibodies onto PEGylated AuNPs through EDC/NHS chemistry. Confocal fluorescence microscopy was used to verify the active targeting of the developed PSMA-AuNPs. Transmission electron microscopy (TEM) was used to demonstrate the intracellular biodistribution of PSMA-AuNPs. LNCaP prostate cancer cells treated with PSMA-AuNPs were irradiated on a Varian 6 MV LINAC under varying depths (2.5 cm, 10 cm, 20 cm, 30 cm) of solid water. Clonogenic assays were carried out to determine the in vitro cell survival fractions. A Monte Carlo (MC) model developed on TOPAS platform was then employed to determine the nano-scale radial dose distribution around AuNPs, which was subsequently used to predict the radiation dose response of LNCaP cells treated with AuNPs. Two different cell models, with AuNPs located within the whole cell or only in the cytoplasm, were used to assess how the intracellular PSMA-AuNP biodistribution impacts the prostate cancer radiosensitization. Then, MC-based microdosimetry was combined with the local effect model (LEM) to calculate cell survival fraction, which was benchmarked against the in vitro clonogenic assays at different depths. In vitro clonogenic assay of LNCaP cells demonstrated the depth dependence of AuNP radiosensitization under clinical megavoltage beams, with sensitization enhancement ratio (SER) of 1.14 ± 0.03 and 1.55 ± 0.05 at 2.5 cm depth and 30 cm depth, respectively. The MC microdosimetry model showed the elevated percent of low-energy photons in the MV beams at greater depth, consequently resulting in increased dose enhancement ratio (DER) of AuNPs with depth. The AuNP-induced DER reached ~5.7 and ~8.1 at depths of 2.5 cm and 30 cm, respectively. Microdosimetry based LEM accurately predicted the cell survival under 6 MV beams at different depths, for the cell model with AuNPs placed only in the cell cytoplasm. TEM results demonstrated the distribution of PSMA-AuNPs in the cytoplasm, confirming the accuracy of MC microdosimetry based LEM with modelled AuNPs distributed within the cytoplasm. We conclude that AuNP radiosensitization can be achieved under megavoltage clinical radiotherapy energies with a dependence on tumor depth. Furthermore, the combination of Monte Carlo microdosimetry and LEM will be a valuable tool to assist with developing AuNP-aided radiotherapy paradigm and drive clinical translation.

Prebiotic synthesis of noncanonical nucleobases under plausible alkaline hydrothermal conditions.

Herein, the potential of alkaline hydrothermal environments for the synthesis of possible ancestral pre-RNA nucleobases using cyanide as a primary source of carbon and nitrogen is described. Water cyanide polymerizations were assisted by microwave radiation to obtain high temperature and a relatively high pressure (MWR, 180 °C, 15 bar) and were also carried out using a conventional thermal system (CTS, 80 °C, 1 bar) to simulate subaerial and aerial hydrothermal conditions, respectively, on the early Earth. For these syntheses, the initial concentration of cyanide and the diffusion effects were studied. In addition, it is well known that hydrolysis conditions are directly related to the amount and diversity of organic molecules released from cyanide polymers. Thus, as a first step, we studied the effect of several hydrolysis procedures, generally used in prebiotic chemistry, on some of the potential pre-RNA nucleobases of interest, together with some of their isomers and/or deamination products, also presumably formed in these complex reactions. The results show that the alkaline hydrothermal scenarios with a relatively constant pH are good geological scenarios for the generation of noncanonical nucleobases using cyanide as a prebiotic precursor.

RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.