DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

Over time cancer patients can become resistant to traditional treatments such as chemotherapy and radiotherapy. In some cases, this can be counteracted by administering a new type of treatment called immune checkpoint inhibition which harnesses a patient's own immune system to eradicate the tumor. However, a significant proportion of cancers remain resistant, even when these immunotherapy drugs are used. This is potentially caused by tumors reactivating a gene called DUX4, which is briefly turned on in the early embryo shortly after fertilization, but suppressed in healthy adults. Activation of DUX4 during the early stages of cancer has been shown to remove the cell surface proteins the immune system uses to recognize tumors. However, it remained unclear whether DUX4 changes the response to immunotherapy in more advanced cancers which have begun to spread and metastasize to other parts of the body. To investigate, Pineda and Bradley analyzed publicly available sequencing data which revealed the genes turned on and off in patients with different types of cancer. The analysis showed that DUX4 is reactivated in approximately 10­50% of advanced bladder, breast, kidney, prostate and skin cancers. Next, Pineda and Bradley studied a cohort of patients with advanced bladder cancer who had been treated with immune checkpoint inhibitors. They found that patients with tumors in which DUX4 had been turned back on had shorter survival times than patients who had not reactivated the gene. These results suggest that the activity of DUX4 could be used to predict which patients with advanced bladder cancer may benefit from immune checkpoint inhibitors. In the future, this work could be extended to see if DUX4 could be used as a prognostic tool for other types of cancer. Future studies could also investigate if the DUX4 gene could be a therapeutic target for mitigating resistance to immunotherapy in metastatic cancers.

Intracranial graft of bioresorbable polymer scaffolds loaded with human Dental Pulp Stem Cells in stab wound murine injury model.

The prevalence of central nervous system (CNS) dysfunction as a result of disease or trauma remains a clinically unsolved problem which is raising increased awareness in our aging society. Human Dental Pulp Stem Cells (hDPSCs) are excellent candidates to be used in tissue engineering and regenerative therapies of the CNS due to their neural differentiation ability and lack of tumorigenicity. Accordingly, they have been successfully used in animal models of spinal cord injury, stroke and peripheral neuropathies. The ideal therapy in brain injury should combine strategies aiming to protect the damaged lesion and, at the same time, accelerate brain tissue regeneration, thus promoting fast recovery while minimizing side or long-term effects. The use of bioresorbable nanopatterned poly(lactide-co-ɛ-caprolactone) (PLCL) polymeric scaffolds as hDPCSs carriers can represent an advantage for tissue regeneration. In this chapter, we describe the surgical procedures to implant functionalized bioresorbable scaffolds loaded with hDPSCs to improve the brain lesion microenvironment in an intracranial stab wound injury model severing the rostral migratory stream (RMS) that connects the brain subventricular zone (SVZ) and the olfactory bulb in nude mice. Additionally, we also describe the technical steps after animal sacrifice for histological tissue observation and characterization.

GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.

Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression.

OBJECTIVES: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response. METHODS: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions. RESULTS: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases. CONCLUSIONS: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.

Interobserver variability in thyroid ultrasound.

PURPOSE: Ultrasound evaluation of thyroid nodules is the preferred technique, but it is dependent on operator interpretation, leading to inter-observer variability. The current study aimed to determine the inter-physician consensus on nodular characteristics, risk categorization in the classification systems, and the need for fine needle aspiration puncture. METHODS: Four endocrinologists from the same center blindly evaluated 100 ultrasound images of thyroid nodules from 100 different patients. The following ultrasound features were evaluated: composition, echogenicity, margins, calcifications, and microcalcifications. Nodules were also classified according to ATA, EU-TIRADS, K-TIRADS, and ACR-TIRADS classifications. Krippendorff's alpha test was used to assess interobserver agreement. RESULTS: The interobserver agreement for ultrasound features was: Krippendorff's coefficient 0.80 (0.71-0.89) for composition, 0.59 (0.47-0.72) for echogenicity, 0.73 (0.57-0.88) for margins, 0.55 (0.40-0.69) for calcifications, and 0.50 (0.34-0.67) for microcalcifications. The concordance for the classification systems was 0.7 (0.61-0.80) for ATA, 0.63 (0.54-0.73) for EU-TIRADS, 0.64 (0.55-0.73) for K-TIRADS, and 0.68 (0.60-0.77) for K-TIRADS. The concordance in the indication of fine needle aspiration puncture (FNA) was 0.86 (0.71-1), 0.80 (0.71-0.88), 0.77 0.67-0.87), and 0.73 (0.64-0.83) for systems previously described respectively. CONCLUSIONS: Interobserver agreement was acceptable for the identification of nodules requiring cytologic study using various classification systems. However, limited concordance was observed in risk stratification and many ultrasonographic characteristics of the nodules.

Capecitabine-Related Thrombotic Microangiopathy.

PURPOSE: Renal injury is common in cancer patients and its etiology is multifactorial. Different patterns of renal histological lesions have been described in relation to oncologic treatments, notably acute tubular necrosis and tubulointerstitial nephritis, but also thrombotic microangiopathy (TMA). METHODS: We report a case of TMA secondary to capecitabine in an 82-year-old woman diagnosed with localized colon adenocarcinoma. RESULTS: The patient, with previous normal kidney function, presented with renal impairment during the fourth cycle of chemotherapy. After potential nephrotoxic factors were ruled out, capecitabine was discontinued and a kidney biopsy was performed, which displayed TMA lesions. An improvement in renal function was observed after definitive cessation of cytotoxic chemotherapy. Although rare, renal toxicity in the form of TMA may be associated with the use of cytotoxic agents such as gemcitabine, but there is no reported evidence of its association to capecitabine. Early withdrawal of the drug and nephrology consultation is necessary to prevent irreversible damage. CONCLUSION: We describe, to our knowledge, the first case reported in the literature regarding the possible association of TMA and capecitabine.

Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

Critical Emergency Department Interventions and Clinical Deterioration in Children With Nonsevere Traumatic Intracranial Hemorrhage.

OBJECTIVE: Substantial practice variation exists in the management of children with nonsevere traumatic intracranial hemorrhage (tICH). A comprehensive understanding of rates and timing of clinically important tICH, including critical interventions and deterioration, along with associated clinical and neuroradiographic characteristics, will inform accurate risk stratification. METHODS: We conducted a single-center retrospective cohort study of children aged younger than 18 years evaluated in the emergency department (ED) from May 1, 2014 to February 28, 2020 with tICH and initial Glasgow Coma Scale (GCS) score of higher than 8. We determined rates of clinically important tICH after injury and within 96 hours of ED arrival, defined as immediate ED interventions (intubation, hyperosmotic agents, or neurosurgery within 4 hours of arrival) or clinically important deterioration (signs/symptoms with change in management). Associations between outcome and clinical and neuroradiographic characteristics were calculated using individual logistic regression models. RESULTS: Our sample included 135 children. Clinically important tICH was observed in 13.3% (n = 18); 9 (6.7%) underwent immediate ED interventions and 9 (6.7%) developed deterioration. Most (93.3%, n = 127) presented with an initial GCS ≥ 14, including all children who later deteriorated. Initial GCS (P = 0.001) and nonaccidental trauma (P = 0.024) mechanism were associated with the outcome. None of the 71 (52.6%) children with initial GCS ≥ 14, isolated, nonepidural hemorrhage after accidental injury developed clinically important tICH. CONCLUSIONS: Clinically important tICH occurred in 13% of children with nonsevere tICH, and 7% of children who did not undergo immediate ED interventions later deteriorated, all of whom had an initial GCS ≥ 14. However, a subgroup of children was identified as low risk based on clinical and neuroradiographic characteristics.

Association Between COVID-19 and Severity of Illness for Children With Hyperglycemic Crisis.

OBJECTIVES: Admissions to the ICU for children with hyperglycemic crisis (HGC, defined as diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, or hyperosmolar ketoacidosis) increased during the COVID-19 pandemic. We sought to identify if severity of illness for HGC also increased from prepandemic to pandemic years 1 and 2. METHODS: Retrospective study of children aged ≤18 years hospitalized in the Pediatric Health Information System for HGC. Pre-COVID-19 years were defined as March 2017-February 2020, COVID-19 year 1 as March 2020-February 2021, and COVID-19 year 2 as March 2021-February 2022. The primary outcome was ICU admission. Secondary outcomes included mortality, length of stay, cost, and use of neurologic therapies, mechanical ventilation, or vasoactive support. RESULTS: There were 46 425 HGC admissions to 42 hospitals, 20 045 (43.2%) of which were ICU admissions. In comparison with pre-COVID-19, children admitted in COVID-19 year 1 (odds ratio, 1.31 [95% confidence interval, 1.25-1.38], P < .0001) and year 2 (odds ratio, 1.17 [95% confidence interval, 1.11-1.22], P < .0001) had a higher odds of ICU admission in multivariable modeling after controlling for confounding variables. Severity of illness was higher during COVID-19 years when considering secondary outcomes, although these associations were not consistent across outcomes and year. There was no difference in mortality. CONCLUSIONS: Children with HGC had a higher severity of illness during the pandemic which was sustained over 2 years. Reduction in social distancing and evolving variants of SARS-CoV-2 over the 2 years of the pandemic did not significantly alter the relationship between HGC and higher requirement for ICU care.

Benthic harmful microalgae and their impacts in South America.

Public awareness about Benthic Harmful Algal Blooms (BHABs) and their negative impacts has increased substantially over the past few decades. Even so, reports of BHABs remain relatively scarce in South America (SA). This paper provides a comprehensive overview of the current state of knowledge on BHABs in the continent, by integrating data from published articles, books, and technical reports. We recorded ∼300 different occurrences of potentially toxic BHAB species over the Caribbean, Atlantic and Pacific coasts, mostly in marine (>95%) but also in estuarine areas located from 12°36' N to 54°53' S. Over 70% of the data was published/released within the past 10 years, and ∼85% were concentrated in Brazil, Venezuela, Ecuador and Colombia. Benthic species were mainly associated with macroalgae, seagrass and sediment. Incidental detection in the plankton was also relevant, mainly in places where studies targeting BHAB species are still rare, like Argentina, Uruguay, Chile and Peru. The study listed 31 infrageneric taxa of potentially toxic benthic dinoflagellates and eight of estuarine cyanobacteria occurring in SA, with the greatest species diversity recorded in the equatorial-tropical zone, mainly in northeastern Brazil (Atlantic), Venezuela and Colombia (Caribbean), and the Galapagos Islands, Ecuador (Pacific). Local strains of Amphidinium, Gambierdiscus, Coolia and Prorocentrum spp. produced toxic compounds of emerging concern. Prorocentrum lima species complex was the most common and widely distributed taxon, followed by Ostreopsis cf. ovata. In fact, these two dinoflagellates were associated with most BHAB events in SA. Whereas the former has caused the contamination of multiple marine organisms and cases of Diarrhetic Shellfish Poisoning in subtropical and temperate areas, the latter has been associated with faunal mortalities and is suspected of causing respiratory illness to beach users in tropical places. Ciguatera Poisoning has been reported in Colombia (∼240 cases; no deaths) and Venezuela (60 cases; two deaths), and may be also a risk in other places where Gambierdiscus spp. and Fukuyoa paulensis have been reported, such as the Galapagos Islands and the tropical Brazilian coast. Despite the recent advances, negative impacts from BHABs in SA are intensified by limited research/training funding, as well as the lack of official HAB monitoring and poor analytical capability for species identification and toxin detection in parts of the continent.

[Academic satisfaction in residents of the north zone, Mexico City]. / Satisfacción académica en residentes de la zona norte, ciudad de México.

Background: Resident academic satisfaction has been linked to academic performance and quality of care. Objective: To analyze the perception of academic satisfaction in medical residents of the North Decentralized Administrative Operation Body 2 of the Instituto Mexicano del Seguro Social (IMSS), north of Mexico City. Material and methods: Cross-sectional analytical study. A total of 346 resident physicians of different specialties and academic degrees were found, enrolled in the residence halls in the northern zone of the IMSS, Mexico City from January to February 2022. The dependent variable was the level of academic satisfaction. Descriptive and inferential statistics and p ≤ 0.05 were produced for statistical significance. Results: The level of high satisfaction was 80.6% and the level of poor or low satisfaction was 1.7%. The dimension most affected in the negative bases was that of "Perception of teaching" in which 13% of the doctors surveyed refer to the need for some retraining of teachers. The best qualified dimension was "Perception of the role of autonomies" where 35.3% have an excellent perception of their personal work. The highest degree of satisfaction decreased during the second year. Conclusion: There is a high degree of satisfaction among resident doctors, however it is necessary to work to improve satisfaction in the remaining 20%.

Introducción: la satisfacción académica del residente se ha vinculado con el rendimiento académico y la calidad en la atención. Objetivo: analizar la percepción de la satisfacción académica en médicos residentes del Órgano de Operación Administrativa Desconcentrada 2 Norte del Instituto Mexicano del Seguro Social (IMSS), zona norte de la Ciudad de México. Material y métodos: estudio transversal analítico. Se encuestó a 346 médicos residentes de diferentes especialidades y grados académicos, inscritos en las sedes de residencia de la zona norte del IMSS, en la Ciudad de México de enero a febrero del 2022. La variable dependiente fue el nivel de satisfacción académica. Se utilizó estadística descriptiva, inferencial y p ≤ 0.05 para la significancia estadística. Resultados: el nivel de satisfacción alta fue del 80.6% y el nivel de satisfacción pobre o bajo fue del 1.7%. La dimensión más afectada en las puntuaciones negativas fue la de Percepción de la enseñanza, en la que el 13% de los médicos encuestados refieren la necesidad de algún reentrenamiento en los profesores. La dimensión mejor calificada fue la de Percepción del rol de autonomías, donde el 35.3% tienen una percepción excelente de su trabajo personal. El mayor grado de satisfacción se observó durante el segundo año. Conclusión: existe un alto grado de satisfacción entre médicos residentes; sin embargo, es necesario trabajar para mejorar la satisfacción en el 20% restante.

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over one year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

Assessment of Brain Magnetic Resonance and Spectroscopy Imaging Findings and Outcomes After Pediatric Cardiac Arrest.

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments. Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest. Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023. Exposure: Brain MRI or MRS. Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes. Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome. Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

A Survey of Pediatric Neurocritical Care Fellowship Training in North America.

BACKGROUND: Pediatric neurocritical care (PNCC) has emerged as a field to care for children at the intersection of critical illness and neurological dysfunction. PNCC fellowship programs evolved over the past decade to train physicians to fill this clinical need. We aimed to characterize PNCC fellowship training infrastructure and curriculum in the United States and Canada. METHODS: Web-based survey of PNCC fellowship program leaders during November 2019 to January 2020. RESULTS: There were 14 self-identified PNCC fellowship programs. The programs were supported by Child Neurology and/or Pediatric Critical Care Medicine divisions at tertiary/quaternary care institutions. Most programs accepted trainees who were board-eligible or board-certified in child neurology or pediatric critical care medicine. Clinical training consisted mostly of rotations providing PNCC consultation (n = 13) or as a provider on the pediatric intensive care unit-based neurointensive care team (n = 2). PNCC-specific didactics were delivered at most institutions (n = 13). All institutions provided training in electroencephalography use in the intensive care unit and declaration of death by neurological criteria (n = 14). Scholarly activity was supported by most programs, including protected time for research (n = 10). CONCLUSIONS: We characterized PNCC fellowship training in the United States and Canada, which in this continuously evolving field, lays the foundation for exploring standardization of training going forward.

The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response.

Cyclic GMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an antitumor immune response. Recent studies reveal that cGAS is frequently inhibited in cancer, and therapeutic targets to promote antitumor cGAS function remain elusive. SRC is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that SRC expression in primary and metastatic bladder cancer negatively correlates with innate immune gene expression and immune cell infiltration. We determine that SRC restricts cGAS signaling in human cell lines through SRC small molecule inhibitors, depletion, and overexpression. cGAS and SRC interact in cells and in vitro, while SRC directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. SRC phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces SRC inhibition. Collectively, our study demonstrates that cGAS antitumor signaling is hindered by the proto-oncogene SRC and describes how cancer-associated proteins can regulate the innate immune system.

[Cost-effectiveness of treatment of type 2 diabetes mellitus in México]. / Costo-efectividad del tratamiento de la diabetes mellitus tipo 2 en México.

Background: Type 2 Diabetes Mellitus (DM2) is a public health and socioeconomic problem, generating direct medical costs for its treatment. Objective: To analyze the cost-effectiveness of monotherapy and bitherapy treatments in patients with DM2. Methods: Cost-effectiveness, observational, ambispective, cross-sectional and analytical analysis of files in a first level medical unit. The data in the cost matrix was executed with the Office Excel 2010 program; the most prescribed drug was identified and compared with monotherapy and bitherapy. Results: The annual direct medical costs of the total population were drug cost $118,561.70MN, hospitalization cost $243,756.00MN, consultation cost $327,414.00MN and clinical trial cost $2416.79MN, obtaining an annual total of $692,148.58MN. metformin was the most indicated in monotherapy (88.4%) and as standard therapy it has higher cost-effectiveness compared to glibenclamide. In bitherapy it was metformin/glibenclamide (35.7%) versus the therapeutics of metformin/NPH insulin, metformin/insulin glargine and metformin/dapagliflozin, which had a better cost-effective result, with an incremental cost effectiveness of -$1,128,428.50MN, -$34,365.00 MN, -$119,848.97MN respectively. Conclusions: Metformin presented a better cost-effectiveness ratio in monotherapy, while in bitherapy it was the metformin/NPH insulin association.

Introducción: La Diabetes Mellitus tipo 2 (DM2) es un problema de salud pública y socioeconómico, tanto por su alta incidencia como por la generación de los costos médicos directos para su tratamiento. Objetivo: Analizar el costo-efectividad de los tratamientos en monoterapia y biterapia en pacientes con DM2. Métodos: Análisis costo-efectividad, observacional, ambispectivo, transversal y analítico. Análisis de expedientes en una unidad médica de primer nivel. Se ejecutaron los datos en la matriz de costos con el programa Office Excel 2010; se identificó el fármaco más prescrito, se comparó con monoterapia y biterapia. Resultados: Los costos médicos directos anuales del total de la población fueron: costo del medicamento $118,561.70MN, costo por hospitalización $243,756.00MN, costo por consultas $ 327,414.00MN y costo por estudios clínicos $2416.79MN, obteniendo un total anual de $692,148.58MN. La metformina fue la más indicada en monoterapia (88.4%) y como terapéutica estándar tiene mayor costo-efectividad comparada con la glibenclamida. En biterapia fue metformina/glibenclamida (35.7%) versus las terapéuticas de metformina/insulina NPH, metformina/insulina glargina y metformina/dapagliflozina, las cuales tuvieron un resultando más costo-efectivo, con un costo efectividad incremental de -$1,128,428.50MN, -$34,365.00MN, -$119,848.97MN respectivamente. Conclusiones: La metformina presento mejor relación costo efectividad en monoterapia, mientras que en biterapia fue la asociación metformina/Insulina NPH.

Notch and Wnt Signaling Modulation to Enhance DPSC Stemness and Therapeutic Potential.

The Dental Pulp of permanent human teeth is home to stem cells with remarkable multilineage differentiation ability: human Dental Pulp Stem Cells (DPSCs). These cells display a very notorious expression of pluripotency core factors, and the ability to give rise to mature cell lineages belonging to the three embryonic layers. For these reasons, several researchers in the field have long considered human DPSCs as pluripotent-like cells. Notably, some signaling pathways such as Notch and Wnt contribute to maintaining the stemness of these cells through a complex network involving metabolic and epigenetic regulatory mechanisms. The use of recombinant proteins and selective pharmacological modulators of Notch and Wnt pathways, together with serum-free media and appropriate scaffolds that allow the maintenance of the non-differentiated state of hDPSC cultures could be an interesting approach to optimize the potency of these stem cells, without a need for genetic modification. In this review, we describe and integrate findings that shed light on the mechanisms responsible for stemness maintenance of hDPSCs, and how these are regulated by Notch/Wnt activation, drawing some interesting parallelisms with pluripotent stem cells. We summarize previous work on the stem cell field that includes interactions between epigenetics, metabolic regulations, and pluripotency core factor expression in hDPSCs and other stem cell types.

Self-assembled three-dimensional hydrogels based on graphene derivatives and cerium oxide nanoparticles: scaffolds for co-culture of oligodendrocytes and neurons derived from neural stem cells.

Stem cell-based therapies have shown promising results for the regeneration of the nervous system. However, the survival and integration of the stem cells in the neural circuitry is suboptimal and might compromise the therapeutic outcomes of this approach. The development of functional scaffolds capable of actively interacting with stem cells may overcome the current limitations of stem cell-based therapies. In this study, three-dimensional hydrogels based on graphene derivatives and cerium oxide (CeO2) nanoparticles are presented as prospective supports allowing neural stem cell adhesion, migration and differentiation. The morphological, mechanical and electrical properties of the resulting hydrogels can be finely tuned by controlling several parameters of the self-assembly of graphene oxide sheets, namely the amount of incorporated reducing agent (ascorbic acid) and CeO2 nanoparticles. The intrinsic properties of the hydrogels, as well as the presence of CeO2 nanoparticles, clearly influence the cell fate. Thus, stiffer adhesion substrates promote differentiation to glial cell lineages, while softer substrates enhance mature neuronal differentiation. Remarkably, CeO2 nanoparticle-containing hydrogels support the differentiation of neural stem cells to neuronal, astroglial and oligodendroglial lineage cells, promoting the in vitro generation of nerve tissue grafts that might be employed in neuroregenerative cell therapies.