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Neutrophil-to-lymphocyte ratio (NLR) has been studied as a prognostic factor for mortality in COVID-19 patients. Our study aimed to evaluate the association between NLR at COVID-19 diagnosis and survival during the following 90 days in hospitalized patients with solid cancer. Between May 2020 and June 2021, 120 patients were included in a retrospective cohort study. Univariable analysis showed patients with an NLR 8.3 were associated with an increased risk of death (HR: 4.34; 95% CI: 1.74-10.84) compared to patients with NLR 3.82 and with NLR ≥3.82 and ≤8.30 (HR: 2.89; 95% CI: 1.32-6.36). Furthermore, on multivariable analysis, NLR 8.30 independently correlated with increased mortality. In patients with solid malignancies with COVID-19, an NLR 8.3 is associated with an increased risk of death.

Cancer patients are exposed to more complications from COVID-19 than non-cancer patients. We report a cohort of 74 cancer patients (87.8% with solid neoplasia and 12.2% with hematological diseases) with COVID-19 infection admitted to a tertiary medical cancer center in Argentina. Pulmonary infiltrates were diagnosed at admission in 78.3% (N = 58) of the cases. COVID-19 infection was hospital-acquired in 20 (27.0%) patients. Thirty-nine patients (52.7%) received anticancer therapy within the 30 days prior to COVID-19 diagnosis; one was on radiation therapy. Twenty-four (32.4%) patients were admitted in the intensive care unit (ICU) and 18 (75.0%) required mechanical ventilation. All cause in-hospital mortality was 32.4% (N = 24) and ICU mortality was 62.5% (N = 15). Mortality under mechanical ventilation was 72.2% (N = 13). In the univariate analysis age, neutrophil count, neutrophil/lymphocyte index, D-dimer, ferritin, smoking, and nosocomial acquired infection were associated with in-hospital mortality. There were no statistically significant differences in mortality related to disease stage for solid tumors, neither cancer treatment within 30 days of COVID-19 diagnosis. Age and smoking were associated with mortality in the multivariate analysis. The adjusted odds ratios (95 CI) for age = 65 years and smoking were 8.87 (1.35-58.02) and 8.64 (1.32 - 56.64), respectively. Our experience can be useful for other institutions that assist cancer patients during the pandemic.Los pacientes con cáncer y COVID-19 tienen más complicaciones que la población general. Comunicamos una cohorte de 74 pacientes con cáncer y COVID-19 internados en una institución oncológica. El 87.8% tenía diagnóstico de tumores sólidos y 12.2% oncohematológicos. Entre los tumores sólidos, el 61.5% presentó enfermedad metastásica. El 78.3% (N = 58) tenía infiltrados pulmonares al diagnóstico de COVID-19. La infección fue intrahospitalaria en 20 pacientes. Habían recibido tratamiento antineoplásico dentro de los 30 días anteriores al diagnóstico 39 pacientes (52.7%); uno se encontraba recibiendo radioterapia. Veinticuatro pacientes (32.4%) se derivaron a terapia intensiva (UTI) y 18 (75%) de ellos requirieron asistencia respiratoria mecánica (ARM). La mortalidad general durante la internación fue 32.4% (N = 24). La mortalidad en UTI fue 62.5% (N = 15). La mortalidad en ARM fue 72.2% (N = 13). La edad, recuento de neutrófilos, índice neutrófilo/linfocito, dímero D, ferritina, tabaquismo y haber adquirido la infección durante la internación resultaron estadísticamente significativos en el análisis univariado para mortalidad. No hallamos diferencias en mortalidad por estadio de enfermedad, en los pacientes con tumores sólidos, ni por haber recibido tratamiento antineoplásico dentro de los 30 días del diagnóstico de COVID-19. En el análisis multivariado con el modelo de regresión logística, solo la edad y el tabaquismo fueron predictores de mortalidad. Los odds ratios (IC 95) ajustados para la edad =65 años y el tabaquismo fueron 8.87 (1.35-58.02) y 8.64 (1.32-56.64), respectivamente. Este trabajo puede resultar de utilidad para instituciones polivalentes que asistan pacientes oncológicos durante la pandemia.

The management of patients with immune-related adverse events (irAEs) frequently demands a multidisciplinary approach. We reviewed the causes and clinical course of medical visits and admissions at the Instituto Alexander Fleming due to irAEs between September 2015 and July 2019. Demographic data, diagnosis, toxicity and its severity, requirement of admission, treatment, mortality, and evaluation of the re-administration of immunotherapy were collected. We found 124 irAEs in 89 patients. Sixty-eight of them received monotherapy (76.4%) and 21 (23.6%) combination of drugs. Cutaneous manifestations were the most frequent cause of irAEs, followed by general manifestations, endocrine dysfunctions (hypothyroidism the most frequent), colitis, pneumonitis, neurologic disorders, and hepatitis. In 26 adverse events (in 25 patients), severity grade was = 3. Fifteen were admitted and 6 required ICU admission. One patient died. Thirty-four received glucocorticoids, 12 of them by intravenous route. One patient received mycophenolate and one IVIG. In 20, the treatment was discontinued; 8 were re-exposed, with definitive discontinuation in one patient. In this case series we report our experience in the diagnosis and management of adverse reactions related to a family of drugs whose use has grown in recent years.El manejo de las reacciones adversas inducidas por los inhibidores del punto de control inmunitario (IPCI) en cáncer, demanda un trabajo multidisciplinario. Revisamos las causas y el curso clínico de las consultas e internaciones debidas a reacciones adversas de los IPCI entre septiembre de 2015 y julio de 2019 en el Instituto Alexander Fleming. Se registraron los datos demográficos, diagnóstico oncológico, reacción adversa y su grado, requerimiento de internación, tratamiento, mortalidad y evaluación de la reexposición. Se registraron 124 reacciones adversas por IPCI en 89 pacientes. Sesenta y ocho recibían monoterapia y 21 terapia combinada. Las manifestaciones cutáneas fueron las más frecuentes, seguidas de las generales, endocrinas (con mayor frecuencia hipotiroidismo), colitis, neumonitis, neurológicas y hepatitis. Fueron graves (grado = 3), 26 toxicidades en 25 pacientes. Se internaron 15, y 6 de ellos requirieron terapia intensiva. Un caso fue fatal. Recibieron glucocorticoides 34 (12 de ellos por vía intravenosa). Un paciente recibió micofenolato y uno inmunoglobulina endovenosa. En 20 se discontinuó el tratamiento. Ocho se reexpusieron y uno de ellos debió suspender definitivamente. Se presenta en esta serie de casos nuestra experiencia con el diagnóstico y tratamiento de las reacciones adversas de una familia de drogas cuya utilización ha crecido en los últimos años.

Ovarian cancer is frequently detected in advanced stages when the chances of survival are very low. Although chemotherapy is the treatment of choice, it is often rapidly compromised by the development of chemoresistance in patients. There are few pharmacological alternatives for managing chemoresistant ovarian cancer and statins have been suggested as an alternative, but their use is considered controversial. We present an overview of the most relevant epidemiological, in vitro and in vivo studies on the effects of statins in mono- or polytherapy for ovarian cancer. We conclude that the negative or inconclusive results of some epidemiological studies on statin-based cancer treatment are probably due, in large part, to the low doses given to patients, equivalent to those prescribed for hypercholesterolemia. Higher concentrations are well tolerated in animal models and by most patients in clinical trials. Future research is necessary to explore this possibility.

The carcinogenic potential of urban particulate matter (PM) has been partly attributed to polycyclic aromatic hydrocarbons (PAHs) content, which activates the aryl hydrocarbon receptor (AhR). Here we report the effect of PM with an aerodynamic size of 10 μm (PM10) on the induction of AhR pathway in A549 cells, evaluating its downstream targets CYP1B1, IL-6, IL-8 and c-Jun. Significant increases in CYP1B1 protein and enzyme activity; IL-6 and IL-8 secretion and c-Jun protein were found in response to PM10. The formation of PAH-DNA adducts was also detected. The involvement of AhR pathway was confirmed with Resveratrol as AhR antagonist, which reversed CYP1B1 and c-Jun induction. Nevertheless, in IL-6 and IL-8 secretion, the Resveratrol was ineffective, suggesting an effect independent of this pathway. Considering the role of c-Jun in oncogenesis, its induction by PM may be contributing to its carcinogenic potential through induction of AhR pathway by PAHs present in PM10.

Particulate matter may promote cardiovascular disease, possibly as a consequence of its oxidative potential. Studies using susceptible animals indicate that particulate matter aggravates atherosclerosis by increasing lipid/macrophage content in plaques. Macrophage lipid uptake requires oxidized low-density lipoprotein and scavenger receptors; same receptors are involved in particulate matter uptake. We studied in vitro particulate matter potential to oxidize low-density lipoproteins and subsequent cell uptake through scavenger receptors. Particulate matter-induced low-density lipoproteins oxidation was evaluated by the thiobarbituric acid assay. Binding/internalization was tested in wild type and scavenger receptor-transfected Chinese hamster ovary cells, and in RAW264.7 cells using fluorescently labeled low-density lipoproteins. Dose-dependent binding/internalization only occurred in scavenger receptor-transfected Chinese hamster ovary cells and RAW264.7 cells. Competition binding/internalization using particles showed that particulate matter induced decreased binding (∼50%) and internalization (∼70%) of particle-oxidized low-density lipoproteins and native low-density lipoproteins. Results indicate that particulate matter was capable of oxidizing low-density lipoproteins, favoring macrophage internalization, and also altered scavenger and low-density lipoproteins receptor function.

Spatial variation in particulate matter-related health and toxicological outcomes is partly due to its composition. We studied spatial variability in particle composition and induced cellular responses in Mexico City to complement an ongoing epidemiologic study. We measured elements, endotoxins, and polycyclic aromatic hydrocarbons in two particle size fractions collected in five sites. We compared the in vitro proinflammatory response of J774A.1 and THP-1 cells after exposure to particles, measuring subsequent TNFα and IL-6 secretion. Particle composition varied by site and size. Particle constituents were subjected to principal component analysis, identifying three components: C(1) (Si, Sr, Mg, Ca, Al, Fe, Mn, endotoxin), C(2) (polycyclic aromatic hydrocarbons), and C(3) (Zn, S, Sb, Ni, Cu, Pb). Induced TNFα levels were higher and more heterogeneous than IL-6 levels. Cytokines produced by both cell lines only correlated with C(1) , suggesting that constituents associated with soil induced the inflammatory response and explain observed spatial differences.

A high prevalence of hypovitaminosis D has been reported in cancer patients. Low levels of 25-(OH)-vitamin D were found in 158 of 162 (97.5%) inpatients with breast, lung, and colorectal cancer under active treatment, with severe deficiency (20 ng/ml) in 77.2% and mild deficiency (20-30 ng/ml) in 20.4%.A high prevalence of vitamin D deficiency has been reported in cancer patients. Nevertheless, vitamin D serum levels have been checked in few patients. Information about the frequency of hypovitaminosis D in cancer patients in Argentina is unknown. The aim of the study was to assess the frequency of vitamin D deficiency in patients with breast, lung, and colorectal cancer.A prospective observational study was designed for cancer patients admitted to the general ward in 2014. The patients included had breast, lung, and colorectal cancer. All of them were under active treatment. The serum level of 25-(OH)-vitamin D [25-(OH)-D] was measured and categorized as sufficiency (30 ng/ml), mild deficiency (20-30 ng/ml), and severe deficiency (20 ng/ml).A total of 162 patients were included, 98.2% were in stages III-IV. Median level of 25-(OH)-D was 15.3 ng/ml (range 4.1-103.6 ng/ml). Serum levels30 ng/ml were found in 158 (97.5%) patients, severe deficiency in 125 cases (77.2%) and mild deficiency in 33 cases (20.4%). In patients under chemo/hormone therapy, the median level was 15.3 ng/ml (range 4.1-103.6 ng/ml) and in those under concurrent therapy was 17.1 ng/ml (range 7.4-58.5 ng/ml); p = 0.1944. There were no statistical differences in severe or mild deficiency of vitamin D among breast, lung, and colorectal cancer patients.The study found a high prevalence of vitamin D deficiency in hospitalized cancer patients under active treatment. Many authors have recommended dosing vitamin D levels in this population; normalizing serum levels is difficult.

The carcinogenic potential of urban particulate matter (PM) has been partly attributed to polycyclic aromatic hydrocarbons (PAHs) content, which activates the aryl hydrocarbon receptor (AhR). Here we report the effect of PM with an aerodynamic size of 10 μm (PM10) on the induction of AhR pathway in A549 cells, evaluating its downstream targets CYP1B1, IL-6, IL-8 and c-Jun. Significant increases in CYP1B1 protein and enzyme activity; IL-6 and IL-8 secretion and c-Jun protein were found in response to PM10. The formation of PAH-DNA adducts was also detected. The involvement of AhR pathway was confirmed with Resveratrol as AhR antagonist, which reversed CYP1B1 and c-Jun induction. Nevertheless, in IL-6 and IL-8 secretion, the Resveratrol was ineffective, suggesting an effect independent of this pathway. Considering the role of c-Jun in oncogenesis, its induction by PM may be contributing to its carcinogenic potential through induction of AhR pathway by PAHs present in PM10.

Scavenger receptors internalize chemically modified low density lipoprotein particles (ac-LDL) and other ligands through the process of receptor-mediated endocytosis. During this investigation using amyloid-beta as a natural ligand for the SR, we studied under a ligand-induced oxidative stress condition, changes in protein expression of several adaptor proteins important in the organization of the endocytic machinery in microglia and macrophages. Differential expression experiments of beta-adaptin, alpha-adaptin, SR-AI, and SR-BI in RAW (macrophages) and EOC (microglia) cells were performed according to dosage and exposure time to amyloid-beta. Our results show that according to dosage, amyloid-beta produces an oxidative stress state that importantly affects the availability of beta-adaptin. Under these conditions, RT-PCR assays show that beta-adaptin mRNA is normally synthesized, reason why protein translation or protein structure of beta-adaptin might be altered. These observations might have impact in the understanding of the mechanisms microglia employ to process amyloid-beta in the brain.

Background: Epidemiological studies have shown correlations between air pollution and adverse birth outcomes. Currently, we are conducting a cohort study in Mexico City exploring pre-term delivery ...

Particulate matter may promote cardiovascular disease, possibly as a consequence of its oxidative potential. Studies using susceptible animals indicate that particulate matter aggravates atherosclerosis by increasing lipid/macrophage content in plaques. Macrophage lipid uptake requires oxidized low-density lipoprotein and scavenger receptors; same receptors are involved in particulate matter uptake. We studied in vitro particulate matter potential to oxidize low-density lipoproteins and subsequent cell uptake through scavenger receptors. Particulate matter-induced low-density lipoproteins oxidation was evaluated by the thiobarbituric acid assay. Binding/internalization was tested in wild type and scavenger receptor–transfected Chinese hamster ovary cells, and in RAW264.7 cells using fluorescently labeled low-density lipoproteins. Dose-dependent binding/internalization only occurred in scavenger receptor–transfected Chinese hamster ovary cells and RAW264.7 cells. Competition binding/internalization using particles showed that particulate matter induced decreased binding (~50%) and internalization (~70%) of particle-oxidized low-density lipoproteins and native low-density lipoproteins. Results indicate that particulate matter was capable of oxidizing low-density lipoproteins, favoring macrophage internalization, and also altered scavenger and low-density lipoproteins receptor function.

As part of a field campaign that studied the impact of Mexico City pollution plume at the local, sub-regional and regional levels, we studied transport-related changes in PM(10) composition, oxidative potential and in vitro toxicological patterns (hemolysis, DNA degradation). We collected PM(10) in Mexico City (T(0)) and at a suburban-receptor site (T(1)), pooled according to two observed ventilation patterns (T(0) → T(1) influence and non-influence). T(0) samples contained more Cu, Zn, and carbon whereas; T(1) samples contained more of Al, Si, P, S, and K (p < 0.05). Only SO(4)(-2) increased in T(1) during the influence periods. Oxidative potential correlated with Cu/Zn content (r = 0.74; p < 0.05) but not with biological effects. T(1) PM(10) induced greater hemolysis and T(0) PM(10) induced greater DNA degradation. Influence/non-influence did not affect oxidative potential nor biological effects. Results indicate that ventilation patterns had little effect on intrinsic PM(10) composition and toxicological potential, which suggests a significant involvement of local sources.

Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.

Hyperlipidemia occurs during nephrotic syndrome (NS). It is known that cholesterol and fatty acid biosynthesis is controlled by the transcription factors sterol regulatory element binding proteins (SREBPs). Soy protein consumption reduces the concentration of these lipids, although its mechanism of action is not well known. The aim of the present study was to establish whether soy protein consumption reduces cholesterol and triglycerides levels by regulating of SREBPs. Male Wistar rats with experimental NS were studied for 64 days. The results showed that rats fed with soy protein had significantly lower plasma cholesterol and triglyceride concentrations as well as proteinuria than rats fed with casein diet. These decrements were associated with a decrease in the expression of SREBP-1 and fatty acid biosynthetic enzymes. In addition, Western blot analysis revealed that in nuclear extracts from hepatocytes of rats fed with soy protein, there was a lower concentration of SREBP-1 than in rats fed with casein. The results of this study indicate that consumption of a soy protein diet has beneficial effects on nephrotic syndrome.

Cholesterol is an important lipid in higher organisms, and its concentration must be maintained in narrow limits depending of the cell needs. An excess of dietary cholesterol can lead to serious health problems, however, if consumption of this lipid is restricted in the diet, cells have the capacity to synthesize it. For the synthesis of cholesterol, the cell uses a family of proteins named sterol regulatory element binding proteins (SREBP's), that are transcriptional factors involved in the control of expression of genes of cholesterol and fatty acids synthesis. SREBP's regulate gene transcription by binding to cis-acting elements denominated sterol regulatory elements (SRE-1). SREBP's are localized in the endoplasmic reticulum, but in the event that the cell needs to synthesize cholesterol, the NH2-terminal portion of these proteins is cleaved by two specific proteases, and then travels into the nucleus to function as transcriptional factor. The present review shows the details of the mechanism that the cell uses to regulate cholesterol biosynthesis by the SREBP's, and its potential metabolic implications.