Helper T cell immunity in humans with inherited CD4 deficiency.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Cost-Effectiveness of Lorlatinib for the Treatment of Adult Patients with Anaplastic Lymphoma Kinase Positive Advanced Non-Small Cell Lung Cancer in Spain.

Purpose: The objective of the present study was to evaluate the efficiency of lorlatinib compared to alectinib and brigatinib for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously not treated, in Spain. Methods: A partitioned survival model comprised progression free, non-intracranial progression, intracranial progression, and death health states was constructed to estimate the total costs, life-years gained (LYG) and quality-adjusted life years (QALYs) accumulated in a lifetime horizon. Overall survival (OS) and progression-free survival (PFS) for lorlatinib were obtained from the CROWN study. For alectinib and brigatinib, a network meta-analysis of randomized controlled trials was conducted to estimate OS and PFS hazard ratios versus crizotinib. Utilities were estimated based on EQ-5D-5L data derived from the CROWN (lorlatinib), ALEX (alectinib) and ALTA-1L (brigatinib) studies. According to the Spanish National Health Service perspective the total costs (expressed in euros using a 2021 cost year) included drug acquisition and the administration's subsequent treatment, ALK+ advanced NSCLC management and adverse-event management, and palliative care. Unitary costs were obtained from local cost databases and literature. Costs, LYGs and QALYs were discounted at 3% annually. Deterministic and probabilistic sensitivity analyses were used to test the model's robustness. Results: Lorlatinib provided higher health outcomes (+0.70 LYG/patient, +1.42 QALYs/patient) and lower costs (-€9239/patient) than alectinib. Lorlatinib yielded higher LYG (+1.74) and QALYs (+2.30) versus brigatinib but higher costs/patient (+€36,627), resulting in an incremental-cost-effectiveness-ratio of €15,912/QALY gained. Conclusion: The results of this study suggest that lorlatinib may be a dominant treatment option versus alectinib. Considering a willingness-to-pay threshold of €25,000/QALY, lorlatinib may be an efficient option compared to brigatinib.

Anti-Ro52/TRIM21 antibodies are associated with aberrant inflammatory circuits in patients with systemic autoimmune rheumatic diseases.

INTRODUCTION: Anti-Ro52/TRIM21 antibodies are markers for several systemic autoimmune rheumatic diseases (SARD). OBJECTIVE: To assess whether anti-Ro52/TRIM21 antibodies are related to abnormalities in inflammatory circuits. METHODS: Cross-sectional study of consecutive outpatients with SARD. Anti-Ro52/TRIM21 antibodies and serum amyloid A protein were measured by ELISA; panels for 18 cytokines and nine chemokines were analyzed on a Luminex reading platform, while high-sensitivity C-reactive protein (hs-CRP) and complement were measured by nephelometry. RESULTS: Among 167 included patients, 143 had systemic lupus erythematosus (SLE), 16 had primary Sjögren's syndrome and eight had systemic sclerosis; 41 (24%) were positive for anti-Ro52/TRIM21 antibodies. Patients with anti-Ro52/TRIM21 antibodies had higher serum levels of IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP and chemokines CCL4, CXCL8, CXCL10 and CXCL12, but lower levels of complement C4. Anti-Ro52/TRIM21 antibody titers were positively correlated with IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10, and hs-CRP, and negatively with complements C3 and C4. When only SLE patients were included, no association was identified between anti-Ro52/TRIM21 antibodies and disease activity or organ-specific involvement. CONCLUSIONS: Anti-Ro52/TRIM21 antibodies are associated with aberrant cytokine circuits and elevated levels of angiogenic molecules and neutrophil and monocyte chemoattractants, which suggests an active role for these antibodies in SARD.

INTRODUCCIÓN: Los anticuerpos anti-Ro52/TRIM21 son marcadores de varias enfermedades reumáticas autoinmunes sistémicas (ERAS). OBJETIVO: Evaluar si los anticuerpos anti-Ro52/TRIM21 están relacionados con anomalías en los circuitos inflamatorios. MÉTODOS: Estudio transversal de pacientes consecutivos y ambulatorios con ERAS. Los anticuerpos anti-Ro52/TRIM21 y la proteína amiloide sérica se midieron mediante ELISA; los paneles para 18 citocinas y nueve quimiocinas se analizaron en una plataforma de lectura Luminex; la proteína C reactiva (hs-CRP) y el complemento se midieron mediante nefelometría. RESULTADOS: Se incluyeron 167 pacientes, 143 con lupus eritematoso sistémico (LES), 16 con síndrome de Sjögren primario y ocho con esclerosis sistémica; 41 fueron positivos para anticuerpos anti-Ro52/TRIM21 (24 %). Los pacientes con anticuerpos anti-Ro52/TRIM21 tuvieron niveles séricos más altos de IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP y quimiocinas CCL4, CXCL8, CXCL10 y CXCL12; y más bajos de complemento C4. Los títulos de anticuerpos anti-Ro52/TRIM21 correlacionaron positivamente con IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10 y hs-CRP; y negativamente con complemento C3 y C4. Al incluir solo LES, no se identificó asociación entre los anticuerpos anti-Ro52/TRIM21 y la actividad de la enfermedad o la afectación específica de órganos. CONCLUSIONES: Los anticuerpos anti-Ro52/TRIM21 se asocian a circuitos aberrantes de citocinas y niveles elevados de moléculas angiogénicas y quimioatrayentes de neutrófilos y monocitos, lo que sugiere un papel activo de esos anticuerpos en las ERAS.

Los anticuerpos anti-Ro52/TRIM21 están asociados a circuitos inflamatorios aberrantes en pacientes con enfermedades reumáticas autoinmunes sistémicas / Anti-Ro52/TRIM21 antibodies are associated with aberrant inflammatory circuits in patients with systemic autoimmune rheumatic diseases

Resumen Introducción: Los anticuerpos anti-Ro52/TRIM21 son marcadores de varias enfermedades reumáticas autoinmunes sistémicas (ERAS). Objetivo: Evaluar si los anticuerpos anti-Ro52/TRIM21 están relacionados con anomalías en los circuitos inflamatorios. Métodos: Estudio transversal de pacientes consecutivos y ambulatorios con ERAS. Los anticuerpos anti-Ro52/TRIM21 y la proteína amiloide sérica se midieron mediante ELISA; los paneles para 18 citocinas y nueve quimiocinas se analizaron en una plataforma de lectura Luminex; la proteína C reactiva (hs-CRP) y el complemento se midieron mediante nefelometría. Resultados: Se incluyeron 167 pacientes, 143 con lupus eritematoso sistémico (LES), 16 con síndrome de Sjögren primario y ocho con esclerosis sistémica; 41 fueron positivos para anticuerpos anti-Ro52/TRIM21 (24 %). Los pacientes con anticuerpos anti-Ro52/TRIM21 tuvieron niveles séricos más altos de IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP y quimiocinas CCL4, CXCL8, CXCL10 y CXCL12; y más bajos de complemento C4. Los títulos de anticuerpos anti-Ro52/TRIM21 correlacionaron positivamente con IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10 y hs-CRP; y negativamente con complemento C3 y C4. Al incluir solo LES, no se identificó asociación entre los anticuerpos anti-Ro52/TRIM21 y la actividad de la enfermedad o la afectación específica de órganos. Conclusiones: Los anticuerpos anti-Ro52/TRIM21 se asocian a circuitos aberrantes de citocinas y niveles elevados de moléculas angiogénicas y quimioatrayentes de neutrófilos y monocitos, lo que sugiere un papel activo de esos anticuerpos en las ERAS.

Abstract Introduction: Anti-Ro52/TRIM21 antibodies are markers for several systemic autoimmune rheumatic diseases (SARD). Objective: To assess whether anti-Ro52/TRIM21 antibodies are related to abnormalities in inflammatory circuits. Methods: Cross-sectional study of consecutive outpatients with SARD. Anti-Ro52/TRIM21 antibodies and serum amyloid A protein were measured by ELISA; panels for 18 cytokines and nine chemokines were analyzed on a Luminex reading platform, while high-sensitivity C-reactive protein (hs-CRP) and complement were measured by nephelometry. Results: Among 167 included patients, 143 had systemic lupus erythematosus (SLE), 16 had primary Sjögren's syndrome and eight had systemic sclerosis; 41 (24%) were positive for anti-Ro52/TRIM21 antibodies. Patients with anti-Ro52/TRIM21 antibodies had higher serum levels of IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP and chemokines CCL4, CXCL8, CXCL10 and CXCL12, but lower levels of complement C4. Anti-Ro52/TRIM21 antibody titers were positively correlated with IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10, and hs-CRP, and negatively with complement C3 and C4. When only SLE patients were included, no association was identified between anti-Ro52/TRIM21 antibodies and disease activity or organ-specific involvement. Conclusions: Anti-Ro52/TRIM21 antibodies are associated with aberrant cytokine circuits and elevated levels of angiogenic molecules and neutrophil and monocyte chemoattractants, which suggests an active role for these antibodies in SARD.

COVID-19: perspectivas terapéuticas en IL-17/Th17 / COVID-19: a perspective focus on IL-17/Th17

RESUMEN Las células T helper-17 (Th17) y la interleuquina (IL) IL-17 desempeñan funciones biológicas relacionadas con la protección contra infecciones por bacterias extracelulares y hongos. En algunas enfermedades inflamatorias y autoinmunes hay una secreción persistente y estas participan en su patogénesis. Recientemente, se ha postulado la participación de las respuestas IL-17/Th17 en la patogénesis de la enfermedad por coronavirus 2019 (COVID-19). El objetivo de esta revisión es resumir la evidencia del papel de la IL-17/Th17 en la inmunopatogénesis del COVID-19, como sustento de la possible utilización de los inhibidores de IL-17 en el manejo terapéutico de esta infección.

SUMMARY Interleukin 17 (IL-17)-producing helper T cells (Th17) and IL-17 play an important role in the defense against extracellular bacteria and fungi; however, persistent secretion of IL-17 is also an important component in the pathogenesis of many inflammatory and autoimmune diseases. Recent evidence suggests that Th17 cells and IL-17 are also involved in the immunopathogenesis of COVID-19. This review summarizes the evidence related with the role of Th17/IL-17 in severe COVID-19, which support the possible use of IL-17/IL-17R inhibitors in the treatment of this infection.

Bioinspired Threonine-Based Polymers with Potent Ice Recrystallization Inhibition Activity.

Ice growth mitigation is a pervasive challenge for multiple industries. In nature, ice-binding proteins (IBPs) demonstrate potent ice growth prevention through ice recrystallization inhibition (IRI). However, IBPs are expensive, difficult to produce in large quantities, and exhibit minimal resilience to nonphysiological environmental stressors, such as pH. For these reasons, researchers have turned to bioinspired polymeric materials that mimic IBP behavior. To date, however, no synthetic polymer has rivaled the ability of native IBPs to display IRI activity at ultralow nanomolar concentrations. In this work, we study the IRI activity of peptides and polypeptides inspired by common ice-binding residues of IBPs to inform the synthesis and characterization of a potent bioinspired polymer that mimics IBP behavior. We show first that the threonine polypeptide (pThr) displays the best IRI activity in phosphate-buffered saline (PBS). Second, we use pThr as a molecular model to synthesize and test a bioinspired polymer, poly(2-hydroxypropyl methacrylamide) (pHPMA). We show that pHPMA exhibits potent IRI activity in neutral PBS at ultralow concentrations (0.01 mg/mL). pHPMA demonstrates potent IRI activity at low molecular weights (2.3 kDa), with improved activity at higher molecular weights (32.8 kDa). These results substantiate that pHPMA is a robust molecule that mitigates ice crystal growth at concentrations similar to native IBPs.

La inmunología en Antioquia: una historia con futuro. III. El presente y los retos del futuro / Immunology in Antioquia: a history with future. III. It's present and challenges for the future

RESUMEN La inmunología es una de las ciencias biomédicas con mayor desarrollo en la segunda parte del siglo XX y principios del presente en al ámbito mundial. También ha tenido un desarrollo muy importante en Antioquia a partir de los años sesenta del siglo pasado. En la tercera parte de esta reseña histórica el autor expone, según su criterio, cuál es el estado actual y los retos futuros de la inmunología en lo científico, pedagógico y administrativo en la Universidad de Antioquia.

SUMMARY Immunology is one of the biomedical sciences that had, worldwide, a greater development in the last part of the XX century and the beginning of the present century. In Antioquia, immunology also had important developments that began in the 1960s. In the third part of this historical review, the author exposes his personal view about the present situation and the future challenges of immunology at the scientific, pedagogical and administrative levels in the Universidad de Antioquia.

Immune Response, Inflammation, and the Clinical Spectrum of COVID-19.

The current COVID-19 pandemic began in December 2019 in Wuhan (China) and rapidly extended to become a global sanitary and economic emergency. Its etiological agent is the coronavirus SARS-CoV-2. COVID-19 presents a wide spectrum of clinical manifestations, which ranges from an asymptomatic infection to a severe pneumonia accompanied by multisystemic failure that can lead to a patient's death. The immune response to SARS-CoV-2 is known to involve all the components of the immune system that together appear responsible for viral elimination and recovery from the infection. Nonetheless, such immune responses are implicated in the disease's progression to a more severe and lethal process. This review describes the general aspects of both COVID-19 and its etiological agent SARS-CoV-2, stressing the similarities with other severe coronavirus infections, such as SARS and MERS, but more importantly, pointing toward the evidence supporting the hypothesis that the clinical spectrum of COVID-19 is a consequence of the corresponding variable spectrum of the immune responses to the virus. The critical point where progression of the disease ensues appears to center on loss of the immune regulation between protective and altered responses due to exacerbation of the inflammatory components. Finally, it appears possible to delineate certain major challenges deserving of exhaustive investigation to further understand COVID-19 immunopathogenesis, thus helping to design more effective diagnostic, therapeutic, and prophylactic strategies.

La inmunología en Antioquia: una historia con futuro. I. La creación de una Escuela

Mundialmente la inmunología es una de las ciencias biomédicas con mayor desarrollo en la segunda parte del siglo xx y principios del siglo xxi, además ha tenido un desarrollo muy importante en Antioquia a partir de los años sesenta del siglo xx. En la presente reseña histórica, el autor, quien ha participado activamente durante cincuenta años como estudiante y profesor de inmunología en la Universidad de Antioquia, relata los momentos más significativos y el papel que han desempeñado algunos distinguidos profesores en el desarrollo de la investigación y la docencia de pregrado y posgrado en esta disciplina. En esta primera parte se relatan los antecedentes y los eventos que en las décadas de 1960 y 1970 permitieron establecer la inmunología como una disciplina biomédica independiente en la Universidad de Antioquia.

SUMMARY Immunology is one of the biomedical sciences that had undergo, worldwide, a greater development in the last part of the XX century and the beginning of the XXI century. In Antioquia, immunology also had important developments that began the 1960s. In this historical review, the author who have actively participated in these developments in the Universidad de Antioquia, as an undergraduate and graduate student and later on as faculty member, describes the more significant local events and the role played by some distinguished faculty members in research, and in undergraduate and graduate teaching of immunology. The first part describes the historical events that occurred in the 1960 and 1970 decades that lead to the establishment of immunology as an independent biomedical.

La inmunología en Antioquia: una historia con futuro. II. La consolidación de una disciplina / Immunology in Antioquia: a history with future. II. The consolidation of a discipline

RESUMEN La inmunología es una de las ciencias biomédicas con mayor desarrollo en la segunda parte del siglo XX y principios del presente en el mundo, también, ha tenido un desarrollo muy importante en Antioquia a partir de los años sesenta del siglo pasado. En la segunda parte de este recuento histórico, el autor relata los desarrollos ocurridos a finales de los años setenta, en la década de 1980 y la primera mitad de la década de 1990 que llevaron a la creación de los laboratorios, grupos de investigación y programas de posgrado en inmunología que permitieron que esta sea una de las disciplinas biomédicas más sobresalientes en la Universidad de Antioquia.

SUMMARY Immunology is one of the biomedical sciences that had, worldwide, a greater development in the last part of the XX century and the beginning of the present century. In Antioquia, immunology also had important developments that began the 1960s. In the second part of this historical review, the author describes the developments that occurred in the last years of the 1970s, the 1980s and the first half of the 1990s that lead to the establishment of the laboratories, groups and graduated programs Immunology that allowed immunology to be one of the more outstanding biomedical disciplines in the University of Antioquia.

Risk of infection and disease progression in children exposed to tuberculosis at home, Colombia / Riesgo de infección y progresión de la enfermedad en niños expuestos a tuberculosis en el hogar, Colombia

Abstract Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.

Resumen Objetivo: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). Métodos: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). Conclusión: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.

RNA proximity sequencing reveals the spatial organization of the transcriptome in the nucleus.

The global, three-dimensional organization of RNA molecules in the nucleus is difficult to determine using existing methods. Here we introduce Proximity RNA-seq, which identifies colocalization preferences for pairs or groups of nascent and fully transcribed RNAs in the nucleus. Proximity RNA-seq is based on massive-throughput RNA barcoding of subnuclear particles in water-in-oil emulsion droplets, followed by cDNA sequencing. Our results show RNAs of varying tissue-specificity of expression, speed of RNA polymerase elongation and extent of alternative splicing positioned at varying distances from nucleoli. The simultaneous detection of multiple RNAs in proximity to each other distinguishes RNA-dense from sparse compartments. Application of Proximity RNA-seq will facilitate study of the spatial organization of transcripts in the nucleus, including non-coding RNAs, and its functional relevance.

FREQUENCY OF DEPRESSION AND ANXIETY SYMPTOMS IN MEXICAN PATIENTS WITH RHEUMATIC DISEASES DETERMINED BY SELF-ADMINISTERED QUESTIONNAIRES ADAPTED TO THE SPANISH LANGUAGE.

BACKGROUND: The frequency of depression and anxiety symptoms in Spanish-speaking patients suffering from rheumatic conditions is unknown when using self-administered detection tools. METHODS: A single-center, cross-sectional survey including 413 patients (341 women) with well-defined rheumatic diseases was conducted. The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder (GAD)-7 questionnaires were used to detect depression and anxiety symptoms, respectively. RESULTS: A total of 193 patients (46.7%) reported depression symptoms, and increased PHQ-9 scores were more frequently observed in women than in men (23% vs. 13%; p = 0.038), particularly in association with osteoarthritis, fibromyalgia, Sjögren's syndrome, and osteoporosis. From 88 patients (21.3%) with PHQ-9 scores ≥ 10 points (moderate-to-severe depression symptoms), 27 (30.6%) were previously diagnosed to have depression and only four were under antidepressant treatment. Anxiety symptoms were observed in 168 patients (40.6%) and classified as moderate-to-severe by elevated GAD-7 scores in 68 subjects (16.4%). Of them, 12 (17.6%) were previously diagnosed with GAD, but only 4 (5.8%) were under therapy. CONCLUSIONS: An unexpected and unusually high frequency of undiagnosed depression and anxiety symptoms was found in rheumatic patients. Self-administered screening tools adapted to the Spanish language are useful and may help clinicians to suspect these conditions.

Microfluidic Model for Evaluation of Immune Checkpoint Inhibitors in Human Tumors.

Presented is the first demonstration of real-time monitoring of the response of resident lymphocyte populations in biopsied tumor tissue to immunotherapeutic agents in a perfused tumor microenvironment. This technology comprises a microfluidic tumor trapping device constructed from a novel 3D-printed, transparent, noncytotoxic substrate. The 3D-printed device sustains viability of biopsied tissue fragments under dynamic perfusion for at least 72 h while enabling simultaneous administration of various drug treatments, illustrating a useful tool for drug development and precision medicine for immunotherapy. Confocal microscopy of the tumor tissue and resident lymphocytes in the presence of fluorescent tracers provides real-time monitoring of tumor response to various immunotherapies. Devices are additively manufactured in Pro3dure GR-10 (i.e., a relatively new, high-resolution stereolithographic resin with properties suitable for biomedical applications), allowing integration of a set of finely featured functional components into a monolithically constructed platform. The presented platform comprises a new methodology for modeling and analyzing tumor response for the improved prediction of patient-specific immunotherapy efficacy. It is acknowledged that this is the first report of human tumor fragments cultured in a dynamic perfusion system capable of testing the effect of circulating immune checkpoint inhibitors on resident tumor-infiltrating lymphocytes.

Frequency of depression and anxiety symptoms in mexican patients with rheumatic diseases determined by self-administered questionnaires adapted to the spanish language

Abstract Background The frequency of depression and anxiety symptoms in Spanish-speaking patients suffering from rheumatic conditions is unknown when using self-administered detection tools. Methods A single-center, cross-sectional survey including 413 patients (341 women) with well-defined rheumatic diseases was conducted. The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder (GAD)-7 questionnaires were used to detect depression and anxiety symptoms, respectively. Results A total of 193 patients (46.7%) reported depression symptoms, and increased PHQ-9 scores were more frequently observed in women than in men (23% vs. 13%; p = 0.038), particularly in association with osteoarthritis, fibromyalgia, Sjögren’s syndrome, and osteoporosis. From 88 patients (21.3%) with PHQ-9 scores ≥ 10 points (moderate-to-severe depression symptoms), 27 (30.6%) were previously diagnosed to have depression and only four were under antidepressant treatment. Anxiety symptoms were observed in 168 patients (40.6%) and classified as moderate-to-severe by elevated GAD-7 scores in 68 subjects (16.4%). Of them, 12 (17.6%) were previously diagnosed with GAD, but only 4 (5.8%) were under therapy. Conclusions An unexpected and unusually high frequency of undiagnosed depression and anxiety symptoms was found in rheumatic patients. Self-administered screening tools adapted to the Spanish language are useful and may help clinicians to suspect these conditions.

XPS of carbon nanostructures obtained by underwater arc discharge of graphite electrodes / XPS de nanoestructuras de carbono obtenidas por descarga de arco de electrodos de grafito sumergidos en agua

Abstract Carbon nanostructures, obtained by underwater arc discharge of graphite electrodes, were studied by X-Ray Photoelectron Spectroscopy (XPS). It was observed that the spectra of the samples taken from the floating part of the synthesis products, composed basically by Carbon nano-onions (CNO), present differences with those obtained from the precipitate, which contains a mixture of CNOs and multi-walled Carbon Nanotubes (MWCNT). These differences are related with the presence of atoms of carbon located in orbitals with different degree of hybridization (sp2-sp3), which in turn is related to the diverse grade of curvature of the planes of carbon in the nanostructures present in the samples. The obtained results indicate that XPS can be an important element in the characterization of the products obtained by the above-mentioned method of synthesis.

Resumen Se utilizó la Espectroscopia Fotoelectrónica de Rayos X (XPS) para estudiar nanoestructuras de carbono obtenidas por descarga de arco de electrodos de grafito sumergidos en agua. Se observó que los espectros de las muestras tomadas de la fracción flotante de los productos de la síntesis, compuestas básicamente por nano-cebollas de carbono (CNO), presentan diferencias con los de las muestras obtenidas del precipitado, que contiene una mezcla de CNOs y nano-tubos de carbono de capas múltiples (MWCNT). Estas diferencias están asociadas con la presencia de átomos de carbono localizados en orbitales con diferente grado de hibridación (sp2-sp3), lo que a su vez se relaciona con las diferentes curvaturas de los planos de carbono en las nanoestructuras presentes en la muestras. Los resultados obtenidos indican que XPS puede ser un elemento importante en la caracterización de los productos obtenidos por el citado método de síntesis.

The role of CD30 and CD153 (CD30L) in the anti-mycobacterial immune response.

The establishment of a protective T-cell response against mycobacterial infections involves different co-stimulatory molecules and their respective ligands. Among these molecules the Tumor Necrosis Factor Receptor Super-family (TNFRSF) and the Tumor Necrosis Factor Super-family (TNFSF) are known to be important members. This review analyzes the evidence that CD30 and CD153 (CD30L), members of the TNFRSF and TNSF, play key roles in the T cell-dependent anti-mycobacterial immune response. Mice deficient in either CD30 or CD153, or treated with antibodies blocking the effects or CD30 and CD153, and infected with M.avium or M.bovis BCG exhibit higher bacterial burden, abnormal inflammatory responses with decreased Th1 responses, this is evidenced by the reduced number of IFN-γ-producing cells. Recent evidence also showed that CD30+ CD153+ Tγδ cells participate in the early stages of M.bovis BCG infection by producing IL-17A. In humans, stimulation of T-cells with mycobacterial antigens induces CD30 expression mainly by CD4+ cells; CD30+ cells have been demonstrated in tissues of patients with tuberculosis (TB) and in positive tuberculin skin test reactions. In addition, the levels of soluble CD30 are increased in serum and BAL of TB patients and these levels seems to correlate with the severity of the disease. These findings suggest that CD30/CD153 interactions during the anti-mycobacterial immune response are important for the establishment and maintenance of a protective response. Further studies would be required to determine whether these molecules may be good clinical biomarkers or potential targets for immune manipulation.

Electrospray-printed nanostructured graphene oxide gas sensors.

We report low-cost conductometric gas sensors that use an ultrathin film made of graphene oxide (GO) nanoflakes as transducing element. The devices were fabricated by lift-off metallization and near-room temperature, atmospheric pressure electrospray printing using a shadow mask. The sensors are sensitive to reactive gases at room temperature without requiring any post heat treatment, harsh chemical reduction, or doping with metal nanoparticles. The sensors' response to humidity at atmospheric pressure tracks that of a commercial sensor, and is linear with changes in humidity in the 10%-60% relative humidity range while consuming <6 µW. Devices with GO layers printed by different deposition recipes yielded nearly identical response characteristics, suggesting that intrinsic properties of the film control the sensing mechanism. The gas sensors successfully detected ammonia at concentrations down to 500 ppm (absolute partial pressure of ∼5 × 10(-4) T) at ∼1 T pressure, room temperature conditions. The sensor technology can be used in a great variety of applications including air conditioning and sensing of reactive gas species in vacuum lines and abatement systems.