Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

Outcomes and Associated Extracardiac Malformations in Neonates from Colombia with Severe Congenital Heart Disease.

Congenital heart disease (CHD) is a common structural anomaly, affecting ~ 1% of live births worldwide. Advancements in medical and surgical management have significantly improved survival for children with CHD, however, extracardiac malformations (ECM) continue to be a significant cause of morbidity and mortality. Despite clinical significance, there is limited literature available on ECM in neonates with CHD, especially from Latin America. A cross-sectional study of neonates with severe CHD evaluated by the medical-surgical board team at Fundación Cardiovascular de Colombia from 2014 to 2019 was completed to characterize morbidity, mortality, surgical outcomes, and ECM. Demographics and surgical outcomes were compared between neonates with and without ECM. Medical record data were abstracted and descriptive statistical analysis was performed. Of 378 neonates with CHD, 262 had isolated CHD (69.3%) and 116 had ECM (30.7%). The most common ECM was gastrointestinal (n = 18, 15.5%) followed by central nervous system (n = 14, 12%). Most neonates required a biventricular surgical approach (n = 220, 58.2%). Genetic testing was performed more often for neonates with ECM (n = 65, 56%) than neonates with isolated CHD (n = 14, 5.3%). Neonates with ECM had lower birth weight, longer hospital stays, and higher postsurgical complications rates. There was no difference in survival between groups. Overall, Screening for ECM in neonates with CHD is important and identification of ECM can guide clinical decision-making. These findings have important implications for pediatric healthcare providers, especially in low- and middle-income countries, where the burden of CHD is high and resources for managing CHD and extracardiac malformations may be limited.

Smartphone Ownership, Minors' Well-being, and Parental Mediation Strategies. An Analysis in the Context of Social Media Influencers.

Although smartphone ownership among minors has become an important social phenomenon, its impact on children's and adolescents' well-being, as well as the mechanisms by which this might take place are not yet sufficiently well-established. To date, no research has examined the effect of smartphone ownership on the well-being of minors through the consumption of influencer-generated content, nor has it explored the effectiveness of the main prevention strategies employed by parents in this context. To fill those gaps, 800 Spanish minors (50% female) aged from 8 to 16 years old (M = 12.33, SD = 2.38) participated in a correlational study in which the ownership of electronic devices, the consumption of influencer generated content, the parasocial relationship with the influencer, and the most common parental mediation strategies were considered. The results showed a positive association between electronic device ownership and psychological discomfort, problematic usage, and imitation of dangerous behaviors. This association was mediated by the consumption of influencer-generated content and the parasocial relationship established by the minor with the influencer. Regarding preventive strategies, only active mediation was inversely related to poorer well-being indicators, however this positive effect significantly decreased when a smartphone or a similar electronic device was owned by the minor (vs. no owned). These findings contribute to the understanding of how smartphone ownership can affect the well-being of children, emphasizing the need for thoughtful consideration when deciding whether to provide smartphones to minors.

Adipose tissue homeostasis orchestrates the oxidative, energetic, metabolic and endocrine disruption induced by binge drinking in adolescent rats.

Binge drinking (BD) is the most common alcohol consumption model for adolescents, and has recently been related to the generation of high oxidation and insulin resistance (IR). White adipose tissue (WAT) is a target organ for insulin action that regulates whole-body metabolism by secreting adipokines. The present study aimed to analyse the oxidative, inflammatory, energetic and endocrine profile in the WAT of BD-exposed adolescent rats, to obtain an integrative view of insulin secretion and WAT in IR progression. Two groups of male adolescent rats were used: control (n = 8) and BD (n = 8). An intermittent i.p. BD model (20% v/v) was used during 3 consecutive weeks. BD exposure led to a pancreatic oxidative imbalance, which was joint to high insulin secretion by augmenting deacetylase sirtuin-1 (SIRT-1) pancreatic expression and serum adipsin levels. However, BD rats had hyperglycaemia and high homeostasis model assessment of insulin resistance value (HOMA-IR). BD exposure in WAT increased lipid oxidation, as well as decreased insulin receptor substrate 1 (IRS-1) and AKT expression, sterol regulatory element-binding protein 1 (SREBP1), forkhead box O3A (FOXO3a) and peroxisome proliferator-activated receptor γ (PPARγ), and adipocyte size. BD also affected the expression of proteins related to energy balance, such as SIRT-1 and AMP activated protein kinase (AMPK), affecting the adipokine secretion profile (increasing resistin/adiponectin ratio). BD altered the entire serum lipid profile, increasing the concentration of free fatty acids. In conclusion, BD led to an oxidative imbalance and IR process in WAT, which modified the energy balance in this tissue, decreasing the WAT lipogenic/lipolytic ratio, affecting adipokine secretion and the systemic lipid profile, and contributing to the progression of IR. Therefore, WAT is key in the generation of metabolic and endocrine disruption after BD exposure during adolescence in rats. KEY POINTS: Adolescent rat binge drinking (BD) exposure leads to hepatic and systemic oxidative stress (OS) via reactive oxygen species generation, causing hepatic insulin resistance (IR) and altered energy metabolism. In the present study, BD exposure in adolescent rats induces OS in the pancreas, with increased insulin secretion despite hyperglycaemia, indicating a role for IR in white adipose tissue (WAT) homeostasis. In WAT, BD produces IR and an oxidative and energetic imbalance, triggering an intense lipolysis where the serum lipid profile is altered and free fatty acids are increased, consistent with liver lipid accumulation and steatosis. BD exposure heightens inflammation in WAT, elevating pro-inflammatory and reducing anti-inflammatory adipokines, favouring cardiovascular damage. This research provides a comprehensive view of how adolescent BD in rats impacts liver, WAT and pancreas homeostasis, posing a risk for future cardiometabolic complications in adulthood.

Switchable CAR T cell strategy against osteosarcoma.

Immunotherapy with chimeric antigen receptor T (CAR T) cells has changed the treatment of hematological malignances, but they are still a challenge for solid tumors, including pediatric sarcomas. Here, we report a switchable CAR T cell strategy based on anti-FITC CAR T cells and a switch molecule conjugated with FITC for targeting osteosarcoma (OS) tumors. As a potential target, we analyzed the expression of B7-H3, an immune checkpoint inhibitor, in OS cell lines. In addition, we evaluate the capacity of an anti-B7-H3 monoclonal antibody conjugated with FITC (anti-B7-H3-FITC mAb) to control the antitumor activity of anti-FITC CAR T cells. The effector functions of anti-FITC CAR T cells against OS, measured in vitro by tumor cell killing activity and cytokine production, are dependent on the presence of the anti-B7-H3-FITC mAb switch. Moreover, OS cells stimulate anti-FITC CAR T cells migration. In vivo, anti-B7-H3 mAb penetrates in the tumor and binds 143B OS tumor cells. Furthermore, anti-FITC CAR T cells reach tumor region and exert antitumor effect in an OS NSG mouse model only in the presence of the switch molecule. We demonstrate that anti-B7-H3-FITC mAb redirects the cytotoxic activity of anti-FITC CAR T cells against OS tumors suggesting that switchable CAR T cell platforms might be a plausible strategy against OS.

Tocilizumab-related hypertriglyceridemia is independent of key molecules regulating lipid metabolism.

INTRODUCTION: Tocilizumab (TCZ) treatment is associated with dyslipidaemia, including a rise in triglycerides through a mechanism poorly understood. Three molecules play key roles in the regulation of triglyceride metabolism: apolipoprotein C-III (ApoC-III), angiopoietin-like protein 4(ANGPLT4) and lipoprotein lipase (LPL). The aim of this work was to analyse whether the changes in triglycerides shown by TCZ-treated RA patients could stem from the dysregulation that can occur in these regulatory molecules. METHODS: Twenty-seven RA patients included in the TOCRIVAR study who received TCZ (8 mg/kg IV/q4w) were evaluated at baseline and at Weeks 12, 24 and 52 of treatment. ANGPTL4, ApoC-III and LPL, a complete lipid profile and RA disease activity, were analysed at baseline and at each visit. Multivariable linear mixed models were performed to study changes over time in lipids and regulatory molecules. RESULTS: After 24 weeks of TCZ treatment, HDL cholesterol, apolipoprotein A1 and triglycerides increased, whereas lipoprotein (a) decreased significantly from baseline values. However, 1 year after TCZ, no significant differences in lipid pattern were observed with respect to baseline. Serum ANGPTL4 and Apo-CIII levels decreased gradually over time, both being significantly lower than baseline values at Week 52. LPL concentration did not change significantly during TCZ treatment. Remarkably, the elevation of triglycerides at Week 24 maintained its statistical significance after adjusting for the changes in ApoC-III, ANGPTL4 and LPL. CONCLUSION: In TCZ-treated RA patients basal serum levels of ANGPLT4 and ApoC-III, but not LPL, decreased significantly. However, the elevation of triglycerides after TCZ was not related to changes in these regulatory molecules.

Radiological features characterising indeterminate testes masses: a systematic review and meta-analysis.

CONTEXT: The use of scrotal ultrasonography (SUS) has increased the detection rate of indeterminate testicular masses. Defining radiological characteristics that identify malignancy may reduce the number of men undergoing unnecessary radical orchidectomy. OBJECTIVE: To define which SUS or scrotal magnetic resonance imaging (MRI) characteristics can predict benign or malignant disease in pre- or post-pubertal males with indeterminate testicular masses. EVIDENCE ACQUISITION: This systematic review was conducted in accordance with Cochrane Collaboration guidance. Medline, Embase, Cochrane controlled trials and systematic reviews databases were searched from (1970 to 26 March 2021). Benign and malignant masses were classified using the reported reference test: i.e., histopathology, or 12 months progression-free radiological surveillance. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). EVIDENCE SYNTHESIS: A total of 32 studies were identified, including 1692 masses of which 28 studies and 1550 masses reported SUS features, four studies and 142 masses reported MRI features. Meta-analysis of different SUS (B-mode) values in post-pubertal men demonstrated that a size of ≤0.5 cm had a significantly lower odds ratio (OR) of malignancy compared to masses of >0.5 cm (P < 0.001). Comparison of masses of 0.6-1.0 cm and masses of >1.5 cm also demonstrated a significantly lower OR of malignancy (P = 0.04). There was no significant difference between masses of 0.6-1.0 and 1.1-1.5 cm. SUS in post-pubertal men also had a statistically significantly lower OR of malignancy for heterogenous masses vs homogenous masses (P = 0.04), hyperechogenic vs hypoechogenic masses (P < 0.01), normal vs increased enhancement (P < 0.01), and peripheral vs central vascularity (P < 0.01), respectively. There were limited data on pre-pubertal SUS, pre-pubertal MRI and post-pubertal MRI. CONCLUSIONS: This meta-analysis identifies radiological characteristics that have a lower OR of malignancy and may be of value in the management of the indeterminate testis mass.

Economic burden of locoregional and metastatic relapses in resectable early-stage non-small cell lung cancer in Spain.

BACKGROUND: There are scarce data of the costs of non-small cell lung cancer (NSCLC) recurrence in Spain. The objective of this study is to assess the economic burden of disease recurrence, for both locoregional and/or metastatic relapses, after appropriate early-stage NSCLC treatment in Spain. MATERIALS AND METHODS: A two-round consensus panel of Spanish oncologists and hospital pharmacists was conducted to collect information on patient's flow, treatments, use of healthcare resources and sick leaves in patients with relapsed NSCLC. A decision-tree model was developed to calculate the economic burden of disease recurrence after appropriate early-stage NSCLC. Both direct and indirect costs were considered. Direct costs included drug acquisition and healthcare resources costs. Indirect costs were estimated using the human-capital approach. Unit costs were obtained from national databases (euros of 2022). A multi-way sensitivity analysis was performed to provide a range to the mean values. RESULTS: Among a cohort of 100 patients with relapsed NSCLC, 45 patients would have locoregional relapse (36.3 would eventually progress to metastasis and 8.7 would be considered in remission) and 55 patients would have metastatic relapse. Over time, 91.3 patients would experience a metastatic relapse (55 as first relapse and 36.6 after previous locoregional relapse). The overall cost incurred by the 100-patients cohort is €10,095,846 (€9,336,782 direct costs, €795,064 indirect costs). The average cost of a locoregional relapse is €25,194 (€19,658 direct costs, €5536 indirect costs), while the average cost a patient with metastasis who receives up to 4 lines of treatment is €127,167 (€117,328 direct, €9839 indirect). CONCLUSIONS: To our knowledge, this is the first study that specifically quantifies the cost of relapse in NSCLC in Spain. Our findings shown that the overall cost of a relapse after appropriate treatment of early-stage NSCLC patients is substantial, and it increases considerably in the metastatic relapse setting, mainly due to the high cost and long duration of first-line treatments.

Effects of three spontaneous ventilation modes on respiratory drive and muscle effort in COVID-19 pneumonia patients.

BACKGROUND: High drive and high effort during spontaneous breathing can generate patient self-inflicted lung injury (P-SILI) due to uncontrolled high transpulmonary and transvascular pressures, with deterioration of respiratory failure. P-SILI has been demonstrated in experimental studies and supported in recent computational models. Different treatment strategies have been proposed according to the phenotype of elastance of the respiratory system (Ers) for patients with COVID-19. This study aimed to investigate the effect of three spontaneous ventilation modes on respiratory drive and muscle effort in clinical practice and their relationship with different phenotypes. This was achieved by obtaining the following respiratory signals: airway pressure (Paw), flow (V´) and volume (V) and calculating muscle pressure (Pmus). METHODS: A physiologic observational study of a series of cases in a university medical-surgical ICU involving 11 mechanically ventilated patients with COVID-19 pneumonia at the initiation of spontaneous breathing was conducted. Three spontaneous ventilation modes were evaluated in each of the patients: pressure support ventilation (PSV), airway pressure release ventilation (APRV), and BiLevel positive airway pressure ventilation (BIPAP). Pmus was calculated through the equation of motion. For this purpose, we acquired the signals of Paw, V´ and V directly from the data transmission protocol of the ventilator (Dräger). The main physiological measurements were calculation of the respiratory drive (P0.1), muscle effort through the ΔPmus, pressure‒time product (PTP/min) and work of breathing of the patient in joules multiplied by respiratory frequency (WOBp, J/min). RESULTS: Ten mechanically ventilated patients with COVID-19 pneumonia at the initiation of spontaneous breathing were evaluated. Our results showed similar high drive and muscle effort in each of the spontaneous ventilatory modes tested, without significant differences between them: median (IQR): P0.1 6.28 (4.92-7.44) cm H2O, ∆Pmus 13.48 (11.09-17.81) cm H2O, PTP 166.29 (124.02-253.33) cm H2O*sec/min, and WOBp 12.76 (7.46-18.04) J/min. High drive and effort were found in patients even with low Ers. There was a significant relationship between respiratory drive and WOBp and Ers, though the coefficient of variation widely varied. CONCLUSIONS: In our study, none of the spontaneous ventilatory methods tested succeeded in reducing high respiratory drive or muscle effort, regardless of the Ers, with subsequent risk of P-SILI.

On-the-Fly Phase Transition and Density Changes of Aqueous Two-Phase Systems on a Centrifugal Microfluidic Platform.

This paper describes on-the-fly physical property changes of aqueous two-phase systems (ATPS) in microfluidic devices. The properties and phases of the ATPS are modulated on-demand by using a centrifugal microfluidic device filled with poly(ethylene glycol) (PEG) and dextran (DEX) solutions. By use of the centrifugal force and active pneumatic controls provided by a centrifugal microfluidic platform (CMP), PEG-DEX mixtures are manipulated and processed inside simple thermoplastic microfluidic devices. First, we experimentally demonstrate an on-chip ATPS transition from two phases to a single phase and vice versa by dynamically changing the concentration of the solution to bring ATPS across the binodal curve. We also demonstrate a density modulation scheme by introducing an ATPS solution mixed with sodium diatrizoate hydrate, which allows to increase the liquid density. By adding precisely metered volumes of water, we spontaneously change the density of the solution on the CMP and show that density marker microbeads fall into the solution according to their corresponding densities. The measured densities of ATPS show a good agreement with densities of microbeads and analytical plots. The results presented in this paper highlight the tremendous potential of CMPs for performing complex on-chip processing of ATPS. We anticipate that this method will be useful in applications such as microparticle-based plasma protein analysis and blood cell fractionation.

Fermented goat's milk modulates immune response during iron deficiency anemia recovery.

BACKGROUND: Iron deficiency and iron overload can affect the normal functioning of the innate and adaptive immune responses. Fermented milk products may enhance immune functions, but little is known about the effect of fermented milks on modulation of the immune response during iron deficiency anemia and recovery with normal or high dietary iron intake. Eighty male Wistar rats were randomly assigned to a control group fed a standard diet or to an anemic group fed a diet deficit in iron. Control and anemic groups were fed for 30 days with diets based on a fermented goat's or cow's milk product, with normal iron content or iron overload. RESULTS: In general, during anemia recovery lectin and alternative complement pathway activity and lactoferrin decreased, because it improves iron homeostasis, which is critically important in immune system functions. Fermented goat's milk diet enhanced immune function during iron deficiency recovery, suppressed oxidant-induced eotaxin and fractalkine expression due to the concurrent reduction of free radical production and pro-inflammatory cytokines, and decreased monocyte chemoattractant protein-1 and monocyte migration and adhesion. The increase in interferon-γ can confer immunological colonization of gut microbiota and downregulate inflammation. CONCLUSION: Fermented goat's milk consumption enhances immune function, modifying complement pathway activity and decreasing pro-inflammatory cytokines as well as lactoferrin concentration, due to the improvement of iron homeostasis, which is critically important in the normal function of the immune system. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Neural cue-reactivity in pathological gambling as evidence for behavioral addiction: a systematic review.

Increasing incidence of problem gambling has led to prioritizing the problem from the point of view of public health. Additionally, gambling disorder has been recently classified as a behavioral addiction, with implications for both its diagnosis and treatment. However, the shared neural substrate of addictions, to substances and behavioral, is still discussed. Thus, this systematic review aims to provide up-to-date knowledge from the past five years (2017-2022) concerning the neural correlates of gambling related stimuli (cue-reactivity) on the basis of a previous review (Brevers et al., Cognitive, Affective and Behavioral Neuroscience 18:718-729, 2019). A total of five studies were included in the review. Activation of brain areas related to memory, reward and executive functions could be the underlying mechanism of this behavioral addiction. Specifically, nucleus accumbens and striatum (ventral and dorsal), parahippocampal regions, the right amygdala and several prefrontal cortex regions have systematically been found more active in those subjects exposed to gambling-related cues. Also, the insula could play a pivotal role connecting these three systems in a highly integrated neural network with several implications for reward processing modulation, associative learning and top-down attentional regulation to improve saliency of addiction-related cues. These results are consistent with previous findings on other substance addictions, such as alcohol, tobacco, marijuana or cocaine. The study of neural reactivity to stimuli related to addiction could be useful as a biomarker of the severity of the disorder, the efficacy of the treatment, the risk of relapse, in addition to being an objective criterion to measure the effectiveness of prevention campaigns.

Novel SLC12A2-ROS1 Fusion in Non-Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next-Generation Sequencing Assay.

Identifying the druggable target is crucial for patients with nonsquamous advanced non-small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2-ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2-ROS1 fusion and it was confirmed through hybrid capture-based next-generation sequencing (NGS); however, the fusion could not be detected by amplicon-based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications. KEY POINTS: This is the first known description of an SLC12A2-ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non-small cell lung cancer. The success of implementing next-generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice.

Humoral responses to SARS-CoV-2 by healthy and sick dogs during the COVID-19 pandemic in Spain.

COVID-19 is a zoonotic disease caused by SARS-CoV-2. Infections of animals with SARS-CoV-2 have recently been reported, and an increase of severe lung pathologies in domestic dogs has also been detected by veterinarians in Spain. Therefore, further descriptions of the pathological processes in those animals that show symptoms similar to those described in humans affected by COVID-19 would be highly valuable. The potential for companion animals to contribute to the continued transmission and community spread of this known human-to-human disease is an urgent issue to be considered. Forty animals with pulmonary pathologies were studied by chest X-ray, ultrasound analysis, and computed tomography. Nasopharyngeal and rectal swabs were analyzed to detect canine pathogens, including SARS-CoV-2. An additional twenty healthy dogs living in SARS-CoV-2-positive households were included. Immunoglobulin detection by several immunoassays was performed. Our findings show that sick dogs presented severe alveolar or interstitial patterns with pulmonary opacity, parenchymal abnormalities, and bilateral lesions. The forty sick dogs were negative for SARS-CoV-2 but Mycoplasma spp. was detected in 26 of 33 dogs. Five healthy and one pathological dog presented IgG against SARS-CoV-2. Here we report that despite detecting dogs with α-SARS-CoV-2 IgG, we never obtained a positive RT-qPCR for SARS-SoV-2, not even in dogs with severe pulmonary disease; suggesting that even in the case of canine infection, transmission would be unlikely. Moreover, dogs living in COVID-19-positive households could have been more highly exposed to infection with SARS-CoV-2.

Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges.

Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.

Lay abstract Despite major therapeutic advances over the last decade, lung cancer continues to present the highest mortality rate of all cancers. Precision and personalized therapy directed at specific alterations in the genetic material of the tumor as well as immunotherapy has significantly improved survival in metastatic non-small-cell lung cancer. The next step will be to incorporate precision medicine into the treatment of earlier stages of non-small-cell lung cancer. The recent publication of the results of the ADAURA phase III trial showing a significant improvement in disease-free survival in patients with resected EGFR-mutated non-small-cell lung cancer who received an adjuvant EGFR-directed tyrosine kinase inhibitor called osimertinib has opened the doors to the incorporation of this novel agent into routine clinical practice. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of precision medicine in nonmetastatic disease.

First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors.

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.

Peripheral artery disease in outpatients with a recent history of acute coronary syndrome or at high atherothrombotic risk.

OBJECTIVES: The frequency and implications of peripheral artery disease (PAD) in some risk groups are not entirely characterized in Latin America. We studied PAD prevalence, risk factors, and six-month outcomes in stable outpatients with a history of a recent acute coronary syndrome (ACS), or at high coronary risk. METHODS: We recruited 830 outpatients in 43 Mexican sites (median age: 64.8 years; 57.8% men). Inclusion criteria were age >18 years, and ACS within 30 days, or age <55 years plus ≥2 major vascular risk factors, or age ≥55 years plus ≥1 vascular risk factors. Patients received standardized assessments at baseline and six-month follow-up for medical history, ankle-brachial index (ABI), and the Edinburgh Claudication Questionnaire (ECQ). RESULTS: ABI <0.8 was found in 10.5%, <0.9 in 22.5%, >1.3 in 4.8%, and >1.4 in 3.6%, without differences according to sex or selection criteria. Positive ECQ was found in 7.6%. ABI <0.9 was directly associated with age, diabetes, ACS, and chronic kidney disease, but inversely associated with BMI >27. The six-month case-fatality and atherothrombotic events rates were 1.6% and 3.6%, respectively. In patients with ABI <0.9 and ABI <0.8, the six-month case-fatality rates were 2.5% (p = 0.27) and 5.4% (p = 0.03), respectively. In a Cox proportional-hazards model, baseline factors associated with death were age ≥65, ABI <0.8, and ACS. CONCLUSIONS: Subclinical PAD is more common than symptomatic claudication in high-risk coronary outpatients. Low ABI is associated with reduced short-term survival in patients with recent ACS or at high coronary risk.

Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy.

Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19.

Polymer Micropillar Arrays for Colorimetric DNA Detection.

We describe the use of periodic micropillar arrays, produced from cyclic olefin copolymer using high-fidelity microfabrication, as templates for colorimetric DNA detection. The assay involves PCR-amplified gene markers for E. coli O157:H7 (rfbO157, eae, vt1, and vt2) incorporating a detectable digoxigenin label, which is revealed through an immunoenzymatic process following hybridization with target-specific oligonucleotide capture probes. The capacity of micropillar arrays to induce wicking is used to distribute and confine capture probes with spatial control, making it possible to achieve a uniform signal while allowing multiple, independent probes to be arranged in close proximity on the same substrate. The kinetic profile of color pigment formation on the surface was followed using absorbance measurements, showing maximum signal increase between 20 and 60 min of reaction time. The relationship between microstructure and colorimetric signal was investigated through variation of geometric parameters, such as pitch (10-50 µm), pillar diameter (5-40 µm), and height (16-48 µm). Our findings suggest that signal intensity is largely influenced by the edges of the pillars and less by their height such that it deviates from a linear relationship when both aspect ratio and pillar density become very high. A theoretical model used to simulate the changes in surface composition at the molecular level suggests that differences in the temporal and spatial accumulation of assay components account for this observation.

Engineered LINE-1 retrotransposition in nondividing human neurons.

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.